Contribution of different classes of glutamate receptors in the corticostriatal polysynaptic responses from striatal direct and indirect projection neurons.
Previous work showed differences in the polysynaptic activation of GABAergic synapses during corticostriatal suprathreshold responses in direct and indirect striatal projection neurons (dSPNs and iSPNs). Here, we now show differences and similarities in the polysynaptic activation of cortical glutamatergic synapses on the same responses. Corticostriatal contacts have been extensively studied. However, several questions remain unanswered, e.g.: what are the differences and similarities in the responses to glutamate in dSPNs and iSPNs? Does glutamatergic synaptic activation exhibits a distribution of latencies over time in vitro? That would be a strong suggestion of polysynaptic cortical convergence. What is the role of kainate receptors in corticostriatal transmission? Current-clamp recordings were used to answer these questions. One hypothesis was: if prolonged synaptic activation distributed along time was present, then it would be mainly generated from the cortex, and not from the striatum. By isolating responses from AMPA-receptors out of the complex suprathreshold response of SPNs, it is shown that a single cortical stimulus induces early and late synaptic activation lasting hundreds of milliseconds. Prolonged responses depended on cortical stimulation because they could not be elicited using intrastriatal stimulation, even if GABAergic transmission was blocked. Thus, the results are not explained by differences in evoked inhibition. Moreover, inhibitory participation was larger after cortical than after intrastriatal stimulation. A strong activation of interneurons was obtained from the cortex, demonstrating that polysynaptic activation includes the striatum. Prolonged kainate (KA) receptor responses were also elicited from the cortex. Responses of dSPNs and iSPNs did not depend on the cortical area stimulated. In contrast to AMPA-receptors, responses from NMDA- and KA-receptors do not exhibit early and late responses, but generate slow responses that contribute to plateau depolarizations. As it has been established in previous physiological studies in vivo, synaptic invasion over different latencies, spanning hundreds of milliseconds after a single stimulus strongly indicates convergent polysynaptic activation. Interconnected cortical neurons converging on the same SPNs may explain prolonged corticostriatal responses. Glutamate receptors participation in these responses is described as well as differences and similarities between dSPNs and iSPNs.


Proteolysis of human thrombin generates novel host defense peptides.
The coagulation system is characterized by the sequential and highly localized activation of a series of serine proteases, culminating in the conversion of fibrinogen into fibrin, and formation of a fibrin clot. Here we show that C-terminal peptides of thrombin, a key enzyme in the coagulation cascade, constitute a novel class of host defense peptides, released upon proteolysis of thrombin in vitro, and detected in human wounds in vivo. Under physiological conditions, these peptides exert antimicrobial effects against Gram-positive and Gram-negative bacteria, mediated by membrane lysis, as well as immunomodulatory functions, by inhibiting macrophage responses to bacterial lipopolysaccharide. In mice, they are protective against P. aeruginosa sepsis, as well as lipopolysaccharide-induced shock. Moreover, the thrombin-derived peptides exhibit helical structures upon binding to lipopolysaccharide and can also permeabilize liposomes, features typical of "classical" helical antimicrobial peptides. These findings provide a novel link between the coagulation system and host-defense peptides, two fundamental biological systems activated in response to injury and microbial invasion.


Infrared and Raman imaging for characterizing complex biological materials: a comparative morpho-spectroscopic study of colon tissue.
Complementary diagnostic methods to conventional histopathology are currently being investigated for developing rapid and objective molecular-level understanding of various disorders, especially cancers. Spectral histopathology using vibrational spectroscopic imaging has been put in the frontline as potentially promising in this regard as it provides a "spectral fingerprint" of the biochemical composition of cells and tissues. In order to ascertain the feasible conditions of vibrational spectroscopic methods for tissue-imaging analysis, vibrational multimodal imaging (infrared transmission, infrared-attenuated total reflection, and Raman imaging) of the same colon tissue has been implemented. The spectral images acquired were subjected to multivariate clustering analysis in order to identify on a molecular level the constituent histological organization of the colon tissue such as the epithelium, connective tissue, etc., by comparing the cluster images with the histological reference images. Based on this study, a comparative analysis of important factors involved in the vibrational multimodal imaging approaches such as image resolution, time constraints, their advantages and limitations, and their applicability to biological tissues has been carried out. Out of the three different vibrational imaging modalities tested, infrared-attenuated total reflection mode of imaging appears to provide a good compromise between the tissue histology and the time constraints in achieving similar image contrast to that of Raman imaging at an approximately 33-fold faster measurement time. The present study demonstrates the advantages, the limitations of the important parameters involved in vibrational multimodal imaging approaches, and their potential application toward imaging of biological tissues.


Humans can integrate force feedback to toes in their sensorimotor control of a robotic hand.
Tactile sensory feedback is essential for dexterous object manipulation. Users of hand myoelectric prostheses without tactile feedback must depend essentially on vision to control their device. Indeed, improved tactile feedback is one of their main priorities. Previous research has provided evidence that conveying tactile feedback can improve prostheses control, although additional effort is required to solve problems related to pattern recognition learning, unpleasant sensations, sensory adaptation, and low spatiotemporal resolution. Still, these studies have mainly focused on providing stimulation to hairy skin regions close to the amputation site, i.e., usually to the upper arm. Here, we explored the possibility to provide tactile feedback to the glabrous skin of toes, which have mechanical and neurophysiological properties similar to the fingertips. We explored this paradigm in a grasp-and-lift task, in which healthy participants controlled two opposing digits of a robotic hand by changing the spacing of their index finger and thumb. The normal forces applied by the robotic fingertips to a test object were fed back to the right big and second toe. We show that within a few lifting trials, all the participants incorporated the force feedback received by the foot in their sensorimotor control of the robotic hand.


Comparison of Drug Availability in the Inner Ear After Oral, Transtympanic, and Combined Administration.
Although combination of oral and transtympanic drug therapy (CT) has been proved more effective and safer for idiopathic sudden sensorineural hearing loss (ISSNHL) by some clinical trials, there are few laboratory researches on the pharmacokinetics in the inner ear following CT on account of structural limitations of the inner ear. The aim of the present study was to investigate the pharmacokinetic behaviors of CT in the inner ear of mice. Eighteen transgenic GFAP-Luc mice which express luciferase in cochlear spiral ganglion cells were divided into oral administration (OR) group, transtympanic injection route (TT) group and CT group, and luciferin was delivered into the inner ear of these mice through oral, transtympanic or combined routes, respectively. A new in vivo imaging system was used to observe luciferin/luciferase signals and the compare the pharmacokinetics of different administration routes in the inner ear of mice. Bioluminescence signals were observed in the inner ear 3.3 ± 2.6 min after CT, significantly earlier than that of OR group (15.8 ± 7.4 min). CT owned the longest reaching-peak time and largest area under the curve (AUC) among three groups. Compared to TT, CT had longer biological half-life and higher AUC value, but did not displayed stronger peak value. There were significant differences in the peak values between OR group and TT group and between OR group and CT group. This study suggests that the OR route is less effective than the TT or CT route, and combination of OR and TT can deliver more drugs into the inner ear and confer a longer therapeutic window, but cannot increase drug intensity.


