Numerical study on heterodyne terahertz detection in field effect transistor.
Numerical method on the heterodyne terahertz detection characteristics of field effect characteristics of field effect transistors is studied in this paper which is based on the hydrodynamic equations which govern the terahertz signal transport in field effect transistors (FETs). A modification is made in an existed numerical tool established by our group by coupling the heterodyne characteristics. This modified numerical tool work well in all operation regions of FETs from sub-threshold to strong inversion and from linear to saturation. And the results are used to demonstrate the potential for using MOS transistors as THz detectors and investigate the optimization of the device structure.


Plasmonic nanosponges filled with silicon for enhanced white light emission.
Plasmonic nanosponges are a powerful platform for various nanophotonic applications owing to extremely high local field enhancement in metallic nanopores. The filling of the nanopores with high-refractive index semiconductors (e.g. Si, Ge, GaP, etc.) opens up opportunities for the enhancement of nonlinear effects in these materials. However, this task remains challenging due to the lack of knowledge on the integration process of metal and high-index semiconductor components in such nanoobjects. Here, we investigate metal-dielectric nanoparticles fabricated from bilayer Si/Au films by the laser printing technique via a combination of theoretical and experimental methods. We reveal that these hybrid nanoparticles represent the Au sponge-like nanostructure filled with Si nanocrystallites. We also demonstrate that the Au net provides strong near-field enhancement in the Si grains increasing the white light photoluminescence in the hybrid nanostructures compared to uniform Si nanoparticles. These results pave the way for engineering the internal structure of the sponge-like hybrid nanoparticles possessing white light luminescence and control of their optical properties on demand.


Insights into the metabolism and microbial biotransformation of dietary flavan-3-ols and the bioactivity of their metabolites.
Flavan-3-ols, occurring in monomeric, as well as in oligomeric and polymeric forms (also known as condensed tannins or proanthocyanidins), are among the most abundant and bioactive dietary polyphenols, but their in vivo health effects in humans may be limited because of their recognition as xenobiotics. Bioavailability of flavan-3-ols is largely influenced by their degree of polymerization; while monomers are readily absorbed in the small intestine, oligomers and polymers need to be biotransformed by the colonic microbiota before absorption. Therefore, phenolic metabolites, rather than the original high molecular weight compounds found in foods, may be responsible for the health effects derived from flavan-3-ol consumption. Flavan-3-ol phenolic metabolites differ in structure, amount and excretion site. Phase II or tissular metabolites derived from the small intestine and hepatic metabolism are presented as conjugated derivatives (glucuronic acid or sulfate esters, methyl ether, or their combined forms) of monomeric flavan-3-ols and are preferentially eliminated in the bile, whereas microbial metabolites are rather simple conjugated lactones and phenolic acids that are largely excreted in urine. Although the colon is seen as an important organ for the metabolism of flavan-3-ols, the microbial catabolic pathways of these compounds are still under consideration, partly due to the lack of identification of bacteria with such capacity. Studies performed with synthesized or isolated phase II conjugated metabolites have revealed that they could have an effect beyond their antioxidant properties, by interacting with signalling pathways implicated in important processes involved in the development of diseases, among other bioactivities. However, the biological properties of microbe-derived metabolites in their actual conjugated forms remain largely unknown. Currently, there is an increasing interest in their effects on intestinal infections, inflammatory intestinal diseases and overall gut health. The present review will give an insight into the metabolism and microbial biotransformation of flavan-3-ols, including tentative catabolic pathways and aspects related to the identification of bacteria with the ability to catabolize these kinds of polyphenols. Also, the in vitro bioactivities of phase II and microbial phenolic metabolites will be covered in detail.


Peripheral Nerve Society Guideline on processing and evaluation of nerve biopsies.
Nerve biopsy is often the final step in the diagnostic work-up of neuropathies of unknown origin. The aim of this guideline was to prepare an evidence-based guideline on the methods for performing and evaluating nerve biopsy. The panel performed a search of MEDLINE, hand search of bibliographies of the references retrieved, review of the evidence, and reached agreement by consensus. There were not enough formal studies of diagnostic test accuracy to allow evidence-based recommendations of levels A-C for most questions. The panel summarized the class IV evidence and reached agreement by consensus on the following recommendations: (1) Nerve biopsy should not be performed before adequate clinical, electrophysiological, and laboratory investigation and only be performed with appropriate informed consent. (2) An interactive working relationship with the relevant disciplines involved and the provision of sufficient clinical information is encouraged. (3) Biopsies should be processed and read by professionals with adequate training and experience. (4) Optimal analysis of nerve biopsy is best performed by laboratories that have the facilities and expertise to prepare and evaluate frozen and fixed sections (cryostat, paraffin, and epoxy sections). (5) Immunohistochemistry, teased fiber analysis, electron microscopy, and morphometry may help clarify the diagnosis in some conditions and should be considered as additional studies.


First Report of Pseudomonas cichorii Associated with Leaf Spot on Soybean in South Korea.
Unusual symptoms were observed on 5% of the soybean (Glycine max (L.) Merill) plants in commercial fields in South Korea in September 2008 and 2009. The lesions were at first water soaked, then enlarged and turned dark brown or black, often with concentric white rings and sometimes surrounded by a bright yellow halo. Most lesions were roughly circular to irregular. Six bacteria were isolated on tryptic soy agar (TSA) media from plants of soybean cv. Daewon. The isolate JBC1 formed colonies that were whitish to greenish, circular with convex elevation, and unable to grow anaerobically or at 37°C. Cells of the isolate were rod shaped with polar multitrichous flagella. The isolate was positive for the following characteristics: production of fluorescent and diffusible pigment on King's medium B, production of oxidase, ability to rot potato, and utilization of l-arabinose, d-aspartate, citrate, galactose, glucose, meso-inositol, mannitol, and meso-tartrate. However, the isolate was negative in the following tests: formation of yellow colonies on peptone sucrose agar and yeast extract dextrose calcium carbonate agar media, levan formation, production of nondiffusible pigment, urease and arginine dihydrolase, hydrolysis of starch, nitrate reduction, and utilization of d-arabinose, benzoate, geraniol, l-rhamnose, d-sorbitol, sucrose, and trehalose (1). The isolates elicited a clear hypersensitive reaction in tobacco leaves. The carbon source oxidation pattern analyzed by Biolog (Hayward, CA) GN database indicated that the isolate belonged to Pseudomonas cichorii (Swingle 1925) Stapp 1928. DNA was isolated with a commercial genomic DNA extraction kit (Solgent, Daejeon, South Korea) and the 16S rDNA was amplified using universal 27F and 1492R primers. The 1,367-bp amplicon was sequenced (GenBank Accession No. JF951725) and had 100% sequence identity with P. cichorii Accession No. EF101976.1. Phylogenetic analysis based on 1,367 bp of the 16S rDNA sequence also revealed that isolate JBC1 was closely related to P. cichorii. Healthy soybean plants of cv. Jangyeop were spray inoculated with 20 ml of a 108 suspension prepared from a 2-day-old culture grown on TSA. Healthy plants sprayed with just water served as noninoculated checks. Typical disease symptoms that were observed in the field developed on leaves of soybean plants 3 days after spray inoculation, while the check plants remained symptomless. The bacteria reisolated from inoculated plants were confirmed to be identical to the original strain by 16S rDNA analysis and the Biolog test. Inoculation on tomato, watermelon, melon, and oriental melon plants resulted in dark brown or black lesions forming on leaf margins and tips, which is different from those on soybean plants (2,3). With paprika and eggplant, necrotic spots with concentric white rings developed on the leaves of each plant. We propose leaf spot as the name for this disease on soybean. To our knowledge, this is the first report of leaf spot on soybean caused by P. cichorii, which is becoming a more important pathogen in subtropical regions and greenhouses (4). References: (1) B. Cottyn et al. Syst. Appl. Microbiol. 32:211, 2009. (2) A. Obradovic et al. Plant Dis. 86:443, 2002. (3) E. Pauwelyn et al. J. Phytopathol. 159:298, 2011. (4) S. M. Walkil et al. Nigeria J. Appl. Biosci. 38:2540, 2011.


Medication adherence and tolerability of Alzheimer's disease medications: study protocol for a randomized controlled trial.
The class of acetylcholinesterase inhibitors (ChEI), including donepezil, rivastigmine, and galantamine, have similar efficacy profiles in patients with mild to moderate Alzheimer's disease (AD). However, few studies have evaluated adherence to these agents. We sought to prospectively capture the rates and reasons for nonadherence to ChEI and determine factors influencing tolerability and adherence. We designed a pragmatic randomized clinical trial to evaluate the adherence to ChEIs among older adults with AD. Participants include AD patients receiving care within memory care practices in the greater Indianapolis area. Participants will be followed at 6-week intervals up to 18 weeks to measure the primary outcome of ChEI discontinuation and adherence rates and secondary outcomes of behavioral and psychological symptoms of dementia. The primary outcome will be assessed through two methods, a telephone interview of an informal caregiver and electronic medical record data captured from each healthcare system through a regional health information exchange. The secondary outcome will be measured by the Healthy Aging Brain Care Monitor and the Neuropsychiatric Inventory. In addition, the trial will conduct an exploratory evaluation of the pharmacogenomic signatures for the efficacy and the adverse effect responses to ChEIs. We hypothesized that patient-specific factors, including pharmacogenomics and pharmacokinetic characteristics, may influence the study outcomes. This pragmatic trial will engage a diverse population from multiple memory care practices to evaluate the adherence to and tolerability of ChEIs in a real world setting. Engaging participants from multiple healthcare systems connected through a health information exchange will capture valuable clinical and non-clinical influences on the patterns of utilization and tolerability of a class of medications with a high rate of discontinuation. Clinicaltrials.gov: NCT01362686.