Alternative HbA1c cutoffs to identify high-risk adults for diabetes prevention: a cost-effectiveness perspective.
New recommendations about the use of hemoglobin A1c (HbA1c) for diagnosing diabetes have stimulated a debate about the optimal HbA1c cutoff to identify prediabetes for preventive intervention. To assess the cost effectiveness associated with the alternative HbA1c cutoffs for identifying prediabetes. A Markov simulation model was used to examine the cost effectiveness associated with a progressive 0.1% decrease in the HbA1c cutoff from 6.4% to 5.5%. The target population was the U.S. nondiabetic population aged ≥18 years. The simulation sample was created using the data of nondiabetic American adults from the National Health and Nutritional Examination Survey (NHANES 1999-2006). People identified as having prediabetes were assumed to receive a preventive intervention, with effectiveness the same as that in the Diabetes Prevention Program study under a high-cost intervention (HCI) scenario and in the Promoting a Lifestyle of Activity and Nutrition for Working to Alter the Risk of Diabetes study under a low-cost intervention (LCI) scenario. The analysis was conducted for a lifetime horizon from a healthcare system perspective. Lowering the HbA1c cutoff would increase the health benefits of the preventive interventions at higher costs. For the HCI, lowering the HbA1c cutoff from 6.0% to 5.9% and from 5.9% to 5.8% would result in $27,000 and $34,000 per QALY gained, respectively. Continuing to decrease the cutoff from 5.8% to 5.7%, from 5.7% to 5.6%, and from 5.6% to 5.5% would cost $45,000, $58,000, and $96,000 per QALY gained, respectively. For the LCI, lowering the HbA1c cutoff from 6.0% to 5.9% and from 5.9% to 5.8% would result in $24,000 and $27,000 per QALY gained, respectively. Continuing to lower the cutoff from 5.8% to 5.7%, 5.7% to 5.6%, and 5.6% to 5.5% would cost $34,000, $43,000 and $70,000 per QALY gained, respectively. Lowering the HbA1c cutoff for prediabetes leads to less cost-effective preventive interventions. Assuming a conventional $50,000/QALY cost-effectiveness benchmark, the HbA1c cutoffs of 5.7% and higher were found to be cost effective. Lowering the cutoff from 5.7% to 5.6% also may be cost effective, however, if the costs of preventive interventions were to be lowered.


A new method for estimation of homolytic C-H bond dissociation enthalpies
In this work we have quantitatively analyzed substituent effects on the homolytic bond dissociation enthalpy of 79 different compounds using a method based on discrete distance dependent atomic contributions to a molecular property. The resulting empirical relationship can be used to predict C-H bond dissociation enthalpies (within +/-10 kJ mol(-1)) for molecules where resonance contributions and captodative stabilization are insignificant. For species where captodative stabilization of the corresponding C-centered radical is possible, the method clearly overestimates the C-H bond dissociation enthalpy.


Presence and severity of intensive care unit-acquired paresis at time of awakening are associated with increased intensive care unit and hospital mortality.
To assess whether the presence and severity of intensive care unit-acquired paresis are associated with intensive care unit and in-hospital mortality. Prospective, observational study. Two medical, one surgical, and one medico-surgical intensive care units in two university hospitals and one university-affiliated hospital. A total of 115 consecutive patients were enrolled after > 7 days of mechanical ventilation. None. The Medical Research Council score (from 0-60) was used to evaluate upper and lower limb strength at time of awakening, identified as the ability to follow five commands. Intensive care unit-acquired paresis was defined as a Medical Research Council score <48. Patients were followed-up until hospital discharge. The primary end point was hospital mortality. At awakening, median Medical Research Council score was 41 (interquartile range, 21-52), and 75 (65%) patients had intensive care unit-acquired paresis. Hospital non-survivors had a significantly lower Medical Research Council score at awakening (21 [11-43]) vs. 41 [28-53]; p = .008) and a significantly higher rate of intensive care unit-acquired paresis (85.1% vs. 58.4%; p = .02) compared to survivors. After multivariate risk adjustment, intensive care unit-acquired paresis was independently associated with higher hospital and intensive care unit mortality (odds ratio for hospital mortality, 2.02; 95% confidence interval, 1.03-8.03; p = .048). Each Medical Research Council point decrease was associated with a significantly higher hospital mortality (odds ratio, 1.03; 95% confidence interval, 1.01-1.05; p = .033). Both the presence and severity of intensive care unit-acquired paresis at the time of awakening are associated with increased intensive care unit and hospital mortality; the mechanisms underlying this association need further study.


Tuning phase behaviour of PEG-functionalized ionic liquids from UCST to LCST in alcohol-water mixtures.
Thermo-responsive materials with reversible phase transition in molecular solvents are of great importance for catalysis reaction, product separation, and catalyst recycling among others. In this work, liquid-liquid phase transition of PEG-functionalized ionic liquids [PEGm(mim)2][NTf2]2 (m = 200, 400, 600, 800, 1000) in aliphatic alcohol (ethanol, 1-propanol or isopropanol) and in aqueous aliphatic alcohol was investigated by turbidity and dynamic light scattering (DLS) measurements, and the effects of the alkyl chain length of the alcohol molecules and molecular weight of the PEG middle block of the ionic liquids on the phase transition behaviour were examined. It was found that these ionic liquids exhibited a unique UCST phase transition in the aliphatic alcohol, but their liquid-liquid phase transition behaviour could be tuned precisely from UCST to LCST in aqueous aliphatic alcohol. Furthermore, temperature-dependent FT-IR and/or 1H NMR measurements were performed to understand the possible origin of phase behavior of both [PEGm(mim)2][NTf2]2 in the aliphatic alcohol and [PEG800(mim)2][NTf2]2 in ethanol-d6/H2O.


The acute potentiating effects of back squats on athlete performance.
Crewther, BT, Kilduff, LP, Cook, CJ, Middleton, MK, Bunce, PJ, and Yang, G-Z. The acute potentiating effects of back squats on athlete performance. J Strength Cond Res 25(12): 3319-3325, 2011-This study examined the acute potentiating effects of back squats on athlete performance with a specific focus on movement specificity and the individual timing of potentiation. Nine subelite male rugby players performed 3 protocols on separate occasions using a randomized, crossover, and counterbalanced design. Each protocol consisted of performance testing before a single set of 3 repetition maximum (3RM) back squats, followed by retesting at ∼15 seconds, 4, 8, 12, and 16 minutes. The 3 tests were countermovement jumps (CMJs), sprint performance (5 and 10 m), and 3-m horizontal sled pushes with a 100-kg load. Relationships between the individual changes in salivary testosterone and cortisol concentrations and performance were also examined. The 3RM squats significantly (p < 0.001) improved CMJ height at 4 (3.9 ± 1.9%), 8 (3.5 ± 1.5%), and 12 (3.0 ± 1.4%) minutes compared with baseline values, but no temporal changes in sprinting and sled times were identified. On an individual level, the peak relative changes in CMJ height (6.4 ± 2.1%, p < 0.001) were greater than the 3-m sled (1.4 ± 0.6%), 5-m (2.6 ± 1.0%), and 10-m sprint tests (1.8 ± 1.0%). In conclusion, a single set of 3RM squats was found effective in acutely enhancing CMJ height in the study population, especially when the recovery period was individualized for each athlete. The study results also suggest that the potentiating effects of squats may exhibit some degree of movement specificity, being greater for those exercises with similar movement patterns. The current findings have practical implications for prescribing warm-up exercises, individualizing training programs, and for interpreting postactivation potentiation research.


CO2 adsorption-induced structural changes in coordination polymer ligands elucidated via molecular simulations and experiments.
Aiming to elucidate guest-induced structural changes in the coordination polymer CPL-2, grand canonical Monte Carlo (GCMC) simulations were used to predict CO2 loadings in this material, and the results were compared with experimental isotherms. Our calculations suggest that CPL-2 exhibits more pronounced CO2-induced structural changes than previously reported. As the initial evidence, the isotherm simulated in the previously reported CPL-2 structure (experimentally resolved from X-ray diffraction in the "as-synthesized" CPL-2) underestimated the measured CO2 loadings at high pressure, indicating that CPL-2 might undergo structural changes that enable higher pore volumes at high pressure. GCMC simulations in CPL-2 structures considering moderate unit cell expansions reported in the literature still underestimated high-pressure experimental loadings. However, considering an incremental rotation of the CPL-2 bipyridyl pillars with increasing CO2 pressure, we were able to trace the measured isotherm with the simulation data. Computational analysis shows that ligand rotation in CPL-2 enables higher pore volumes, which, in turn, accommodate more CO2 as the gas pressure increases. Desorption measurements suggest that hysteresis in the CO2 isotherm of CPL-2 may also be linked to ligand rotation, and the measured adsorption/desorption cycles show that the rotation is reversible. Based on our simulations for CPL-4 and CPL-5 and previously reported experimental data, it is likely that these materials, which differ from CPL-2 in the bipyridyl ligand, behave similarly in the presence of CO2. Our results help understand the behavior of these materials, which present the kind of structural changes that could be potentially exploited to enhance the CO2 working capacity of ultra-microporous materials for carbon capture applications.


[Results of questionnaire on decision-making to treat advanced non-small cell lung cancer based on American and European practical guidelines].
During 2009, practical routine guidelines for advanced non-small cell lung cancer used in Europe or USA were updated because the clinical benefits of molecular target agents were confirmed through several pivotal clinical trials. These molecular target agents appeared in guidelines which became available in Japan by the end of 2009. We made a questionnaire for decision-making to treat advanced non-small cell lung cancer based on these practical guidelines. Oncologists of lung cancer working in the Shinjuku area of Tokyo in Japan were eligible. Between March 15th and April 9th in 2010, 28 oncologists from 12 departments in 7 hospitals completed this questionnaire. Most of them made the global standard decision-making according to the new guidelines, including new proposals such as usage of epidermal growth factor receptor-tyrosine kinase inhibitors. There were 3 differences from the guidelines. 1)Platinum doublets were selected even in 2nd- or 3rd-line treatment because of the expected tumor shrinkage. 2)Single cytotoxic agents were selected even for 3rd-line treatment. The tendency of a backward shift in decision-making was observed. 3)There were few selections of regimens including bevacizumab because of medical systems such as DPC(Diagnosis Procedure Combination)that is Japanese DRG(Diagnosis-Related Group)/PPS(Prospective Payment System).


Occurrence of Vibrio spp. in fish and shellfish collected from the Swiss market.
The genus Vibrio includes gram-negative bacteria that inhabit estuarine ecosystems. V. cholerae, V. parahaemolyticus, and V. vulnificus pose a considerable public health threat as agents of sporadic and epidemic foodborne infections associated with the consumption of raw or undercooked contaminated fish or shellfish. In this study, we analyzed 138 fish and shellfish samples collected from the Swiss market (fish fillets [n = 102], bivalves [n = 34], and squid [n = 2]). Microbiological analysis was done according to International Organization for Standardization method 21872-1/21872-2:2007, using thiosulfate citrate bile sucrose agar and chromID Vibrio agar as selective agar. Presumptive-positive colonies on thiosulfate citrate bile sucrose agar or chromID Vibrio agar were picked and were identified by the API 20E and species-specific PCR systems. V. cholerae isolates were tested further by PCR for the presence of the cholera toxin A subunit gene (ctxA). V. parahaemolyticus isolates were tested by PCR for genes encoding for thermostable direct hemolysin (tdh) and TDH-related hemolysin (trh). V. cholerae was isolated from three samples and V. parahaemolyticus from eight samples. None of these strains harbored species-specific virulence factors. Further, V. alginolyticus was isolated from 40 samples, and V. fluvialis was isolated from 1 sample. Our study provides, for the first time, data for the assessment of exposure to Vibrio spp. in raw fish and bivalves consumed in Switzerland.


Live Imaging Reveals Listeria Hijacking of E-Cadherin Recycling as It Crosses the Intestinal Barrier.
Listeria monocytogenes is a foodborne bacterial pathogen that causes human listeriosis, a severe systemic infection.1 Its translocation across the intestinal epithelium is mediated by the interaction of internalin (InlA), a Listeria surface protein, with its host-species-specific receptor E-cadherin (Ecad).2-5 It occurs through goblet cells, on which Ecad is luminally accessible,6 via an unknown mechanism. In the absence of cell lines recapitulating this phenotype in vitro, we developed an ex vivo experimental system, based on the intraluminal microinjection of Listeria in untreated, pharmacologically treated, and genetically modified intestinal organoids. Using both live light-sheet microscopy and confocal imaging, we show that Listeria translocates through goblet cells within a membrane vacuole in an InlA- and microtubule-dependent manner. As Ecad undergoes constant apical-basal recycling,7,8 we hypothesized that Lm may transit through goblet cells by hijacking Ecad recycling pathway. Indeed, Listeria is stuck at goblet cell apex when Ecad endocytosis is blocked and remains trapped intracellularly at the basolateral pole of goblet cells when Rab11-dependent Ecad recycling is compromised. Together, these results show that Listeria, upon docking onto its luminally accessible receptor Ecad, hijacks its recycling pathway to be transferred by transcytosis across goblet cells. Live imaging of host-pathogen interactions in organoids is a promising approach to dissect their underlying cell and molecular biology.


Nectonema zealandica n. sp. (Nematomorpha: Nectonematoidea) parasitising the purple rock crab Hemigrapsus edwardsi (Brachyura: Decapoda) in New Zealand, with notes on the prevalence of infection and host defence reactions.
A new species of marine hairworm, Nectonema zealandica (Nematomorpha: Nectonematoidea), is described from the purple rock crab Hemigrapsus edwardsi Hilgendorf from the South Island, New Zealand. This is the first record of Nectonema in the South Pacific Ocean and the southernmost locality for the genus. The description is based on juveniles and pre-adults taken from crabs. The new species is characterised by its stomal structure, presence of four cephalic papillae, mesenchyme arranged in eight lobes in pre-adults, insertion of muscle layer increasing body diameter at the septum and translucent anterior chamber. Data on the prevalence of infection over a three-year period, rates of parasitism in relation to host sex and size, and host defence reactions are presented. A list of all reported hosts of nectonematids is included.


Management of Febrile Neutropenia: A Description of Clinical and Microbiological Findings by Focusing on Risk Factors and Pitfalls.
Febrile neutropenia (FN) is one of the most serious clinical problems in patients with hematologic malignancies and patients receiving chemotherapy. The present study was implemented to determine precisely how FN is managed in most referral hospitals in Isfahan (Iran) and what are the characteristics of FN patients as well as risk factors associated with FN development. This study was a cross-sectional study performed over a period of 6 months on patients hospitalized in the Hematology-Oncology Center of Omid Hospital, Isfahan, Iran. The information was collected by filling the designed data abstraction form. A total of 115 oncology patients were admitted with or encountered to FN. This equates to a cumulative incidence of 1.26% of FN cases per 1000 oncology admissions. The average age was 49.5 ± 18.02 years (range 18-85 years), with 42.6% of patients being female. The most frequently prescribed antibiotic agents were meropenem (91.3%) and vancomycin (47.82%) alone or in combination. Empiric antifungal agents initiated in 20.86% of cases, and we could not find any patients who needed to receive antiviral treatment. From all positive cultures, Gram-positive microorganisms were the most found pathogen. Among them, female sex (42.6%) and lymphopenia (26.5%) were the most noted predictors. Neutropenia (81.7%) was the most reported risk factors for serious complications. Although our center is university-affiliated, there are still several points, and pitfalls must be considered and revised in the management of FN patients. Obtaining and assessing the samples microbiologically and antibiotic therapy accordingly were the most troublesome complications.