Determinants of racial/ethnic colorectal cancer screening disparities.
The contributions of demographic, socioeconomic, access, language, and nativity factors to racial/ethnic colorectal cancer (CRC) screening disparities are uncertain. Using linked data from 22 973 respondents to the 2001-2005 Medical Expenditure Panel Survey and the 2000-2004 National Health Interview Survey, we modeled disparities in CRC screening (fecal occult blood testing [FOBT], endoscopy, and combined FOBT and endoscopy) between non-Hispanic whites and Asians, blacks, and Hispanics, sequentially adjusting for demographics, socioeconomic status, clinical and access variables, and race/ethnicity-related variables (language spoken at home and nativity). With demographic adjustment, minorities reported less CRC screening (all measures) than non-Hispanic whites. Disparities were largest for combined screening in Asians (adjusted odds ratio [AOR], 0.40; 95% confidence interval [CI], 0.32-0.49) and Hispanics (AOR, 0.43; 95% CI, 0.39-0.48) and for endoscopic screening in Asians (AOR, 0.41; 95% CI, 0.33-0.50) and Hispanics (AOR, 0.43; 95% CI, 0.38-0.48). With full adjustment, all Hispanic/non-Hispanic white disparities and black/non-Hispanic white FOBT disparities were eliminated, whereas Asian/non-Hispanic white disparities remained significant (FOBT: AOR, 0.72 [95% CI, 0.52-1.00]; endoscopic screening: AOR, 0.63 [95% CI, 0.49-0.81]; and combined screening: AOR, 0.66 [95% CI, 0.52-0.84]). Determinants of racial/ethnic CRC screening disparities vary among minority groups, suggesting the need for different interventions to mitigate those disparities. Whereas socioeconomic, access, and language barriers seem to drive the CRC screening disparities experienced by blacks and Hispanics, additional factors may exacerbate the disparities experienced by Asians.


Analyses of muscle spindles in the soleus of six inbred mouse strains.
Adult muscle size and fibre-type composition are heritable traits that vary substantially between individuals. We used inbred mouse strains in which soleus muscle mass varied by an order of magnitude to explore whether properties of muscle spindles can also be influenced by genetic factors. Skip-serial cross-sections of soleus muscles dissected from 15 male mice of BEH, BEL, C57BL/6J, DUH, LG/J and SM/J strains were analysed for number of muscle spindles and characteristics of intrafusal and extrafusal fibres following ATPase staining. The BEL and DUH strains determined the range of: soleus mean size, a 10-fold difference from 2.1 to 22.3 mg, respectively; the mean number of extrafusal fibres, a 2.5-fold difference from 497 to 1249; and mean fibre-cross-sectional area, three-fold difference, e.g. for type 1 fibres, from 678 to 1948 μm². The range of mean proportion of type 1 fibres was determined by C57BL/6J (31%) and DUH (64%) strains. The mean number of spindles per muscle ranged between nine (LG/J) and 13 (BEL) (strain effect P < 0.02). Genetic correlations between spindle count and muscle weight or properties of extrafusal fibres were weak and not statistically significant. However, there was a strong correlation between the proportion of spindles with more than one bag2 fibre and the proportion of extrafusal fibres that were of type 1, and strain-dependent variation in the numbers of such spindles was statistically significant. The numbers of intrafusal fibres per spindle ranged from 2 to 8, with the most common complement of four found in 75.6% of spindles. There were no significant differences between the strains in the mean numbers of intrafusal fibres; however, the variance of the number was significantly less for the C57BL/6J strain than for any of the others. We conclude that abundance of muscle spindles and their intrafusal-fibre composition are substantially determined by genetic factors, which are different from those affecting muscle size and properties of the extrafusal fibres.


Exercise-based cardiac rehabilitation in twelve European countries results of the European cardiac rehabilitation registry.
Results from EuroCaReD study should serve as a benchmark to improve guideline adherence and treatment quality of cardiac rehabilitation (CR) in Europe. Data from 2.054 CR patients in 12 European countries were derived from 69 centres. 76% were male. Indication for CR differed between countries being predominantly ACS in Switzerland (79%), Portugal (62%) and Germany (61%), elective PCI in Greece (37%), Austria (36%) and Spain (32%), and CABG in Croatia and Russia (36%). A minority of patients presented with chronic heart failure (4%). At CR start, most patients already were under medication according to current guidelines for the treatment of CV risk factors. A wide range of CR programme designs was found (duration 3 to 24weeks; total number of sessions 30 to 196). Patient programme adherence after admission was high (85%). With reservations that eCRF follow-up data exchange remained incomplete, patient CV risk profiles experienced only small improvements. CR success as defined by an increase of exercise capacity >25W was significantly higher in young patients and those who were employed. Results differed by countries. After CR only 9% of patients were admitted to a structured post-CR programme. Clinical characteristics of CR patients, indications and programmes in Europe are different. Guideline adherence is poor. Thus, patient selection and CR programme designs should become more evidence-based. Routine eCRF documentation of CR results throughout European countries was not sufficient in its first application because of incomplete data exchange. Therefore better adherence of CR centres to minimal routine clinical standards is requested.


Sequence defined antibodies improve the detection of cadherin 2 (N-cadherin) during zebrafish development.
Cadherin-2 plays a fundamental role during zebrafish CNS and heart morphogenesis. Profiling zCdh2 expression via antibody staining is essential to achieving better understanding of its role during zebrafish development. Generation of recombinant human antibodies to zCdh2 by phage display was used to identify monoclonal antibodies with reduced unspecific binding patterns when compared to available commercial antibodies. Specificity was profiled using flow cytometry of wild type, zCdh2-defective mutant and zCdh2-GFP zebrafish cells. The epitopes recognized by the novel antibodies were mapped to peptides located in the first or second extracellular domains of zCdh2. These antibodies allowed improved observations of the spatial distribution of zCdh2 from imaging of whole mount zebrafish preparations. Since the generated antibodies are sequence defined, they can always be reconstituted from the information stored in the respective computer file, securing future reproducibility of respective experiments. The results further suggest that sequence defined antibodies with specificities thoroughly controlled by flow cytometry and genetic antigen-defective mutants or knockouts can substantially reduce the risk of misleading, false-positive results in whole mount imaging and other assays, and thus can improve the scientific value of such assays.


Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine.
Mesenchymal stem cells (MSCs) are partially defined by their ability to differentiate into tissues including bone, cartilage and adipose in vitro, but it is their trophic, paracrine and immunomodulatory functions that may have the greatest therapeutic impact in vivo. Unlike pharmaceutical treatments that deliver a single agent at a specific dose, MSCs are site regulated and secrete bioactive factors and signals at variable concentrations in response to local microenvironmental cues. Significant progress has been made in understanding the biochemical and metabolic mechanisms and feedback associated with MSC response. The anti-inflammatory and immunomodulatory capacity of MSC may be paramount in the restoration of localized or systemic conditions for normal healing and tissue regeneration. Allogeneic MSC treatments, categorized as a drug by regulatory agencies, have been widely pursued, but new studies demonstrate the efficacy of autologous MSC therapies, even for individuals affected by a disease state. Safety and regulatory concerns surrounding allogeneic cell preparations make autologous and minimally manipulated cell therapies an attractive option for many regenerative, anti-inflammatory and autoimmune applications.


Characterization of the pathway for transport of the cytoadherence-mediating protein, PfEMP1, to the host cell surface in malaria parasite-infected erythrocytes.
The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family of antigenically diverse proteins is expressed on the surface of human erythrocytes infected with the malaria parasite P. falciparum, and mediates cytoadherence to the host vascular endothelium. In this report, we show that export of PfEMP1 is slow and inefficient as it takes several hours to traffic newly synthesized proteins to the erythrocyte membrane. Upon removal by trypsin treatment, the surface-exposed population of PfEMP1 is not replenished during subsequent culture indicating that there is no cycling of PfEMP1 between the erythrocyte surface and an intracellular compartment. The role of Maurer's clefts as an intermediate sorting compartment in trafficking of PfEMP1 was investigated using immunoelectron microscopy and proteolytic digestion of streptolysin O-permeabilized parasitized erythrocytes. We show that PfEMP1 is inserted into the Maurer's cleft membrane with the C-terminal domain exposed to the erythrocyte cytoplasm, whereas the N-terminal domain is buried inside the cleft. Transfer of PfEMP1 to the erythrocyte surface appears to involve electron-lucent extensions of the Maurer's clefts. Thus, we have delineated some important aspects of the unusual trafficking mechanism for delivery of this critical parasite virulence factor to the erythrocyte surface.


Sex differences in major bleeding with glycoprotein IIb/IIIa inhibitors: results from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) initiative.
Glycoprotein (GP) IIb/IIIa inhibitors are beneficial in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS); their safe use in women, however, remains a concern. The contribution of dosing to the observed sex-related differences in bleeding is unknown. We explored the relationship between patient sex, GP IIb/IIIa inhibitor use, dose, and bleeding in 32 601 patients with NSTE ACS across 400 CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) hospitals, of whom 18 436 were treated. GP IIb/IIIa inhibitor dose was defined as excessive if not reduced when creatinine clearance was < 50 mL/min for eptifibatide or < 30 mL/min for tirofiban. Major bleeding was defined as a hematocrit drop > or = 0.12, need for transfusion, or intracranial bleeding. Major bleeding was adjusted for clinical factors and antithrombotic dose. The risk for bleeding attributable to excess GP IIb/IIIa dose was determined by sex using prevalence and adjusted odds ratios (ORs). Women had higher rates of major bleeding than men among those treated with GP IIb/IIIa inhibitors (15.7% versus 7.3%, P<0.0001) and among those not treated (8.5% versus 5.4%, P<0.0001). Despite similar serum creatinine levels, creatinine clearance averaged 20 points lower among treated women than men. Treated women were also more likely to receive excess GP IIb/IIIa doses than men (46.4% versus 17.2%, P<0.0001; adjusted OR 3.81, 95% confidence interval [CI] 3.39 to 4.27). Excess dosing was associated with increased risk of bleeding in women (OR 1.72, 95% CI 1.30 to 2.28) and men (OR 1.27, 95% CI 0.97 to 1.66); however, bleeding risk attributable to dosing was much higher in women (25.0% versus 4.4%). Women experience more bleeding than men whether or not they are treated with GP IIb/IIIa inhibitors; however, because of frequent excessive dosing in women, up to one fourth of this sex-related risk difference in bleeding is avoidable. Appropriate dosing will improve care of all patients with NSTE ACS, with a particular benefit for women.


To decide medical therapy according to ECG criteria in patients with supraventricular tachycardia in emergency department: adenosine or diltiazem.
The aim of this study is to investigate the effect of ECG criteria which are used for the distinction between AVNRT and AVRT for the choice of treatment in patients with Supraventricular Tachycardia (SVT). The 77 patients with narrow QRS complex SVT which was treated with Adenosine or Diltiazem in the Emergency Department were evaluated retrospectively. All 12-lead ECG during tachycardia were blindly reviewed according to ECG criteria (Pseudo-r` in V1, Pseudo-S-wave in the inferior leads, Visible P-wave, aVL notch) by a cardiologist and an emergency physician. In this study, while 59.6% of the patients returned to normal sinus rhythm (NSR) after the first dose 6 mg, 64.91% of them after the first dose 12 mg and 71.92% of them after the second dose of 12 mg adenosine, 95% of the patients returned to NSR after the 0.25 mg/kg diltiazem. The most visible ECG findings were visible P waves and the least visible ECG findings were Pseudo-S waves in the inferior leads. It was statistically significant between converted by adenosine to NSR and converted by diltiazem to NSR to the presence of visible P-wave and the aVL lead notch in their ECG findings. The rate of return to NSR through diltiazem was found higher than that of adenosine in narrow complex SVT patients. Also, diltiazem may be the first medication to be preferred in the presence of retrograt P wave and aVL notch in the ECG of the patients with narrow QRS complex stable SVT.


In vivo monitoring of protein-bound and free NADH during ischemia by nonlinear spectral imaging microscopy.
Nonlinear spectral imaging microscopy (NSIM) allows simultaneous morphological and spectroscopic investigation of intercellular events within living animals. In this study we used NSIM for in vivo time-lapse in-depth spectral imaging and monitoring of protein-bound and free reduced nicotinamide adenine dinucleotide (NADH) in mouse keratinocytes following total acute ischemia for 3.3 h at ~3 min time intervals. The high spectral resolution of NSIM images allows discrimination between the two-photon excited fluorescence emission of protein-bound and free NAD(P)H by applying linear spectral unmixing to the spectral image data. Results reveal the difference in the dynamic response between protein-bound and free NAD(P)H to ischemia-induced hypoxia/anoxia. Our results demonstrate the capability of nonlinear spectral imaging microscopy in unraveling dynamic cellular metabolic events within living animals for long periods of time.


Endoscope-assisted contralateral transmaxillary approach to the clivus and the hypoglossal canal: technical case report.
Clival lesions are still considered surgically complex due to their anatomical location. Critical structures, such as the internal carotid arteries (ICAs), cavernous sinuses, cranial nerves, and brainstem, may be encased within the lesion. Although advances in endoscopic endonasal approaches have provided new routes to these lesions, exposure and resection of clival tumors through the endonasal route remain a technical challenge. Here, the authors report a left-sided endoscopic transmaxillary approach to access the right aspect of the clivus and the hypoglossal canal.A 35-year-old woman presented with progressive right 6th cranial nerve palsy. MRI revealed a contrast-enhancing right petroclival chondrosarcoma that involved Meckel's cave and extended into the right hypoglossal canal. An endoscopic-contralateral-transmaxillary approach through a left sublabial incision was used to access the right petroclival region and right hypoglossal canal. A left maxillary osteoplastic flap was elevated to expose the left maxillary sinus. This was followed by a left medial maxillectomy, gaining access to the left posterior nasal cavity. The posterior third of the left inferior turbinate and nasal septum were removed to access the right side of the petroclival region. Near-total resection was achieved without any vascular or neurological complications. A thin shell of residual tumor was left behind due to involvement of vital structures, such as the ICA, and further treated with proton-beam radiotherapy.The endoscopic-contralateral-transmaxillary approach provides a direct surgical corridor and good lateral visualization of the skull base vasculature. This approach allows wide maneuverability around the ICA and hypoglossal canal, which, in this case, allowed maximal tumor resection with full preservation of neurological function.


Substrate availability and transcriptional regulation of metabolic genes in human skeletal muscle during recovery from exercise.
In skeletal muscle of humans, transcription of several metabolic genes is transiently induced during recovery from exercise when no food is consumed. To determine the potential influence of substrate availability on the transcriptional regulation of metabolic genes during recovery from exercise, 9 male subjects (aged 22-27) completed 75 minutes of cycling exercise at 75% Vo2 max on 2 occasions, consuming either a high-carbohydrate (HC) or low-carbohydrate (LC) diet during the subsequent 24 hours of recovery. Nuclei were isolated and tissue frozen from vastus lateralis muscle biopsies obtained before exercise and 2, 5, 8, and 24 hours after exercise. Muscle glycogen was restored to near resting levels within 5 hours in the HC trial, but remained depressed through 24 hours in the LC trial. During the 2- to 8-hour recovery period, leg glucose uptake was 5- to 15-fold higher with HC ingestion, whereas arterial plasma free fatty acid levels were approximately 3- to 7-fold higher with LC ingestion. Exercise increased (P < .05) transcription and/or mRNA content of the pyruvate dehydrogenase kinase 4, uncoupling protein 3, lipoprotein lipase, carnitine palmitoyltransferase I, hexokinase II, peroxisome proliferator activated receptor gamma coactivator-1 alpha, and peroxisome proliferator activated receptor alpha. Providing HC during recovery reversed the activation of pyruvate dehydrogenase kinase 4, uncoupling protein 3, lipoprotein lipase, and carnitine palmitoyltransferase I within 5 to 8 hours after exercise, whereas providing LC during recovery elicited a sustained/enhanced increase in activation of these genes through 8 to 24 hours of recovery. These findings provide evidence that factors associated with substrate availability and/or cellular metabolic recovery (eg, muscle glycogen restoration) influence the transcriptional regulation of metabolic genes in skeletal muscle of humans during recovery from exercise.


Factors associated with intracranial hypertension in children and teenagers who suffered severe head injuries.
To analyze factors associated with intracranial hypertension in pediatric patients who suffered severe head injuries. Retrospective cohort study, with data collected from September 1998 through August 2003, including patients aged 0 to 16 who suffered severe head injuries, Glasgow score < 9, and submitted to intracranial pressure (ICP) monitoring (n = 132). Intracranial hypertension (IH) was defined as an episode of ICP > 20 mmHg requiring treatment, while refractory IH was ICP over 25 mmHg requiring barbiturates or decompressive craniectomy. Univariate analysis was followed by multivariate analysis; variables were considered significant if p < 0.05. Ages ranged from 2 months to 16 years, median age 9.7 (6.0-2.3) years. Glasgow scores ranged from 3 to 8, median 6 (4-7). Traffic accidents were responsible for 79.5% of events. Monitoring devices were installed, on average, 14 hours after trauma, median time 24 hours. One hundred and three patients (78%) had IH, while 57 (43.2%) had refractory IH. In multivariate analysis, younger age ranges were associated with IH [relative risk = 1.67 (1.03-2.72); p = 0.037], and abnormal postures were associated with refractory IH [relative risk = 2.25 (1.06-4.78)]. The group mortality rate was 51.5%; it was correlated with use of barbiturates in refractory IH and low cerebral perfusion pressure at the intensive care unit. IH and refractory IH were frequent events in pediatric patients who suffered severe head injuries. The younger the patient, the greater the chance of developing IH. The presence of abnormal postures was found to be a risk factor for refractory IH.


[Valve repair surgery for incompetent bicuspid aortic valves].
Surgical valve repair is a good alternative for correction of incompetent bicuspid aortic valve. To report the early and late surgical, clinical and ecochardiographic results of surgical repair of incompetent bicuspid aortic valves. Retrospective review of medical records of 18 patients aged 19 to 61 years, with incompetent bicuspid aortic valve in whom a valve repair was performed. Four patients had infectious endocarditis and 17 were in functional class I or II. Follow up ranged from 3 to 113 months after surgery. A triangular resection of the prolapsing larger cusp, which included the middle raphe, was performed in 17 cases; in 13 of these, a complementary subcommisural annuloplasty was performed. In the remaining case, with a perforation of the non-coronary cusp, a pericardial patch was implanted; this procedure was also performed in 2 other cases. In 3 cases large vegetations were removed. Postoperative transesophageal echocardiography showed no regurgitation in 11 patients (62%) and mild regurgitation in 7 (38%). There was no operative morbidity or mortality. There were no deaths during the follow-up period. In 3 patients (17%) the aortic valve was replaced with a mechanical prosthesis, 8 to 108 months after the first operation. Reoperation was not needed in 93%+/-6,4% at 1 year and 85%+/-9,5% at 5 years, these patients were all in functional class I at the end of the follow-up period. 60% had no aortic regurgitation, 20% had mild and 20% moderate aortic regurgitation on echocardiographic examination. A significant reduction of the diastolic diameter of the left ventricle was observed, but there were no significant changes in systolic diameter or shortening fraction. Surgical repair of incompetent bicuspid aortic valves has low operative morbidity and mortality and has a low risk of reoperation.


Bronx Community Collaborative Opportunities for Research and Education: Implementation and Evaluation of a Community-Academic Partnership.
Collaborations between community health and academic partners hold promise for improving community health through research. To develop, implement, and evaluate a partnership to build capacity for community-based research. Development of the partnership was based on a participatory model that aimed to nurture strong infrastructure, clear communication, and trust between partners. Research training was individualized to assessed needs. Methods of evaluation included online surveys of partnership members comparing years 1 and 2 and appreciative inquiry (AI) interviews in year 3.Results and Lessons Learned: Course corrections from year 1 responses were implemented, and reflected in improvements on the second survey. Interviews highlighted mutual benefits of infrastructure developed in partnership; threats to sustainability were identified. Lessons learned included the importance of early course correction based on feedback, opportunities for communication, and building trust and a shared language. Partnerships develop through commitment and trust. Routine assessments and course correction may enable productive research partnerships.


Distinct APCs explain the cytokine bias of α-galactosylceramide variants in vivo.
α-Galactosylceramide represents a new class of vaccine adjuvants and immunomodulators that stimulate NKT cells to secrete Th1 and Th2 cytokines. Synthetic variants with short or unsaturated acyl chains exhibit a striking Th2 bias in vivo but no evidence of defect in TCR signaling or stimulation of NKT cells in vitro. Using cd1d1(fl/fl) mice, we demonstrated that distinct APC types explained the cytokine bias in vivo. Whereas NKT stimulation by α-Galactosylceramide required CD1d expression by dendritic cells (DCs), presentation of the Th2 variants was promiscuous and unaffected by DC-specific ablation of CD1d. This DC-independent stimulation failed to activate the feedback loop between DC IL-12 and NK cell IFN-γ, explaining the Th2 bias. Conversely, forced presentation of the Th2 variants by DC induced high IL-12. Thus, lipid structural variations that do not alter TCR recognition can activate distinct Th1 or Th2 cellular networks by changing APC targeting in vivo.