Prostate apoptosis response protein 4 sensitizes human colon cancer cells to chemotherapeutic 5-FU through mediation of an NF kappaB and microRNA network.
Diminished expression or activity of prostate apoptosis response protein 4 (Par-4) has been demonstrated in a number of cancers, although reports on Par-4 expression during colon cancer progression are lacking. An understanding of the molecular events in conjunction with the genetic networks affected by Par-4 is warranted. Colon cancer specimens derived from patients have significantly diminished expression of Par-4 mRNA relative to paired normal colon. Hence, the functional consequences of reintroducing Par-4 into HT29 colon cancer cells were assessed. Overexpression augmented the interaction of Par-4 with NF kappaB in the cytosol but not nucleus, and facilitated apoptosis in the presence of 5-fluorouracil (5-FU). Analogous findings were obtained when AKT1 pro-survival signaling was inhibited. Transcriptome profiling identified approximately 700 genes differentially regulated by Par-4 overexpression in HT29 cells. Nearly all Par-4-regulated genes were shown by promoter analysis to contain cis-binding sequences for NF kappaB, and meta-analysis of patient expression data revealed that one-third of these genes exist as a recurrent co-regulated network in colon cancer specimens. Sets of genes involved in programmed cell death, cell cycle regulation and interestingly the microRNA pathway were found overrepresented in the network. Noteworthy, Par-4 overexpression decreased NF kappaB occupancy at the promoter of one particular network gene DROSHA, encoding a microRNA processing enzyme. The resulting down-regulation of DROSHA was associated with expression changes in a cohort of microRNAs. Many of these microRNAs are predicted to target mRNAs encoding proteins with apoptosis-related functions. Western and functional analyses were employed to validate several predictions. For instance, miR-34a up-regulation corresponded with a down-regulation of BCL2 protein. Treating Par-4-overexpressing HT29 cells with a miR-34a antagomir functionally reversed both BCL2 down-regulation and apoptosis by 5-FU. Conversely, bypassing Par-4 overexpression by direct knockdown of DROSHA expression in native HT29 cells increased miR-34a expression and 5-FU sensitivity. Our findings suggest that the initiation of apoptotic sensitivity in colon cancer cells can be mediated by Par-4 binding to NF kappaB in the cytoplasm with consequential changes in the expression of microRNA pathway components.


Minimizing transfusions in primary cranial vault remodeling: the role of aminocaproic acid.
Cranial vault remodeling (CVR) for craniosynostosis is a procedure with the potential for significant blood loss. Aminocaproic acid (ACA) has been used at our institution during CVR for its antifibrinolytic effects. The purpose of this study was to investigate the effect of ACA on blood loss and transfusion rates during primary CVR. Three hundred eighty-three patients with craniosynostosis underwent primary CVR at a single institution by a single surgeon over 15 years. Patients were included if they received either ACA or no antifibrinolytic. The estimated blood loss (EBL) and volume of blood transfused was recorded. Thrombotic-related complications were identified. Comparisons were made between subgroups using independent Student t test and Fisher exact test. Among the study population, 148 patients met inclusion criteria. ACA was given to 30 patients, while 118 patients received no antifibrinolytic. There was no difference in the average intraoperative EBL between the ACA (322 mL) and control groups (327 mL, P > 0.05). Additionally, the incidence of transfusion was not significantly different between subgroups (97% vs. 86%, respectively, P > 0.05). Patients treated with ACA, however, received lower average perioperative transfusion volumes (25.5 mL/kg) compared to control patients (53.3 mL/kg, P < 0.0001). Furthermore, patients in the ACA subgroup were less likely to require a second unit of blood (21% vs. 43%, P < 0.0001) and therefore had fewer exposures to donor blood antigens (ARR = 22%, NNT = 4.6). The use of intraoperative ACA minimizes blood transfusion volumes and donor exposures in children who undergo primary CVR for craniosynostosis. Antifibrinolytics should be considered for routine use in pediatric craniofacial surgery.


Risk factors of recurrence of macular oedema associated with branch retinal vein occlusion after intravitreal bevacizumab injection.
To identify risk factors of recurrence of macular oedema in branch retinal vein occlusion (BRVO) after intravitreal bevacizumab (IVB) injection. The records of 63 patients who underwent IVB injection for macular oedema secondary to BRVO with at least 6 months of follow-up were reviewed. Patients were evaluated at baseline with fluorescein angiography (FA), optical coherence tomography (OCT) and ultra-wide-field fundus photography (WFP). During follow-up, OCT and WFP were repeated. The area of retinal haemorrhage, central retinal thickness (CRT), area (mm2) of capillary non-perfusion within the 1 mm (NPA1), 1-3 mm and 6 mm zones of the ETDRS circle, foveal capillary filling time, degree (°) of foveal capillary network destruction and FA pattern were analysed. Macular oedema recurred in 41 of 63 (65.1%) eyes after initial IVB injection. A binary logistic regression model showed that NPA1 (OR=434.97; 95% CI=5.52 to 34262.12, p=0.006) and initial CRT (OR=1.004; 95% CI=1.000 to 1.008, p=0.015) were significantly associated with the recurrence of macular oedema. Receiver operating characteristic curve analysis identified an NPA1 of 0.36 mm2 (AUC: 0.735, sensitivity: 70.7%; specificity: 63.6%) and an initial CRT of 570 µm (AUC: 0.745, sensitivity: 63.4%; specificity: 77.3%) as cut-off values for predicting recurrence of macular oedema. Patients with BRVO with non-perfusion of more than half of the 1 mm zone of the ETDRS circle or with an initial CRT >570 µm should be closely monitored for macular oedema recurrence within 6 months of IVB injection.


The relationship between maternal psychopathology and parental perceptions of their children's reactions in survivors of the 1998 US Embassy bombing in Nairobi, Kenya.
The increase in terrorism worldwide has stimulated research on directly and indirectly exposed survivors, but there have been few investigations of the children of highly exposed survivors. This study examined the relationship between parental psychopathology and outcomes in their children who were exposed indirectly to a terrorist incident through their parents' exposures. Eight to 10 months after the 1998 US Embassy bombing in Nairobi, Kenya, 280 survivors were interviewed about themselves and their 611 children using the Diagnostic Interview Schedule for DSM-IV to perform a full diagnostic assessment of survivors' pre- and post-disaster psychiatric disorders. The Disaster Supplement was used to obtain information about the survivors' demographics and disaster experiences and their children's disaster-related experiences. Survivors who experienced high rates of post-disaster psychiatric disorders reported that their children had low levels of disasterrelated posttraumatic stress symptoms, post-disaster behavior problems, and changes in school functioning. Only maternal psychopathology predicted adverse outcomes in survivors' children. The relationship between maternal psychopathology and youth outcomes has important clinical implications. Clinicians working with disaster survivors should ask individuals about their children routinely, refer family members-including children-for assessment and services as indicated, and offer child-oriented and/or family-focused interventions when appropriate.


Tissue distribution and pharmacokinetics of 3-t-[methyl-14C] butyl-4-hydroxyanisole in rats.
Tissue distribution and pharmacokinetics of 3-t-[methyl-14C]butyl-4-hydroxyanisole was studied in male rats. 3-t-[methyl-14C]butyl-4-hydroxyanisole was administered by gavage at a single dose of 1.5 mmol/kg. Urine, feces, blood, and 20 major tissues were collected at 0.5, 1, 3, 6, 12, 16, 17, 18, 24, 48, 72, 168, and 240 hr after dosing and were analyzed for radioactivity. Almost all radioactivity was eliminated from rats in 48 hrs. Forty one per cent of the administered dose was recovered in urine, while feces accounted for 53%. At early time points radioactivity was mainly found in gastrointestinal tissues with concentrations remaining high up to 16-18 hr after administration indicating a slow absorption and elimination of the compound. The maximum concentration of radiolabel in kidney, liver, bladder, spleen, heart, pancreas, and brain was reached at 6 hr and remained up to 24 hr. The concentration of radioactivity in liver and kidney was approximately 10-fold higher than other tissues at the peak time of 16-18 hrs. Calculated absorption and elimination rate constants demonstrated slow uptake and clearance of label by many tissues. Covalent binding in eight representative tissues at 10 time points was also studied. Results indicate that binding increases slowly and exponentially with time reaching maximum levels at 12-24 hr in most of the tissues followed by a slow decline with time.


'Ad Diction Ary' of drug users' terms.
Physicians obtain information by verbally communicating with patients. But communication is frequently impaired for varied reasons. Often, physicians and patients speak different languages, even when both use English as their vernacular. Intravenous drug users have their own way of referring to their lifestyle and habits. Without understanding the terms they use, the physician will have difficulty appreciating the course of events leading up to a disease. Terms unique to the drug culture, or terms that have a different meaning to drug users than they do to the general public are defined herein. This special lexicon is the culmination of the author's 5-year file-card collection of terms.


Impulsivity and cigarette smoking: delay discounting in current, never, and ex-smokers.
Impulsivity is implicated in drug dependence. Recent studies show problems with alcohol and opioid dependence are associated with rapid discounting of the value of delayed outcomes. Furthermore, discounting may be particularly steep for the drug of dependence. We determined if these findings could be extended to the behavior of cigarette smokers. In particular, we compared the discounting of hypothetical monetary outcomes by current, never, and ex-smokers of cigarettes. We also examined discounting of delayed hypothetical cigarettes by current smokers. Current cigarette smokers (n=23), never-smokers (n=22) and ex-smokers (n=21) indicated preference for immediate versus delayed money in a titration procedure that determined indifference points at various delays. The titration procedure was repeated with cigarettes for smokers. The degree to which the delayed outcomes were discounted was estimated with two non-linear decay models: an exponential model and a hyperbolic model. Current smokers discounted the value of delayed money more than did the comparison groups. Never- and ex-smokers did not differ in their discounting of money. For current smokers, delayed cigarettes lost subjective value more rapidly than delayed money. The hyperbolic equation provided better fits to the data than did the exponential equation for 74 out of 89 comparisons. Cigarette smoking, like other forms of drug dependence, is characterized by rapid loss of subjective value for delayed outcomes, particularly for the drug of dependence. Never- and ex-smokers could discount similarly because cigarette smoking is associated with a reversible increase in discounting or due to selection bias.


Parallel phase-shifting digital holographic microscopy.
We propose parallel phase-shifting digital holographic microscopy (PPSDHM) which has the ability of three-dimensional (3-D) motion measurement using space-division multiplexing technique. By the PPSDHM, instantaneous information of both the 3-D structure and the phase distributions of specimens can be simultaneously acquired with a single-shot exposure. We constructed a parallel phase-shifting digital holographic microscope consisting of an optical interferometer and an image sensor on which micro polarizers are attached pixel by pixel. The validity of the PPSDHM was experimentally verified by demonstrating the single-shot 3-D imaging and phase-imaging ability of the constructed microscope.


Environmental impact assessment of Gonabad municipal waste landfill site using Leopold Matrix.
An environmental impact assessment (EIA) before embarking on any project is a useful tool to reduce the potential effects of each project, including landfill, if possible. The main objective of this study was to assess the environmental impact of the current municipal solid waste disposal site of Gonabad by using the Iranian Leopold matrix method. This cross-sectional study was conducted to assess the environmental impacts of a landfill site in Gonabad in 2015 by an Iranian matrix (modified Leopold matrix). This study was conducted based on field visits of the landfill, and collected information from various sources and analyzing and comparing between five available options, including the continuation of the current disposal practices, construction of new sanitary landfills, recycling plans, composting, and incineration plants was examined. The best option was proposed to replace the existing landfill. The current approach has a score of 2.35, the construction of new sanitary landfill has a score of 1.59, a score of 1.57 for the compost plant, and recycling and incineration plant, respectively, have scores of 1.68 and 2.3. Results showed that continuation of the current method of disposal, due to severe environmental damage and health problems, is rejected. A compost plant with the lowest negative score is the best option for the waste disposal site of Gonabad City and has priority over the other four options.


Molecular dynamics study of naturally existing cavity couplings in proteins.
Couplings between protein sub-structures are a common property of protein dynamics. Some of these couplings are especially interesting since they relate to function and its regulation. In this article we have studied the case of cavity couplings because cavities can host functional sites, allosteric sites, and are the locus of interactions with the cell milieu. We have divided this problem into two parts. In the first part, we have explored the presence of cavity couplings in the natural dynamics of 75 proteins, using 20 ns molecular dynamics simulations. For each of these proteins, we have obtained two trajectories around their native state. After applying a stringent filtering procedure, we found significant cavity correlations in 60% of the proteins. We analyze and discuss the structure origins of these correlations, including neighbourhood, cavity distance, etc. In the second part of our study, we have used longer simulations (≥100 ns) from the MoDEL project, to obtain a broader view of cavity couplings, particularly about their dependence on time. Using moving window computations we explored the fluctuations of cavity couplings along time, finding that these couplings could fluctuate substantially during the trajectory, reaching in several cases correlations above 0.25/0.5. In summary, we describe the structural origin and the variations with time of cavity couplings. We complete our work with a brief discussion of the biological implications of these results.


In vitro effects of the active metabolite of leflunomide, A77 1726, on feline herpesvirus-1.
To determine whether the active metabolite of leflunomide, A77 1726 (A77), inhibits replication of feline herpesvirus-1 (FHV-1) in cell culture. Crandell Rees feline kidney (CRFK) cell cultures. Cell cultures were inoculated with FHV-1 and treated simultaneously with concentrations of A77 ranging from 0 to 200microM. The antiviral effect of A77 was determined by use of conventional plaque reduction assays. The effect of A77 on viral load was determined via real-time PCR analysis, and transmission electron microscopy was used to evaluate the effect of A77 on viral morphology. To determine whether the antiviral effect was attributable to alterations in CRFK cell viability and number, CRFK cells were treated with various concentrations of A77 and stained with Annexin V and propidium iodide to assess apoptosis and a mitochondrial function assay was used to determine cell viability. Concentrations of A77 > or = 20microM were associated with substantial reduction in plaque number and viral load. Concentrations > or = 100microM were associated with complete suppression of plaque formation. At low concentrations of A77, clusters of intracytoplasmic virus particles that appeared to lack tegument and an external membrane were detected. Treatment of uninfected CRFK cell monolayers with A77 was associated with reduction in mitochondrial function with minimal evidence of apoptosis. Leflunomide may be an alternative to current calcineurin-based immunosuppressive protocols used in feline organ transplantation because of its antiherpesviral activity.


A case of human strongyloidosis apparently contracted from asymptomatic colony dogs.
A 63-year-old, white, animal caretaker suffered intermittent abdominal pain and diarrhea of 3 weeks duration. Hematological findings included leukocytosis (18,600) with eosinophilia (73%). Fecal examination revealed Stongyloides rhabditiform larvae which on culture yielded a preponderance of filariform larvae and a few free-living adults. Thiabendazole therapy resulted in rapid recovery. Epidemiological investigation yielded no history of previous Strongyloides infection or exposure; his wife and pet dog were not infected, but about one-third of the dogs in the colony under his care were found to be discharging Stongyloides rhaditiform larvae in their feces. Strongyloides infection was successfully trasmitted to specific pathogen-free pups using filariform larvae derived both from the human case and from the dog colony. Specimens recovered from one pup infected with filariform larvae of human origin were identified as Strongyloides stercoralis.


Smart nanogels at the air/water interface: structural studies by neutron reflectivity.
The development of effective transdermal drug delivery systems based on nanosized polymers requires a better understanding of the behaviour of such nanomaterials at interfaces. N-Isopropylacrylamide-based nanogels synthesized with different percentages of N,N'-methylenebisacrylamide as cross-linker, ranging from 10 to 30%, were characterized at physiological temperature at the air/water interface, using neutron reflectivity (NR), with isotopic contrast variation, and surface tension measurements; this allowed us to resolve the adsorbed amount and the volume fraction of nanogels at the interface. A large conformational change for the nanogels results in strong deformations at the interface. As the percentage of cross-linker incorporated in the nanogels becomes higher, more rigid matrices are obtained, although less deformed, and the amount of adsorbed nanogels is increased. The data provide the first experimental evidence of structural changes of nanogels as a function of the degree of cross-linking at the air/water interface.


Accessing Reliable Health Information on the Web: A Review of the HON Approach.
Accessing online health content of high quality and reliability presents challenges. Laypersons cannot easily differentiate trustworthy content from misinformed or manipulated content. This article describes complementary approaches for members of the general public and health professionals to find trustworthy content with as little bias as possible. These include the Khresmoi health search engine (K4E), the Health On the Net Code of Conduct (HONcode) and health trust indicator Web browser extensions.