Dynamics of fintech terms in news and blogs and specialization of companies of the fintech industry.
We perform a large scale analysis of a list of fintech terms in (i) news and blogs in the English language and (ii) professional descriptions of companies operating in many countries. The occurrence and the co-occurrence of fintech terms and locutions show a progressive evolution of the list of fintech terms in a compact and coherent set of terms used worldwide to describe fintech business activities. By using methods of complex networks that are specifically designed to deal with heterogeneous systems, our analysis of a large set of professional descriptions of companies shows that companies having fintech terms in their description present over-expressions of specific attributes of country, municipality, and economic sector. By using the approach of statistically validated networks, we detect geographical and economic over-expressions of a set of companies related to the multi-industry, geographically, and economically distributed fintech movement.


SSAGES: Software Suite for Advanced General Ensemble Simulations.
Molecular simulation has emerged as an essential tool for modern-day research, but obtaining proper results and making reliable conclusions from simulations requires adequate sampling of the system under consideration. To this end, a variety of methods exist in the literature that can enhance sampling considerably, and increasingly sophisticated, effective algorithms continue to be developed at a rapid pace. Implementation of these techniques, however, can be challenging for experts and non-experts alike. There is a clear need for software that provides rapid, reliable, and easy access to a wide range of advanced sampling methods and that facilitates implementation of new techniques as they emerge. Here we present SSAGES, a publicly available Software Suite for Advanced General Ensemble Simulations designed to interface with multiple widely used molecular dynamics simulations packages. SSAGES allows facile application of a variety of enhanced sampling techniques-including adaptive biasing force, string methods, and forward flux sampling-that extract meaningful free energy and transition path data from all-atom and coarse-grained simulations. A noteworthy feature of SSAGES is a user-friendly framework that facilitates further development and implementation of new methods and collective variables. In this work, the use of SSAGES is illustrated in the context of simple representative applications involving distinct methods and different collective variables that are available in the current release of the suite. The code may be found at: https://github.com/MICCoM/SSAGES-public.


Utility of Dual-Energy CT-based Monochromatic Imaging in the Assessment of Myocardial Delayed Enhancement in Patients with Cardiomyopathy.
Purpose To investigate the diagnostic utility of dual-energy computed tomography (CT)-based monochromatic imaging for myocardial delayed enhancement (MDE) assessment in patients with cardiomyopathy. Materials and Methods The institutional review board approved this prospective study, and informed consent was obtained from all participants who were enrolled in the study. Forty patients (27 men and 13 women; mean age, 56 years ± 15 [standard deviation]; age range, 22-81 years) with cardiomyopathy underwent cardiac magnetic resonance (MR) imaging and dual-energy CT. Conventional (120-kV) and monochromatic (60-, 70-, and 80-keV) images were reconstructed from the dual-energy CT acquisition. Subjective quality score, contrast-to-noise ratio (CNR), and beam-hardening artifacts were compared pairwise with the Friedman test at post hoc analysis. With cardiac MR imaging as the reference standard, diagnostic performance of dual-energy CT in MDE detection and its predictive ability for pattern classification were compared pairwise by using logistic regression analysis with the generalized estimating equation in a per-segment analysis. The Bland-Altman method was used to find agreement between cardiac MR imaging and CT in MDE quantification. Results Among the monochromatic images, 70-keV CT images resulted in higher subjective quality (mean score, 3.38 ± 0.54 vs 3.15 ± 0.43; P = .0067), higher CNR (mean, 4.26 ± 1.38 vs 3.93 ± 1.33; P = .0047), and a lower value for beam-hardening artifacts (mean, 3.47 ± 1.56 vs 4.15 ± 1.67; P < .0001) when compared with conventional CT. When compared with conventional CT, 70-keV CT showed improved diagnostic performance for MDE detection (sensitivity, 94.6% vs 90.4% [P = .0032]; specificity, 96.0% vs 94.0% [P = .0031]; and accuracy, 95.6% vs 92.7% [P < .0001]) and improved predictive ability for pattern classification (subendocardial, 91.5% vs 84.3% [P = .0111]; epicardial, 94.3% vs 73.5% [P = .0001]; transmural, 93.0% vs 77.7% [P = .0018]; mesocardial, 85.4% vs 69.2% [P = .0047]; and patchy. 84.4% vs 78.4% [P = .1514]). For MDE quantification, 70-keV CT showed a small bias 0.1534% (95% limits of agreement: -4.7013, 5.0080). Conclusion Dual-energy CT-based 70-keV monochromatic images improve MDE assessment in patients with cardiomyopathy via improved image quality and CNR and reduced beam-hardening artifacts when compared with conventional CT images. © RSNA, 2017 Online supplemental material is available for this article.


[Prevalence of psychiatric disorders among teenage offenders].
There has been a significant number of adolescents admitted to National Youth Service of Chile (SENAME) detention centers in recent years, specifically since the promulgation of a law reform on juveniles' penal responsibility for people aged 14 to 18 years (2006). To determine the prevalence of psychiatric disorders in adolescent male offenders aged between 14 and 17 years. The Mini International Neuropsychiatric Interview for Kids and Adolescents (MINI-KID) was applied to 489 adolescents admitted to detention centers, to determine the presence of psychiatric disorders. (Hypo) maniac episodes, eating disorders, pervasive developmental disorders, tic disorders, and psychotic disorders were excluded. Furthermore, for purposes of analysis, 23 cases that used a substance of abuse or had signs of consumption the day of the interview were excluded. Eighty six percent of respondents had at least one psychiatric disorder. The most common were substance use disorders (76%). Among these, marijuana dependence disorder had the higher frequency (51%). Disruptive behavior disorders had also a high prevalence (38%), followed by anxiety disorders (27%), attention deficit and hyperactivity disorder (26%), and affective disorders (21%). There is a high prevalence of psychiatric morbidity among teenage offenders which could undermine rehabilitation.


Psychometric properties and Confirmatory structure of the Strengths and difficulties questionnaire in a sample of adolescents in Nigeria.
Though the SDQ has been used in selected studies in Nigeria, its theoretical structure has not been fully and appropriately investigated in the setting. The present study employs Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA) to investigate the theoretical structure of the self-reported version of the SDQ in a sample of adolescents in Benue state, Nigeria. A total of 1,244 adolescents from different categories of secondary schools in Makurdi and Vandekya Local government areas of Benue state participated in the study. Preliminary data analyses were performed using descriptive statistics while the theoretical structure of the SDQ was assessed using EFA and CFA. Model fits were assessed using Chi-square test and other fit indices at 5% significance level. Participants were 14.19±2.45 (Vandekya) and 14.19±2.45 (Makurdi) years old. Results of the EFA and CFA revealed a 3-factor oblique model as the best model for the sample of adolescents studied (χ2/df =2.20, p<0.001) with all fit indices yielding better results. A correlated 3-factor model fits the present data better than the 5-factor theoretical model of the SDQ. The use of the original 5-factor model of the SDQ in the present setting should be interpreted with caution.


Compendium of chemical carcinogens by target organ: results of chronic bioassays in rats, mice, hamsters, dogs, and monkeys.
A compendium of carcinogenesis bioassay results organized by target organ is presented for 738 chemicals that are carcinogenic in chronic-exposure, long-term bioassays in at least 1 species. This compendium is based primarily on experiments in rats or mice; results in hamsters, monkeys, and dogs are also reported. The compendium can be used to identify chemicals that induce tumors at particular sites and to determine whether target sites are the same for chemicals positive in more than 1 species. The source of information is the Carcinogenic Potency Database (CPDB). which includes results of 6073 experiments on 1458 chemicals (positive or negative for carcinogenicity) that have been reported in Technical Reports of the National Cancer Institute/National Toxicology Program or in papers in the general published literature. The published CPDB includes detailed analyses of each test and citations. The CPDB is publicly available in several formats (http://potency.berkeley.edu). Chemical carcinogens are reported for 35 different target organs in rats or mice. Target organs in humans are also summarized for 82 agents that have been evaluated as human carcinogens at a particular target site by the International Agency for Research on Cancer (IARC). Comparisons are provided of target organs for mutagens versus nonmutagens and rats versus mice.


Lack of on-going adaptations in the soleus muscle activity during walking in patients affected by large-fiber neuropathy.
The aim of this study was to investigate the contribution of feedback from large-diameter sensory fibers to the adaptation of soleus muscle activity after small ankle trajectory modifications during human walking. Small-amplitude and slow-velocity ankle dorsiflexion enhancements and reductions were applied during the stance phase of the gait cycle to mimic the normal variability of the ankle trajectory during walking. Patients with demyelination of large sensory fibers (Charcot-Marie-Tooth type 1A and antibodies to myelin-associated glycoprotein neuropathy) and age-matched controls participated in this study. The patients had absent light-touch sense in the toes and feet and absent quadriceps and Achilles tendon reflexes, indicating functional loss of large sensory fibers. Moreover, their soleus stretch reflex response consisted of a single electromyographic (EMG) burst with delayed onset and longer duration (P < 0.01) than the short- and medium-latency reflex responses observed in healthy subjects. In healthy subjects, the soleus EMG gradually increased or decreased when the ankle dorsiflexion was, respectively, enhanced or reduced. In the patients, the soleus EMG increased during the dorsiflexion enhancements; however, the velocity sensitivity of this response was decreased compared with the healthy volunteers. When the dorsiflexion was reduced, the soleus EMG was unchanged. These results indicate that the enhancement of the soleus EMG is mainly sensitive to feedback from primary and secondary muscle spindle afferents and that the reduction may be mediated by feedback from the group Ib pathways. This study provides evidence for the role of sensory feedback in the continuous adaptation of the soleus activity during the stance phase of human walking.


International comparisons of the associations between objective measures of the built environment and transport-related walking and cycling: IPEN Adult Study.
Mounting evidence documents the importance of urban form for active travel, but international studies could strengthen the evidence. The aim of the study was to document the strength, shape, and generalizability of relations of objectively measured built environment variables with transport-related walking and cycling. This cross-sectional study maximized variation of environments and demographics by including multiple countries and by selecting adult participants living in neighborhoods based on higher and lower classifications of objectively measured walkability and socioeconomic status. Analyses were conducted on 12,181 adults aged 18-66 years, drawn from 14 cities across 10 countries worldwide. Frequency of transport-related walking and cycling over the last seven days was assessed by questionnaire and four objectively measured built environment variables were calculated. Associations of built environment variables with transport-related walking and cycling variables were estimated using generalized additive mixed models, and were tested for curvilinearity and study site moderation. We found positive associations of walking for transport with all the environmental attributes, but also found that the relationships was only linear for land use mix, but not for residential density, intersection density, and the number of parks. Our findings suggest that there may be optimum values in these attributes, beyond which higher densities or number of parks could have minor or even negative impact. Cycling for transport was associated linearly with residential density, intersection density (only for any cycling), and land use mix, but not with the number of parks. Across 14 diverse cities and countries, living in more densely populated areas, having a well-connected street network, more diverse land uses, and having more parks were positively associated with transport-related walking and/or cycling. Except for land-use-mix, all built environment variables had curvilinear relationships with walking, with a plateau in the relationship at higher levels of the scales.