Bone mass and dementia in hip fracture patients from areas with different aluminium concentrations in water supplies.
The relationship between bone mass and dementia in elderly hip fracture patients from areas with different aluminium concentrations in water supplies has been investigated, to determine whether a high concentration of aluminium in the drinking water and the negative calcium balance of age-related osteoporosis together predispose to senile dementia. Mental test scores were recorded on admission to hospital, and Singh indices of radiographs taken at that time assessed blind by a single trained observer. No significant difference in either mental test score (chi 2 = 1.253, df = 2, P = 0.53) or Singh index (chi 2 = 1.039, df = 5, P = 0.96) was found between patients resident in high versus low water aluminum areas. No correlation was detectable between mental test score and Singh index (chi 2 = 0.95, df = 1, P = 0.33).


Agreeableness, conscientiousness, and psychoticism: distinctive influences of three personality dimensions in adolescence.
Researchers have suggested that the psychoticism (P) personality dimension of the Eysenck Personality Questionnaire may be largely redundant with the agreeableness (A) and conscientiousness (C) constructs of the five-factor model. Little research has examined the distinctiveness of these constructs. We utilized a multi-wave, multi-method design to examine the ability of C, A, and P to uniquely predict a number of important outcomes amongst high school students. A total of 778 students (391 males, 387 females; mean age 15.41 years.) completed personality measures in Grade 10. Self-reported self-esteem, social support, health-related behaviours, religious values as well as teachers' assessments of students, were collected 1 and 2 years later. A, C, and P were distinctive in their ability to predict these outcomes, after controlling for gender and socio-economic status as well as Grade 10 extraversion, openness, and neuroticism. The individual P items explained unique variance over and above that explained by A and C. It was concluded that P is not merely the opposite of A and C. Implications for interventions are raised.


Music and language side by side in the brain: a PET study of the generation of melodies and sentences.
Parallel generational tasks for music and language were compared using positron emission tomography. Amateur musicians vocally improvised melodic or linguistic phrases in response to unfamiliar, auditorily presented melodies or phrases. Core areas for generating melodic phrases appeared to be in left Brodmann area (BA) 45, right BA 44, bilateral temporal planum polare, lateral BA 6, and pre-SMA. Core areas for generating sentences seemed to be in bilateral posterior superior and middle temporal cortex (BA 22, 21), left BA 39, bilateral superior frontal (BA 8, 9), left inferior frontal (BA 44, 45), anterior cingulate, and pre-SMA. Direct comparisons of the two tasks revealed activations in nearly identical functional brain areas, including the primary motor cortex, supplementary motor area, Broca's area, anterior insula, primary and secondary auditory cortices, temporal pole, basal ganglia, ventral thalamus, and posterior cerebellum. Most of the differences between melodic and sentential generation were seen in lateralization tendencies, with the language task favouring the left hemisphere. However, many of the activations for each modality were bilateral, and so there was significant overlap. While clarification of this overlapping activity awaits higher-resolution measurements and interventional assessments, plausible accounts for it include component sharing, interleaved representations, and adaptive coding. With these and related findings, we outline a comparative model of shared, parallel, and distinctive features of the neural systems supporting music and language. The model assumes that music and language show parallel combinatoric generativity for complex sound structures (phonology) but distinctly different informational content (semantics).


Partial-response equalization in magneto-optical disk readout: a theoretical investigation.
We analyze the application of partial-response equalization and maximum-likelihood sequence estimation in magneto-optical readout. Two filters are proposed, and several aspects of their performance are examined. Filter I has 8 states in its state-transition diagram and is therefore easier to implement than filter II, which has 32 states. We discuss the required signal-to-noise ratio as function of the recorded bit density for these filters. The effects of jitter and bloom on the eye patterns of the output signals are also examined by computer simulation. This analysis indicates that filter II is somewhat superior to filter I, presumably because the output of filter II is more similar to the actual readout signal. We determine the distribution of Euclidean distance between pairs of output sequences and compute upper bounds on the probability of sequence error for both filters. Using two different methods of precoding (i.e., mapping of the user data to the magnetic pattern on the disk), we also compute the probability of bit error for the user data and show that one precoding scheme is slightly better than the other.


Hanseniaspora jakobsenii sp. nov., a yeast isolated from Bandji, a traditional palm wine of Borassus akeassii.
Investigation of the microbial diversity of Bandji, a traditional palm wine from Burkina Faso (West Africa) revealed the presence of two yeast isolates (YAV16 and YAV17T) with unusual phenotypic and genotypic characteristics. The isolates divide by bipolar budding with no production of ascospores. Phylogenetic analysis of concatenated sequences of the 26S rRNA gene D1/D2 and internal transcribed spacer (ITS) regions indicated that the novel species was most closely related to Kloeckera lindneri and Hanseniaspora valbyensis. The new isolates differed from K. lindneri NRRL Y-17531T and H. valbyensis CBS 479T by substitutions in the D1/D2 region of 12 and 16 nt respectively. The divergence in the ITS region from the closely related species was characterized by substitutions of 45-46 nt. Repetitive palindromic PCR (rep-PCR) profiles of YAV16 and YAV17T were also significantly different from those of K. lindneri MUCL 31146T ( = NRRL Y-17531T), H. valbyensis NCYC 17T ( = CBS 479T) and other species of the genus Hanseniaspora. Based on the results of the phenotypic and genotypic characterizations, it was concluded that the new isolates represent a novel species for which the name Hanseniaspora jakobsenii sp. nov. is proposed with YAV17T ( = CBS 12942T = DSM 26339T = NCYC 3828T; MycoBank number MB 805785) as the type strain.


Plasmodium vivax mdr1 genotypes in isolates from successfully cured patients living in endemic and non-endemic Brazilian areas.
Plasmodium vivax is the most widely distributed species causing the highest number of malaria cases in the world. In Brazil, P. vivax is responsible for approximately 84 % of reported cases. In the absence of a vaccine, control strategies are based on the management of cases through rapid diagnosis and adequate treatment, in addition to vector control measures. The approaches used to investigate P. vivax resistance to chloroquine (CQ) were exclusively in vivo studies because of the difficulty in keeping parasites in continuous in vitro culture. In view of the limitations related to follow-up of patients and to assessing the plasma dosage of CQ and its metabolites, an alternative approach to monitor chemo-resistance (QR) is to use molecular markers. Single nucleotide polymorphisms (SNPs) in the multidrug resistance gene pvmdr1 are putative determinants of CQ resistance (CQR), but such SNPs in P. vivax isolates from patients with good response to treatment should be further explored. The aim of this study is to investigate the mutations in the gene, supposedly associated to QR, in P. vivax isolates from successfully cured patients, living in Brazilian endemic and non-endemic areas. Blood samples were collected from 49 vivax malaria patients from endemic (Amazon Basin: 45) and non-endemic (Atlantic Forest: four) Brazilian regions and analysed for SNPs in the CQR-related P. vivax gene (pvmdr1), using PCR-based methods. Among the 49 isolates genetically characterized for the gene pvmdr1, 34 (70 %) presented at least one mutation. T958M mutant alleles were the most frequent (73 %) followed Y976F (15 %) and F1076L (12 %). Single mutation was detected in 24 (70.5 %) isolates and double mutations in ten (29.5 %). The most common single mutant genotype was the 958M/Y976/F1076 (79 %), followed by 976F/F1076 (21 %) whereas 958M/Y976/1076L (60 %) and 976F/1076L (40 %) double mutant genotypes were detected. Single mutant profile was observed only in isolates from Amazon Basin, although double mutants were found both in the Amazon and Atlantic Forest regions. Interestingly, the genotype 958M/Y976/1076L was present in all isolates from the Atlantic Forest in the Rio de Janeiro State. Considering that primaquine (PQ) efficacy is highly dependent on concurrent administration of a blood schizontocidal agent and that PQ could not circumvent CQR, together with the fact that no pvmdr1 mutation should be expected in successfully cured patients, these findings seem to indicate that the pvmdr1 gene is not a reliable marker of CQR. Further investigations are needed to define a reliable molecular marker for monitoring P. vivax CQR in P. vivax populations.