Transition metal complexes of the pyridylphosphine ligand o-C6H4(CH2PPy2)2.
The synthesis and coordination behaviour of the pyridylphosphine ligand o-C6H4(CH2PPy2)2 (Py = 2-pyridyl) are reported. The phosphine selenide was synthesised and the 1JPSe value of 738 Hz indicates the phosphorus atoms have a similar basicity to PPh3. The ligand reacts with platinum(ii) and palladium(ii) complexes to give simple diphosphine complexes of the type [MX2(PP)] (M = Pt, X = Cl, I, Me, Et; M = Pd, X = Cl, Me). When the ligand is reacted with chloromethyl(hexa-1,5-diene)platinum the [PtClMe(PP)] complex results, from which a series of unsymmetrical platinum complexes of the type [PtMeL(PP)]+ (L = PPh3, PTA, SEt2 and pyridine) can be made. This enabled the comparison of the cis and trans influences of a range of ligands. The following cis influence series was compiled based on 31P NMR data of these complexes: Py ≈ Cl > SEt2 > PTA > PPh3. Reaction of [PtClMe(PP)] with NaCH(SO2CF3)2 and carbon monoxide slowly formed an acyl complex, where the CO had inserted in the Pt-Me bond. Attempts to achieve P,P,N chelation, through abstracting the chloride ligand in [PtClMe(PP)], were unsuccessful. When the ligand reacted with platinum(0), palladium(0) and silver(i) complexes the bis-chelated complexes [M(PP)2] (M = Pt, Pd) and [Ag(PP)2]+ were formed respectively. Reaction of the ligand with [Ir(COD)(μ-Cl)]2 formed [IrCl(PP)(COD)]. When the chloride ligand was abstracted, the pyridyl nitrogens were able to interact with the iridium centre facilitating the isomerisation of the 1,2,5,6-η4-COD ligand to a 1-κ-4,5,6-η3-C8H12 ligand. The X-ray crystal structure of [Ir(1-κ-4,5,6-η3-C8H12)(PPN)]BPh4 confirmed the P,P,N chelation mode of the ligand. In solution, this complex displayed hemilabile behaviour, with the pyridyl nitrogens exchanging at a rate faster than the NMR time scale at room temperature.


Continuous response variable trial design in motor neuron disease: long term treatment with a TRH analogue (RX77368).
The continuous response variable controlled trial design is developed as a model for the efficient screening of candidate treatments in motor neuron disease. A TRH analogue (RX77368) and placebo were randomly allocated to 15 matched pairs of patients with motor neuron disease. With validated composite interval scores, this trial excluded a 50% or greater improvement with RX77368 at month 12 in scores of respiratory, lower limb, and activities of daily living function with greater than 90% power, and in bulbar function scores with 80% power. For upper limbs, 52% and 75% improvements were excluded at months 9 and 12 respectively with 80% power. Patients who died during the study had faster deterioration rates in bulbar and respiratory scores than their surviving pairs. The feasibility of screening drugs for significant biological effects with small sample sizes and good statistical power is shown. The difficulties of handling deaths and dropouts when using this design are discussed. Comparisons are made with sample sizes required using other scores and rating scales, as well as with those required in hazard and event rate studies. A simple clinical grading scale for motor neuron disease, with its corresponding composite interval scores, is described.


Activities of amikacin, roxithromycin, and azithromycin alone or in combination with tumor necrosis factor against Mycobacterium avium complex.
The effect of amikacin and two new macrolides (roxithromycin and azithromycin) used either alone or in combination with recombinant tumor necrosis factor (TNF) to inhibit or kill Mycobacterium avium complex in human macrophages was examined in vitro. Macrophage monolayers infected with M. avium complex (strain 101, serotype 1) were treated with antibiotics or TNF by using three different protocols: (i) antibiotics or TNF was added to the monolayers immediately after infection and washed out after 24 h, (ii) antibiotics or TNF was replenished daily for 4 dys, or (iii) infected macrophage monolayers were treated with antibiotics plus TNF for 4 consecutive days. The number of viable intracellular bacteria was determined after 2 and 4 days of treatment by lysing cultured macrophages. Treatment for 24 h resulted in an inhibition of growth, as determined by macrophage lysis at day 4, for all three antimicrobial drugs and killing of 22% of intracellular bacteria after treatment with TNF. After treating the monolayers with amikacin, roxithromycin, or azithromycin for 4 consecutive days and replenishing the drug concentration daily, we observed 18 +/- 6, 20 +/- 4, and 22 +/- 1% killing, respectively. TNF (100 U/ml) was added daily to the monolayers, which resulted in 54 +/- 5% killing after 4 days. Combinations of antibiotics with TNF were associated with 62 +/- 3% killing with TNF-azithromycin, 73 +/- 6% killing with TNF-roxithromycin, and 56 +/- 4% killing of intracellular M. avium complex with TNF-amikacin after 4 days. The mycobactericidal effect was enhanced (91 +/- 4% killing by roxithromycinamikacin). Combinations of antimicrobial agents with immunomodulators like TNF may be useful for treatment of M. avium complex infection.


Dual Graph Partitioning Highlights a Small Group of Pseudoknot-Containing RNA Submotifs.
RNA molecules are composed of modular architectural units that define their unique structural and functional properties. Characterization of these building blocks can help interpret RNA structure/function relationships. We present an RNA secondary structure motif and submotif library using dual graph representation and partitioning. Dual graphs represent RNA helices as vertices and loops as edges. Unlike tree graphs, dual graphs can represent RNA pseudoknots (intertwined base pairs). For a representative set of RNA structures, we construct dual graphs from their secondary structures, and apply our partitioning algorithm to identify non-separable subgraphs (or blocks) without breaking pseudoknots. We report 56 subgraph blocks up to nine vertices; among them, 22 are frequently occurring, 15 of which contain pseudoknots. We then catalog atomic fragments corresponding to the subgraph blocks to define a library of building blocks that can be used for RNA design, which we call RAG-3Dual, as we have done for tree graphs. As an application, we analyze the distribution of these subgraph blocks within ribosomal RNAs of various prokaryotic and eukaryotic species to identify common subgraphs and possible ancestry relationships. Other applications of dual graph partitioning and motif library can be envisioned for RNA structure analysis and design.


Digital Health and Machine Learning Technologies for Blood Glucose Monitoring and Management of Gestational Diabetes.
Innovations in digital health and machine learning are changing the path of clinical health and care. People from different geographical locations and cultural backgrounds can benefit from the mobility of wearable devices and smartphones to monitor their health ubiquitously. This paper focuses on reviewing the digital health and machine learning technologies used in gestational diabetes - a subtype of diabetes that occurs during pregnancy. This paper reviews sensor technologies used in blood glucose monitoring devices, digital health innovations and machine learning models for gestational diabetes monitoring and management, in clinical and commercial settings, and discusses future directions. Despite one in six mothers having gestational diabetes, digital health applications were underdeveloped, especially the techniques that can be deployed in clinical practice. There is an urgent need to (1) develop clinically interpretable machine learning methods for patients with gestational diabetes, assisting health professionals with treatment, monitoring, and risk stratification before, during and after their pregnancies; (2) adapt and develop clinically-proven devices for patient self-management of health and well-being at home settings ("virtual ward" and virtual consultation), thereby improving clinical outcomes by facilitating timely intervention; and (3) ensure innovations are affordable and sustainable for all women with different socioeconomic backgrounds and clinical resources.


Phase II Trial of Preoperative Radiation With Concurrent Capecitabine, Oxaliplatin, and Bevacizumab Followed by Surgery and Postoperative 5-Fluorouracil, Leucovorin, Oxaliplatin (FOLFOX), and Bevacizumab in Patients With Locally Advanced Rectal Cancer: 5-Year Clinical Outcomes ECOG-ACRIN Cancer Research Group E3204.
The 5-year oncologic outcomes from the trial regimen were excellent. However, the neoadjuvant and surgical toxicity of this regimen was significant and was the primary reason for the low compliance with adjuvant systemic therapy.Due to the lack of an improvement in the pathologic complete response rate, the substantial associated toxicity, and the negative phase III trials of adjuvant bevacizumab in colon cancer, this regimen will not be pursued for further study. The addition of bevacizumab to chemotherapy improves overall survival for metastatic colorectal cancer. We initiated a phase II trial to evaluate preoperative capecitabine, oxaliplatin, and bevacizumab with radiation therapy (RT) followed by surgery and postoperative 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX), and bevacizumab for locally advanced rectal cancer. The purpose of this report is to describe the 5-year oncologic outcomes of this regimen. In a phase II Simon two-stage design study, we evaluated preoperative treatment with capecitabine (825 mg/m(2) b.i.d. Monday-Friday), oxaliplatin (50 mg/m(2) weekly), bevacizumab (5 mg/kg on days 1, 15, and 29), and RT (50.4 Gy). Surgery was performed by 8 weeks after RT. Beginning 8-12 weeks after surgery, patients received FOLFOX plus bevacizumab (5 mg/kg) every 2 weeks for 12 cycles (oxaliplatin stopped after 9 cycles). The primary endpoint was a pathologic complete response (path-CR) rate of 30%. Fifty-seven patients with resectable T3/T4 rectal adenocarcinoma were enrolled between 2006 and 2010. Of 57 enrolled patients, 53 were eligible and included in the analysis. Forty-eight (91%) patients completed preoperative therapy, all of whom underwent curative surgical resection. Nine patients (17%) achieved path-CR. There were 29 worst grade 3 events, 8 worst grade 4 events, and 2 patient deaths, 1 of which was attributed to study therapy. Twenty-six patients (54%) began adjuvant chemotherapy. After a median follow-up period of 41 months, the 5-year overall survival (OS) rate for all patients was 80%. Only 2 patients experienced cancer recurrence: 1 distant (liver) and 1 loco-regional (pelvic lymph nodes), respectively. Both of these patients are still alive. The 5-year relapse-free survival rate was 81%. Despite the path-CR primary endpoint of this trial not being reached, the 5-year OS and recurrence-free survival rates were excellent. However, the neoadjuvant and surgical toxicity of this regimen was significant and was the primary reason for the low compliance with adjuvant systemic therapy. Because of the lack of an improvement in the path-CR rate, the substantial associated toxicity, and the negative phase III trials of adjuvant bevacizumab in colon cancer, this regimen will not be pursued for further study.