Microeconomics. Harnessing naturally occurring data to measure the response of spending to income.
This paper presents a new data infrastructure for measuring economic activity. The infrastructure records transactions and account balances, yielding measurements with scope and accuracy that have little precedent in economics. The data are drawn from a diverse population that overrepresents males and younger adults but contains large numbers of underrepresented groups. The data infrastructure permits evaluation of a benchmark theory in economics that predicts that individuals should use a combination of cash management, saving, and borrowing to make the timing of income irrelevant for the timing of spending. As in previous studies and in contrast to the predictions of the theory, there is a response of spending to the arrival of anticipated income. The data also show, however, that this apparent excess sensitivity of spending results largely from the coincident timing of regular income and regular spending. The remaining excess sensitivity is concentrated among individuals with less liquidity.


The Arabidopsis mediator subunit MED25 differentially regulates jasmonate and abscisic acid signaling through interacting with the MYC2 and ABI5 transcription factors.
Transcriptional regulation plays a central role in plant hormone signaling. At the core of transcriptional regulation is the Mediator, an evolutionarily conserved, multisubunit complex that serves as a bridge between gene-specific transcription factors and the RNA polymerase machinery to regulate transcription. Here, we report the action mechanisms of the MEDIATOR25 (MED25) subunit of the Arabidopsis thaliana Mediator in regulating jasmonate- and abscisic acid (ABA)-triggered gene transcription. We show that during jasmonate signaling, MED25 physically associates with the basic helix-loop-helix transcription factor MYC2 in promoter regions of MYC2 target genes and exerts a positive effect on MYC2-regulated gene transcription. We also show that MED25 physically associates with the basic Leu zipper transcription factor ABA-INSENSITIVE5 (ABI5) in promoter regions of ABI5 target genes and shows a negative effect on ABI5-regulated gene transcription. Our results reveal that underlying the distinct effects of MED25 on jasmonate and ABA signaling, the interaction mechanisms of MED25 with MYC2 and ABI5 are different. These results highlight that the MED25 subunit of the Arabidopsis Mediator regulates a wide range of signaling pathways through selectively interacting with specific transcription factors.


Double immunoenzymatic detection of surface phenotype of proliferating lymphocytes in situ with monoclonal antibodies against DNA polymerase alpha and lymphocyte membrane antigens.
To detect the proliferating cells in situ, a monoclonal antibody against human DNA polymerase alpha (pol alpha) was employed because this enzyme is known to be present in the nucleus of the cells in G1, S, and G2 phases. In addition, the surface phenotype of pol alpha-positive proliferating lymphocytes in diseased lymph nodes was determined by double staining consisting of immunoperoxidase and immunoalkaline phosphatase methods with various monoclonal antibodies against lymphocyte membrane antigens. In the paracortical area of lymph nodes with reactive changes, proliferating cells were 17% or less, and most of them were helper T-cells, although suppressor T-cells and B-cells also proliferate to a certain extent. In contrast, the proliferating cell population in malignant lymphomas was generally more than 40%, and it showed a single surface phenotype, indicating monoclonal proliferation. In addition, an unusual T-cell antigen phenotype of proliferating cells was observed in some cases of peripheral T-cell lymphomas. Thus, this double staining provided the authors with valuable information regarding the proportion, localization, and surface phenotype of proliferating cells, which should be useful for diagnosis of the diseases of lymphoid system.


Primary stage of feline immunodeficiency virus infection: viral dissemination and cellular targets.
The objective of this study was to identify cellular and organ targets of acute feline immunodeficiency virus (FIV) infection in vivo. Tissues of FIV-infected cats were studied at eight time points during the first 3 months after experimental infection. FIV nucleic acids were first detected by in situ hybridization 21 days after infection, approximately 1.5 weeks after lymph node enlargement was first observed and 3 weeks before the primary acute flu-like illness. The majority of FIV-infected cells were present in lymphoid organs, though low numbers of infected cells were noted in nonlymphoid organs as well. Germinal centers harbored many of the FIV-infected cells within lymphoid tissues. The thymic cortex was also a major site of early infection. Combined in situ hybridization and immunohistochemistry revealed that T lymphocytes were the primary target of early FIV infection in tissues of cats before the onset of clinical signs of acute illness. An unidentified population of mononuclear cells and a few macrophages were also infected. During the ensuing acute flu-like illness, the proportion of FIV-infected macrophages in tissues increased dramatically. This early shift in the predominant cellular localization of FIV from T lymphocytes to macrophages may be important for establishing viral persistence.


The reproducibility of measurements of intramuscular magnesium concentrations and muscle oxidative capacity using 31P MRS.
31P magnetic resonance spectroscopy (31P MRS) has been used to measure intramuscular magnesium concentrations and muscle metabolism. Abnormal intramuscular magnesium has been reported in several patient populations with suspected metabolic disorders. The purpose of this study was to evaluate our ability to measure intramuscular magnesium and muscle metabolism in the quadriceps muscles of healthy subjects, and to test whether these measurements were influenced by prior exercise. Twelve normal, healthy male volunteers were tested in a 3 Tesla magnet on four separate days. Resting [Mg2+] was calculated from the heights and frequency shifts of the phosphate, phosphocreatine and ATP peaks. Phosphocreatine (PCr) recovery kinetics were measured after 30-39 second bouts of isometric exercise. Thirty minutes prior to the 3rd test session the subjects completed a 2 hour treadmill walk at 40-60% of heart rate reserve. Resting [Mg2+] averaged 0.388 mM and had an interclass correlation coefficient between days (ICC) of 0.352. The mean end exercise PCr was 47.6% and the mean end exercise pH was 6.97. PCr recovery averaged 39 seconds (p = 0.892) and had an ICC of 0.819. Prior long duration exercise did not produce significant alterations in either PCr recovery kinetics or intracellular magnesium levels (p = 0.440). In conclusion, the reproducibility of Resting [Mg2+] was less than that of PCr recovery measurements, and may reflect the sensitivity of these measurements to phasing errors. In addition, prior exercise is unlikely to alter measurements of resting metabolites or muscle metabolism suggesting that rigorous control of physical activity prior to metabolic testing is unnecessary.


Examining the use of telehealth in community nursing: identifying the factors affecting frontline staff acceptance and telehealth adoption.
To examine frontline staff acceptance of telehealth and identify barriers to and enablers of successful adoption of remote monitoring for patients with Chronic Obstructive Pulmonary Disease and Chronic Heart Failure. The use of telehealth in the UK has not developed at the pace and scale anticipated by policy. Many existing studies report frontline staff acceptance as a key barrier, however data are limited and there is little evidence of the adoption of telehealth in routine practice. Case studies of four community health services in England that use telehealth to monitor patients with Chronic Obstructive Pulmonary Disease and Chronic Heart Failure. Thematic analysis of qualitative interviews with 84 nursing and other frontline staff; and 21 managers and key stakeholders; data collected May 2012-June 2013. Staff attitudes ranged from resistance to enthusiasm, with varied opinions about the motives for investing in telehealth and the potential impact on nursing roles. Having reliable and flexible technology and dedicated resources for telehealth work were identified as essential in helping to overcome early barriers to acceptance, along with appropriate staff training and a partnership approach to implementation. Early successes were also important, encouraging staff to use telehealth and facilitating clinical learning and increased adoption. The mainstreaming of telehealth hinges on clinical 'buy-in'. Where barriers to successful implementation exist, clinicians can lose faith in using technology to perform tasks traditionally delivered in person. Addressing barriers is therefore crucial if clinicians are to adopt telehealth into routine practice.