Welfare Reform in the mid-2000s: How African-American and Hispanic Families in Three Cities are Faring.
This article reports on a sample of 538 African American and Hispanic women who were receiving TANF in 1999, 416 of whom left the program by 2005. The Hispanic women consisted of a Mexican-origin group and a second group that was primarily Puerto Rican and Dominican. Combining the experiences of the employed and the non-employed welfare leavers, we find at best a modest decline in the average poverty rate among African American welfare leavers between 1999 and 2005. Mexican-origin and other Hispanic leavers showed larger average declines in poverty. Among just the welfare leavers who were employed in 2005, the averages for women in all racial-ethnic groups showed increases in household income and declines in poverty. Among those who were not employed, African-Americans had experienced a decline in household income and were further below the poverty line than in 1999, whereas Hispanic women had experienced modest declines or slight increases in their household incomes.


Mobile point defects and atomic basis for structural transformations of a crystal surface.
Structural transformations on elemental semiconductor surfaces typically occur above several hundred degrees Celsius, and the atomic motions involved are extremely rapid and difficult to observe. However, on the (111) surface of germanium, a few lead atoms catalyze atomic motions so that they can be observed with a tunneling microscope at temperatures below 80 degrees C. Mass transport and structural changes are caused by the creation and propagation of both vacancy-like and interstitial-like point defects within the crystal surface. The availability of dangling bonds on the surface is critical. A detailed atomic model for the observed motions has been developed and is used to explain the structural phase transition Ge(111)-c(2x8) <--> 1x1, which occurs near 300 degrees C.


Stereochemical evaluation of the relative activities of the cinchona alkaloids against Plasmodium falciparum.
Quinine and quinidine were over 100 times more active than 9-epiquinine and 9-epiquinidine against chloroquine-sensitive Plasmodium falciparum and over 10 times more active against chloroquine-resistant P. falciparum. Since the only structural difference between quinine, quinidine, 9-epiquinine, and 9-epiquinidine is their three-dimensional configuration, the three-dimensional structures of these four alkaloids were examined in order to explain the large difference in relative activities between the 9-epi alkaloids and quinine and quinidine. The crystal structure of 9-epiquinidine hydrochloride monohydrate was determined by X-ray diffraction and was compared with the crystal structures of quinine, quinidine sulfate dihydrate, and 9-epiquinine hydrochloride dihydrate. The crystallographic parameters for 9-epiquinidine hydrochloride monohydrate were as follows: chemical formula, C20H25N2O2+.Cl-.H2O; M(r), 378.9; symmetry of unit cell, orthorhombic; space group, P2(1)2(1)2(1); parameters of unit cell, a was 7.042 +/- 0.001 A (1 A = 0.1 nm), b was 9.082 +/- 0.001 A, c was 31.007 +/- 0.005 A; the volume of unit cell was 1,983.1 +/- 0.6 A3; number of molecules per unit cell was 4; the calculated density was 1.27 g cm-3; the source of radiation was Cu K alpha (lambda = 1.54178 A); mu (absorption coefficient) was 18.82 cm-1; F(000) (sum of atomic scattering factors at zero scattering angle) was 808; room temperature was used; final R (residual index) was 5.72% for 1,501 reflections with magnitude of F(o) greater than 3 sigma (F). The intramolecular distance from N-1 to O-12 in 9-epiquinidine and 9-epiquinine, although shorter than the corresponding distance in quinine and quinidine, was similar to those of other active amino alcohol antimalarial agents. In all four alkaloids, both the hydroxyl and amine groups formed intermolecular hydrogen bonds, showing the potential for forming hydrogen bonds with cellular constituents. However, the positioning of the N+-1--H-N1 and O-12--H-O12 groups relative to each other was quite different in the 9-epi alkaloids versus quinidine. This difference in positioning may determine the relative strengths, of the formation of hydrogen bonds with cellular constituents important to antimalarial activity and, therefore, may determine the relative strength of antimalarial activity.


Pervasive transmission of a carbapenem resistance plasmid in the gut microbiota of hospitalized patients.
Infections caused by carbapenemase-producing enterobacteria (CPE) are a major concern in clinical settings worldwide. Two fundamentally different processes shape the epidemiology of CPE in hospitals: the dissemination of CPE clones from patient to patient (between-patient transfer), and the transfer of carbapenemase-encoding plasmids between enterobacteria in the gut microbiota of individual patients (within-patient transfer). The relative contribution of each process to the overall dissemination of carbapenem resistance in hospitals remains poorly understood. Here, we used mechanistic models combining epidemiological data from more than 9,000 patients with whole genome sequence information from 250 enterobacteria clones to characterize the dissemination routes of a pOXA-48-like carbapenemase-encoding plasmid in a hospital setting over a 2-yr period. Our results revealed frequent between-patient transmission of high-risk pOXA-48-carrying clones, mostly of Klebsiella pneumoniae and sporadically Escherichia coli. The results also identified pOXA-48 dissemination hotspots within the hospital, such as specific wards and individual rooms within wards. Using high-resolution plasmid sequence analysis, we uncovered the pervasive within-patient transfer of pOXA-48, suggesting that horizontal plasmid transfer occurs in the gut of virtually every colonized patient. The complex and multifaceted epidemiological scenario exposed by this study provides insights for the development of intervention strategies to control the in-hospital spread of CPE.


Absorption of ipratropium and l-carnitine into the pulmonary circulation of the ex-vivo rat lung is driven by passive processes rather than active uptake by OCT/OCTN transporters.
The organic cation transporters OCT and OCTN have been reported to play a significant role in the cellular uptake of substrates within in vitro lung cells. However, no studies to date have investigated the effect of these transporters upon transepithelial absorption of substrates into the pulmonary circulation. We investigated the contribution of OCT and OCTN transporters to total pulmonary absorption of l-carnitine and the anti-muscarinic drug, ipratropium, across an intact isolated perfused rat lung (IPRL). The results obtained from the IPRL were contrasted with active transport in vitro using three human pulmonary cell lines and primary rat alveolar epithelial cells. Ex-vivo studies showed that OCT/OCTN transporters do not play a role in the overall pulmonary absorption of l-carnitine or ipratropium, as evidenced by the effect of chemical inhibition of these transporters upon pulmonary absorption. In contrast, in vitro studies showed that OCT/OCTN transporters play a significant role in cellular accumulation of substrates with preferential uptake of ipratropium by OCTs, and of l-carnitine uptake by OCTNs. The results show that in vitro uptake studies cannot be predictive of airway to blood absorption in vivo. Nevertheless, localised submucosal pulmonary concentrations of inhaled drugs and their pulmonary pharmacodynamic profiles may be influenced by OCT/OCTN transport activity.


Cytotoxicity of gemcitabine enhanced by polyphenolics from Aronia melanocarpa in pancreatic cancer cell line AsPC-1.
Extending work with brain tumours, the hypothesis that micronutrients may usefully augment anticancer regimens, chokeberry (Aronia melanocarpa) extract was tested to establish whether it has pro-apoptotic effects in AsPC-1, an established human pancreatic cell line, and whether it potentiates cytotoxicity in combination with gemcitabine. Pancreatic cancer was chosen as a target, as its prognosis remains dismal despite advances in therapy. An MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay was used to assess the growth of the single pancreatic cancer cell line AsPC-1, alone and in comparison or combination with gemcitabine. This was backed up by flow cytometric DRAQ7 cell viability analysis. TUNEL assays were also carried out to investigate pro-apoptotic properties as responsible for the effects of chokeberry extract. Chokeberry extract alone and its IC75 value (1 µg/mL) in combination with gemcitabine were used to assess the growth of the AsPC-1 cell line. Gemcitabine in combination with chokeberry extract was more effective than gemcitabine alone. TUNEL assays showed apoptosis to be a mechanism occurring at 1 µg/mL concentration of chokeberry, with apoptotic bodies detected by both colourimetric and fluorometric methods. The implication of this study, using single cancer cell line, is that chemotherapy (at least with gemcitabine) might be usefully augmented with the use of micronutrients such as chokeberry extract.


Approaches to therapy of prion diseases.
Devising approaches to the therapy of transmissible spongiform encephalopathies, or prion diseases, is beset by many difficulties. For one, the nature of the infectious agent, the prion, is understood only in outline, and its composition, structure, and mode of replication are still shrouded in mystery. In addition, the mechanism of pathogenesis is not well understood. Because clinical disease affects mainly the brain parenchyme, therapeutic agents must be able to traverse the brain-blood barrier (BBB) or have to be introduced directly into the cerebrospinal fluid or brain tissue. And finally, because the disease is usually recognized only after onset of severe clinical symptoms, the question arises as to whether the neurodegenerative processes can be reversed to any extent after a successful eradication of the agent.


Determination of inferior vena cava diameter in the angiography suite: comparison of three common methods.
Significant inferior vena cava (IVC) filter migration has been associated with deployment of some filter types in IVCs measuring more than 28 mm in diameter at inferior vena cavography. The purposes of this study were to (a) determine if significant differences exist between IVC measurements obtained using a gold standard technique and two other widely accepted methods, and (b) if differences exist, how often do these differences cause incorrect IVC sizing around a diameter of 28 mm, with its associated filter migration issues. One hundred thirteen consecutive inferior vena cavograms were retrospectively reviewed. The transverse diameter of the infrarenal IVC was determined by using a calibrated intravascular catheter (the gold standard), subtraction of 20% from the measured transverse IVC diameter on a cut-film radiograph, and a radiopaque ruler placed immediately posterior to the patient. The concordance correlation of the 20% magnification method versus internal calibration was 0.94. Kappa analysis to determine agreement at a diameter of 28 mm yielded a Kappa coefficient of 0.490. The concordance correlation of an external ruler versus internal calibration was 0.43, with a Kappa coefficient of 0. The poor Kappa correlations for both methods demonstrate that they are unreliable in identifying megacava. Inferior vena cavography prior to IVC filter placement should be performed with a calibrated intravascular catheter.


The impact of service user involvement in research.
There are many examples of consumer involvement in NHS research but few studies have examined the impact of this on service development or the research process. This study, involving service user and carer researchers working alongside professional researchers, aimed to examine the development of one service user and carer research group in a mental health Trust. DERSIGN/METHODOLOGY/APPROACH: The research involved a review of existing literature on consumer involvement in research, a review of user involvement in research in South West Yorkshire Mental Health NHS Trust, a survey of consumers and NHS staff in the Trust, and a skills audit and training needs analysis of consumers. The study identified the range and extent of consumer involvement and the impact of this on consumers and the Trust. Service users and carers were involved in a range of projects, mainly on the level of consultation or collaboration. The benefits for consumers were principally on a personal level and included gaining knowledge and experience, improved sense of well-being, self esteem, and confidence. The benefit for the Trust was in having a service user perspective and focus. However, there is a tendency to omit service users from planning and setting priorities. The study pointed to the need to build the evidence base on consumer involvement in research, particularly in terms of how consumers can impact on setting research priorities and selecting appropriate methods. It identifies the need for more training for consumers and for NHS staff and for a more coherent strategy. This article will be of value to anyone who is at the start or in the early stages of their journey of consumer involvement. It identifies some of the practical issues faced by consumers and staff in working collaboratively, but also points to the benefits for all the stakeholders.


Supplementing culture and vitrification-warming media with l-ascorbic acid enhances survival rates and redox status of IVP porcine blastocysts via induction of GPX1 and SOD1 expression.
The present study sought to determine the effect of adding l-ascorbic acid (AC) to (1) in vitro culture medium and (2) vitrification and warming solutions on redox status and developmental ability and quality of IVP porcine embryos. In both experiments, embryo quality was analysed in terms of total cell number (TCN), DNA fragmentation, intracellular peroxide levels and expression of three oxidative stress-related genes: glutathione peroxidase 1 (GPX1), superoxide dismutase 1 (SOD1) and 2 (SOD2). In the first experiment, fresh blastocysts were found to upregulate SOD1 expression when cultured with medium supplemented 100 μM AC. No differences were found between culture groups in the other analysed parameters. In the second experiment, blastocysts cultured with or without AC were divided into two groups: vitrified and warmed with solutions containing 0 or 100 μM AC. Addition of AC during culture and vitrification-warming upregulated the expression of GPX1 and SOD1 genes, enhanced survival rates and decreased peroxide levels at 24h post-warming. In addition, peroxide levels were negatively correlated with relative GPX1- and SOD1-transcript abundances, whereas GPX1 was positively correlated with embryo survival at 24h post-warming. No effects of AC-supplementation were seen for TCN, DNA fragmentation or relative SOD2-transcript abundance in vitrified blastocysts. In conclusion, the addition of AC to culture and vitrification-warming media increases gene expression of antioxidant enzymes SOD1 and GPX1. This appears to improve redox balance and is suggested to ultimately enhance embryo cryosurvival.


Gravimetric wear analysis and particulate characterization of bilateral facet-augmentation system--PercuDyn™.
Dynamic stabilization systems are emerging as an alternative to fusion instrumentation. However, cyclic loading and micro-motion at various interfaces may produce wear debris leading to adverse tissue reactions such as osteolysis. Ten million cycles of wear test was performed for PercuDyn™ in axial rotation and the wear profile and the wear rate was mapped. A validation study was undertaken to assess the efficiency of wear debris collection which accounted for experimental errors. The mean wear debris measured at the end of 10 million cycles was 4.01 mg, based on the worst-case recovery rate of 68.2%. Approximately 40% of the particulates were less than 5 μm; 92% less than 10 μm. About 43% of particulates were spherical in shape, 27% particulates were ellipsoidal and the remaining particles were of irregular shapes. The PercuDyn™ exhibited an average polymeric wear rate of 0.4 mg/million cycles; substantially less than the literature derived studies for other motion preservation devices like the Bryan disc and Charité disc. Wear debris size and shape were also similar to these devices.


First Report of White Fir Dwarf Mistletoe (Arceuthobium abietinum f. sp. concoloris) on Durango Fir (Abies durangensis) from Durango, Mexico.
White fir dwarf mistletoe (Arceuthobium abietinum Engelm. ex Munz f. sp. concoloris Hawksw. & Wiens, Viscaceae) is a common parasite of grand fir (Abies grandis (Dougl. ex D. Don) Lindl.) in the Cascade Range and of Sierra white fir (Abies lowiana (Gord. & Glend.) A. Murray) in the Sierra Nevada Mountains (1). It also occurs in isolated populations on Rocky Mountain white fir (Abies concolor (Gord. & Glend.) Hildebr.) in Nevada, Utah, and Arizona (1). In addition, there are two widely separated known populations of white fir dwarf mistletoe on Durango fir (Abies durangensis Mart.) from Chihuahua, Mexico (1,2). The southernmost range of these Mexican populations extends to Cerro Mohinora near Guadalupe y Calvo close to the border with Durango and Sinaloa. In July 2012, white fir dwarf mistletoe was found infecting Durango fir on Cerro Gordo, the highest peak in the state of Durango (Latitude: 23° 12' 37″ N; Longitude: 104° 56″ 23″ W; elevation 3,060 m). Although there are many populations of Durango fir in Durango between Cerro Gordo and Cerro Mohinora, white fir dwarf mistletoe has never been reported from any of those populations (1). More than 70% of the trees were infected in the stand where the mistletoe was observed on Cerro Gordo, but little mortality of Durango fir was observed (4 trees). The infected Durango firs were growing in a mixed conifer forest of Durango fir, Douglas fir (Pseudotsuga menziesii (Mirb.) Franco), Cooper pine (Pinus cooperi Blanco), Mexican white pine (P. ayacahuite Ehrenb. ex Schltdl.), Durango pine (Pinus durangensis Mart.), and aspen (Populus tremuloides Michx.). There were no pure stands of Durango fir in the area. Infection by white fir dwarf mistletoe was only observed on Durango fir and infection was characterized by the formation of witches' brooms and branch swellings. Mistletoe plants collected from Durango fir on Cerro Gordo were identical to white fir dwarf mistletoe plants found on Cerro Mohinora when compared using morphological characters such as plant height (mean approximately 8 cm), plant color (yellow-green, green, green-brown, and rarely red-brown), mean diameter of flowers (2.8 mm), and mean fruit dimensions (5.0 × 3.0 mm) (2). White fir dwarf mistletoe is relatively host-specific and is the only dwarf mistletoe that has been reported to parasitize Durango fir in Mexico (1). Specimens of white fir dwarf mistletoe from Cerro Gordo were collected and deposited at the Hebario (CIIDIR), Instituto Politecnico Nacional, Durango, Mexico (Accession #40190). To our knowledge, this is the first report of white fir dwarf mistletoe from Durango, Mexico, and extends the known southern range of this mistletoe by approximately 370 km (1). References: (1) F. Hawksworth and D. Wiens. USDA For. Serv. Agric. Handb. 709, 1996. (2) R. Mathiasen. Plant Dis. 94:635, 2010.


Iontophoretic fraction collection for coupling capillary zone electrophoresis with matrix-assisted laser desorption/ionization mass spectrometry.
An automated fraction collection interface has been developed for coupling capillary electrophoresis (CE) with matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS). This fraction collection approach is based on electromigration and diffusion and does not rely on the presence of a liquid junction, sheath-liquid, electro-osmotic flow, or a superimposed hydrodynamic flow. Neutrally coated capillary with negligible electro-osmosis can thus be used to provide high-efficiency separations of biological compounds. The in-capillary separation resolution is totally independent from the spotting process. CE-separated species can be collected either in a multiwell plate or directly on a MALDI target. In the present work, an eight-protein mixture, submitted to trypsin proteolysis, has been used as a sample test and separations have been conducted in 50 microm i.d. neutrally coated capillaries. As compared to direct MALDI MS analysis, the integration of CE improved the number of detected peptides from 36 to 87 and the average sequence coverage from 24% to 38%. Internal calibration was used, and an average mass accuracy of 16.1 ppm is reported. Finally, diffusion-migration numerical simulations of the iontophoretic fraction collection process have been carried out.


Fast conversion of digital Fresnel hologram to phase-only hologram based on localized error diffusion and redistribution.
Past research has demonstrated that a digital, complex Fresnel hologram can be converted into a phase-only hologram with the use of the bi-direction error diffusion (BERD) algorithm. However, the recursive nature error diffusion process is lengthy and increases monotonically with hologram size. In this paper, we propose a method to overcome this problem. Briefly, each row of a hologram is partitioned into short non-overlapping segments, and a localized error diffusion algorithm is applied to convert the pixels in each segment into phase only values. Subsequently, the error signal is redistributed with low-pass filtering. As the operation on each segment is independent of others, the conversion process can be conducted at high speed with the graphic processing unit. The hologram obtained with the proposed method, known as the Localized Error Diffusion and Redistribution (LERDR) hologram, is over two orders of magnitude faster than that obtained by BERD for a 2048×2048 hologram, exceeding the capability of generating quality phase-only holograms in video rate.


Tunability of optofluidic distributed feedback dye lasers.
We investigate the tunability of optofluidic distributed feedback (DFB) dye lasers. The lasers rely on light-confinement in a nano-structured polymer film where an array of nanofluidic channels constitutes a third order Bragg grating DFB laser resonator with a central phase-shift. The lasers are operated by filling the DFB laser resonator with a dye solution by capillary action and optical pumping with a frequency doubled Nd:YAG laser. The low reflection order of the DFB laser resonator yields low out-of-plane scattering losses as well as a large free spectral range (FSR), and low threshold fluences down to ~7 microJ/mm2 are observed. The large FSR facilitates wavelength tuning over the full gain spectrum of the chosen laser dye and we demonstrate 45 nm tunability using a single laser dye by changing the grating period and dye solution refractive index. The lasers are straight-forward to integrate on lab-on-a-chip microsystems, e.g. for novel sensor concepts, where coherent light in the visible range is desired.


A new NMR solution structure of the SL1 HIV-1Lai loop-loop dimer.
Dimerization of genomic RNA is directly related with the event of encapsidation and maturation of the virion. The initiating sequence of the dimerization is a short autocomplementary region in the hairpin loop SL1. We describe here a new solution structure of the RNA dimerization initiation site (DIS) of HIV-1(Lai). NMR pulsed field-gradient spin-echo techniques and multidimensional heteronuclear NMR spectroscopy indicate that this structure is formed by two hairpins linked by six Watson-Crick GC base pairs. Hinges between the stems and the loops are stabilized by intra and intermolecular interactions involving the A8, A9 and A16 adenines. The coaxial alignment of the three A-type helices present in the structure is supported by previous crystallography analysis but the A8 and A9 adenines are found in a bulged in position. These data suggest the existence of an equilibrium between bulged in and bulged out conformations in solution.


Unilateral surgical treatment for patients with midportion Achilles tendinopathy may result in bilateral recovery.
Bilateral midportion Achilles tendinopathy/tendinosis is not unusual, and treatment of both sides is often carried out. Experiments in animals suggest of the potential involvement of central neuronal mechanisms in Achilles tendinosis. To evaluate the outcome of surgery for Achilles tendinopathy. This observational study included 13 patients (7 men and 6 women, mean age 53 years) with a long duration (6-120 months) of chronic painful bilateral midportion Achilles tendinopathy. The most painful side at the time for investigation was selected to be operated on first. Treatment was ultrasound-guided and Doppler-guided scraping procedure outside the ventral part of the tendon under local anaesthetic. The patients started walking on the first day after surgery. Follow-ups were conducted and the primary outcome was pain by visual analogue scale. In an additional part of the study, specimens from Achilles and plantaris tendons in three patients with bilateral Achilles tendinosis were examined. Short-term follow-ups showed postoperative improvement on the non-operated side as well as the operated side in 11 of 13 patients. Final follow-up after 37 (mean) months showed significant pain relief and patient satisfaction on both sides for these 11 patients. In 2 of 13 patients operation on the other, initially non-operated side, was instituted due to persisting pain. Morphologically, it was found that there were similar morphological effects, and immunohistochemical patterns of enzyme involved in signal substance production, bilaterally. Unilateral treatment with a scraping operation can have benefits contralaterally; the clinical implication is that unilateral surgery may be a logical first treatment in cases of bilateral Achilles tendinopathy.


Large-scale analysis of delayed recognition using sleeping beauty and the prince.
Delayed recognition in which innovative discoveries are re-evaluated after a long period has significant implications for scientific progress. The quantitative method to detect delayed recognition is described as the pair of Sleeping Beauty (SB) and its Prince (PR), where SB refers to citation bursts and its PR triggers SB's awakeness calculated based on their citation history. This research provides the methods to extract valid and large SB-PR pairs from a comprehensive Scopus dataset and analyses how PR discovers SB. We prove that the proposed method can extract long-sleep and large-scale SB and its PR best covers the previous multi-disciplinary pairs, which enables to observe delayed recognition. Besides, we show that the high-impact SB-PR pairs extracted by the proposed method are more likely to be located in the same field. This indicates that a hidden SB that your research can awaken may exist closer than you think. On the other hand, although SB-PR pairs are fat-tailed in Beauty Coefficient and more likely to integrate separate fields compared to ordinary citations, it is not possible to predict which citation leads to awake SB using the rarity of citation. There is no easy way to limit the areas where SB-PR pairs occur or detect it early, suggesting that researchers and administrators need to focus on a variety of areas. This research provides comprehensive knowledge about the development of scientific findings that will be evaluated over time.


From DNA Damage to Nucleic Acid Sensing: A Strategy to Enhance Radiation Therapy.
Local irradiation (IR) is widely used in the treatment of primary and metastatic tumors. However, the impact of IR on the immune response is currently being defined. Local and distant relapse after radiotherapy often occurs. The current rationale for the use of IR is based on direct cytotoxicity to cancer cells; however, recent studies have shown that reduction of tumor burden following ablative (large-dose) IR largely depends on type I IFN signaling and CD8(+) T-cell response. Here, we review recent findings indicating that antitumor effects of radiation are contributed by both innate and adaptive immune responses. We focus on immune mechanisms, including cytosolic DNA sensing pathways that bridge the traditional view of IR-mediated DNA damage to DNA-sensing immune pathways. Also, we discuss how the efficacy of radiotherapy might be enhanced by targeting nucleic acid-sensing pathways. These findings highlight the mechanisms governing tumor escape from the immune response and the therapeutic potential of synergistic strategies to improve the efficacy of radiotherapy via immunotherapeutic intervention.


Motor impulsivity and delay intolerance are elicited in a dose-dependent manner with a dopaminergic agonist in parkinsonian rats.
Impulse control disorders (ICD) and other impulsive-compulsive behaviours are frequently found in Parkinson's disease (PD) patients treated with dopaminergic agonists. To date, there are no available animal models to investigate their pathophysiology and determine whether they can be elicited by varying doses of dopaminergic drugs. In addition, there is some controversy regarding the predispositional pattern of striatal dopaminergic depletion. To study the effect of two doses of pramipexole (PPX) on motor impulsivity, delay intolerance and compulsive-like behaviour. Male rats with mild dopaminergic denervation in the dorsolateral striatum (bilateral injections of 6-hydroxidopamine (6-OHDA)) treated with two doses of PPX (0.25 mg/kg and 3 mg/kg) and tested in the variable delay-to-signal paradigm. Partial (50%) dopaminergic depletion did not induce significant changes in motor impulsivity or delay intolerance. However, 0.25 mg/kg of PPX increased motor impulsivity, while 3 mg/kg of PPX increased both motor impulsivity and delay intolerance. These effects were independent of the drug's antiparkinsonian effects. Importantly, impulsivity scores before and after dopaminergic lesion were positively associated with the impulsivity observed after administering 3 mg/kg of PPX. No compulsive-like behaviour was induced by PPX administration. We described a rat model, with a moderate dorsolateral dopaminergic lesion resembling that suffered by patients with early PD, that develops different types of impulsivity in a dose-dependent manner dissociated from motor benefits when treated with PPX. This model recapitulates key features of abnormal impulsivity in PD and may be useful for deepening our understanding of the pathophysiology of ICD.


Excess volume and heat of mixing in Cu-Ti liquid mixture.
Molar excess volume of Cu-Ti liquid mixture has been investigated to elucidate how the excess volume in binary alloys is related to mixing enthalpy and microscopic interactions. Cu-Ti is used as a key example for systems showing positive excess volume and negative mixing enthalpy. For this purpose, the density of several Cu-Ti binary mixtures has been measured over the whole composition range by the containerless technique of electromagnetic levitation as a function of temperature. A linear temperature dependence of the density has been found for all investigated alloys. In addition, the density decreases with increasing Ti content in the alloys, showing a negative deviation from the ideal solution model. As mentioned, a positive excess volume was found whereas the enthalpy of mixing is negative. This behavior has been discussed in relation with chemical ordering and the role played by attractive and repulsive interactions in the system, according to previous results obtained by means of molecular dynamics simulation on binary dense fluids.


Zooplankton community changes confound the biodilution theory of methylmercury accumulation in a recovering mercury-contaminated lake.
In this study, the biodilution hypothesis of methylmercury (MeHg) accumulation was examined in a Hg-contaminated ecosystem that has undergone concurrent changes in nutrient loading and zooplankton community composition. Using a long-term record of 17 years (between 1980 and 2009), we demonstrate that zooplankton MeHg concentrations in Onondaga Lake, NY, are strongly driven by changes in the zooplankton community and body size. MeHg concentrations in zooplankton increased with an increase in body size and biomass. The highest concentrations of MeHg were observed under eutrophic and hypereutrophic conditions when large-bodied Daphnia species, Daphnia pulicaria and Daphnia galeata mendotae, were present. Bioconcentration rather than biodilution was governing the accumulation of MeHg in zooplankton without apparent growth dilution or zooplankton biomass dilution. Algal-bloom dilution controlled the variability in the MeHg concentration only under hypereutrophic conditions when Ceriodaphnia predominated the cladoceran population. Our study demonstrates that changes in zooplankton community composition confound the biodilution theory in Onondaga Lake and that the presence of large-bodied zooplankton species drives elevated MeHg concentrations.


Current status of endocrine therapy for prostate cancer in Japan analysis of primary androgen deprivation therapy on the basis of data collected by J-CaP.
Based on the data of current status of endocrine therapy for prostate cancer registered in the Japan Study Group of Prostate Cancer (J-CaP), we conducted an analysis of primary androgen deprivation therapy (PADT) and an interim analysis of the prognosis. Of the 26 272 cases registered in the server of J-CaP, the 19 409 cases initially receiving PADT were included in this study. The initial therapy was divided into eight categories according to its features. Of the 19 409 patients, 1513 (7.8%) were given anti-androgen monotherapy, 955 patients (4.9%) surgical castration only, 1001 patients (5.2%) surgical castration + anti-androgen, 3015 patients (15.5%) LHRH monotherapy, 1658 patients (8.5%) LH-RH + short-term anti-androgen, 10 434 patients (53.8%) LH-RH + anti-androgen, 37 patients (0.2%) watchful waiting and 796 patients (4.1%) other therapy. In progression-free survival, the prognosis was slightly better following maximum androgen blockade (MAB) in each stage. The pattern of PADT is more typical in Japan compared with that in the United States. Patients who received MAB accounted for 59.0% of all the patients. MAB tends to be more often selected for patients who are rated as being at high risk on the basis of high Gleason score or PSA level upon diagnosis in each clinical stage of the disease. Investigations of the outcome are on-going and they will make clear the significance of this trend in Japan.


The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer.
The androgen receptor (AR) plays a central role in establishing an oncogenic cascade that drives prostate cancer progression. Some prostate cancers escape androgen dependence and are often associated with an aggressive phenotype. The oestrogen receptor alpha (ERα) is expressed in prostate cancers, independent of AR status. However, the role of ERα remains elusive. Using a combination of chromatin immunoprecipitation (ChIP) and RNA-sequencing data, we identified an ERα-specific non-coding transcriptome signature. Among putatively ERα-regulated intergenic long non-coding RNAs (lncRNAs), we identified nuclear enriched abundant transcript 1 (NEAT1) as the most significantly overexpressed lncRNA in prostate cancer. Analysis of two large clinical cohorts also revealed that NEAT1 expression is associated with prostate cancer progression. Prostate cancer cells expressing high levels of NEAT1 were recalcitrant to androgen or AR antagonists. Finally, we provide evidence that NEAT1 drives oncogenic growth by altering the epigenetic landscape of target gene promoters to favour transcription.