Evaluation of a 4-protein serum biomarker panel-biglycan, annexin-A6, myeloperoxidase, and protein S100-A9 (B-AMP)-for the detection of esophageal adenocarcinoma.
Esophageal adenocarcinoma (EAC) is associated with a dismal prognosis. The identification of cancer biomarkers can advance the possibility for early detection and better monitoring of tumor progression and/or response to therapy. The authors present results from the development of a serum-based, 4-protein (biglycan, myeloperoxidase, annexin-A6, and protein S100-A9) biomarker panel for EAC. A vertically integrated, proteomics-based biomarker discovery approach was used to identify candidate serum biomarkers for the detection of EAC. Liquid chromatography-tandem mass spectrometry analysis was performed on formalin-fixed, paraffin-embedded tissue samples that were collected from across the Barrett esophagus (BE)-EAC disease spectrum. The mass spectrometry-based spectral count data were used to guide the selection of candidate serum biomarkers. Then, the serum enzyme-linked immunosorbent assay data were validated in an independent cohort and were used to develop a multiparametric risk-assessment model to predict the presence of disease. With a minimum threshold of 10 spectral counts, 351 proteins were identified as differentially abundant along the spectrum of Barrett esophagus, high-grade dysplasia, and EAC (P<.05). Eleven proteins from this data set were then tested using enzyme-linked immunosorbent assays in serum samples, of which 5 proteins were significantly elevated in abundance among patients who had EAC compared with normal controls, which mirrored trends across the disease spectrum present in the tissue data. By using serum data, a Bayesian rule-learning predictive model with 4 biomarkers was developed to accurately classify disease class; the cross-validation results for the merged data set yielded accuracy of 87% and an area under the receiver operating characteristic curve of 93%. Serum biomarkers hold significant promise for the early, noninvasive detection of EAC.


Low multiplicity of infection of Helicobacter pylori suppresses apoptosis of B lymphocytes.
Helicobacter pylori infection of the human stomach causes chronic gastritis that can lead to gastric cancer. Because activated lymphocytes persist in the gastric mucosa, and because a high multiplicity of infection (MOI) of H. pylori is needed to induce apoptosis in vitro, we speculated that resistance of lymphocytes to apoptosis is an important feature of the immune response to H. pylori. Freshly isolated mouse splenocytes underwent substantial spontaneous apoptosis and displayed a biphasic response to H. pylori, in which low MOI (1-10) markedly inhibited apoptosis, whereas high MOI (> or =75) potentiated apoptosis. Low MOI reduced mitochondrial membrane depolarization, caspase-3 and caspase-9 activation, and cytochrome c release and increased Bcl-2 levels. Low MOI also induced cellular proliferation. When cells were subjected to fluorescence-activated cell sorting after coculture with H. pylori, CD19+ B cells were found to be protected from apoptosis and undergoing proliferation at low MOI, whereas CD3+ T cells did not exhibit this pattern. The protective effect of low MOI on apoptosis persisted even when B cells were isolated before activation. Immunophenotyping showed that all B-cell subsets examined were protected from apoptosis at low MOI. Additionally, gastric infection with H. pylori resulted in protection of splenic B cells from spontaneous apoptosis. Our results suggest that the low levels of H. pylori infection that occur in vivo are associated with B-cell survival and proliferation, consistent with their potential to evolve into mucosa-associated lymphoid tissue lymphoma.


Equipment-related incidents in the operating room: an analysis of occurrence, underlying causes and consequences for the clinical process.
Equipment-related incidents in the operating room (OR) can affect quality of care. In this study, the authors determined the occurrence and effects on the care process in a large teaching hospital. During a 4-week period, OR nurses reported equipment-related incidents during surgery procedures in both locations of the hospital. The incidents were reported using a separate form for each incident. A structured analysis (PRISMA) was used to analyse incidents that resulted in serious delays (>15 min). Forms were returned for 911 out of 1580 surgeries (57.7%). In total, 148 incidents were registered, relating to a total of 29 h and 45 min of extra work. In addition, 12 h and 9 min of operational delay was registered. Most incidents involved instruments (46%) or medical devices (28%). 68% occurred during surgery and 32% during the preparation phase. No direct physical harm was reported, although indirect harm, like longer anaesthesia, did occur and can be defined as an adverse event. 10% of the incidents led to a delay of over 15 min. For these incidents, 'management decisions' (eg, inventory capacity, planning procedure) was the most encountered root cause. Only six out of the 148 incidents found corresponded with the blame-free reporting database. Equipment-related incidents occurred frequently in the involved hospital sites (up to 15.9%) and resulted in some extra work and additional minutes of delay per event. Management decisions have considerable influence on the occurrence of equipment-related incidents. There was serious under-reporting of incidents.


Multiple Praziquantel Treatments of Schistosoma mansoni Egg-Negative, CCA-Positive Schoolchildren in a Very Low Endemic Setting in Egypt Do Not Consistently Alter CCA Results.
Forty-four Schistosoma mansoni egg-negative/circulating cathodic antigen (CCA) low-positive (trace or 1+) children in three districts of very low prevalence in Egypt were given three sequential praziquantel (PZQ) treatments. Stool and urine specimens were collected 3 months following the initial treatment, and 3 weeks following the second and following the third PZQ treatments, which were conducted 5 weeks apart. Stool specimens were examined by Kato-Katz (four slides/stool sample) and all S. mansoni egg-negative stools were further tested by the "miracidia hatching test" (MHT). Urine samples were examined by the point-of-care CCA assay (POC-CCA). Over the study period, all stool samples from study subjects remained S. mansoni egg negative and MHT negative. Of the POC-CCA test results, in the first day of the study 3 months following the initial treatment, 29.5% were negative, 61.4% CCA trace positives, and 9.1% CCA 1+ positives. Following each PZQ treatment, the test results fluctuated between 1+, trace, and negative, but did not consistently decrease. The proportions of POC-CCA-positive results obtained in the first day (70.5%) as compared with the last day of the study (72.7%) in all of the three districts were very similar. We conclude that CCA trace and 1+ readings, in Kato-Katz S. mansoni egg-negative children in this area with very low levels of intestinal schistosomiasis, are not consistently altered or rendered consistently negative following repeated PZQ treatments and are therefore likely to represent false-positive readings. This finding is of critical importance for countries such as Egypt as they approach elimination.


Comparison of low-dose CT with CT/CT fluoroscopy guidance in percutaneous sacral and supra-acetabular cementoplasty.
Percutaneous cementoplasty is a minimally invasive treatment modality for painful osteoporotic and pathologic sacral and supra-acetabular iliac fractures. This study compares the use of low-dose CT guidance with CT/CT fluoroscopy in sacral and supra-acetabular cementoplasty. A retrospective review of patients who had undergone sacral or supra-acetabular cementoplasty was performed with patients grouped by use of CT/CT fluoroscopy or low-dose CT guidance during the procedure. Parameters evaluated included type of fracture, laterality of lesions, pain scores, pain medication use, imaging parameters, procedure time, dose-length product, effective dose, cement volume, and complications. There were 17 patients identified who underwent cementoplasty utilizing dual CT/CT fluoroscopy, while 13 patients had their procedures performed with low-dose CT. There was a statistically significant decrease in radiation dose in the low-dose CT group (1481 mGy•cm) compared with the CT/CT fluoroscopy group (2809 mGy•cm) (P = 0.013). There was a significant decrease in procedure time with low-dose CT for bilateral lesions (P = 0.016). There was no significant difference between groups in complication rate (P = 0.999). Clinically nonsignificant cement extravasation occurred in two patients (10%) in the CT/CT fluoroscopy group and in one patient (8%) in the low-dose CT group (P = 0.999). There was a significant decrease in pain scores compared with baseline on the visual analogue scale in both groups at 1 week (low-dose CT P = 0.002, CT/CT fluoroscopy P = 0.008) and 1 month postprocedure (low-dose CT P = 0.014, CT/CT fluoroscopy P = 0.004), but no difference between groups at 1 day (P = 0.196), 1 week (P = 0.368), or 1 month (P = 0.514). Sacral and supra-acetabular cementoplasties can be performed safely and precisely using low-dose multiple-acquisition CT guidance while providing significant radiation dose reduction with no difference in extravasation rates, postprocedural pain reduction, and complications compared with CT/CT fluoroscopy.


Serum Potassium, End-Stage Renal Disease and Mortality in Chronic Kidney Disease.
Hypokalemia and hyperkalemia are often noted in chronic kidney disease (CKD) patients, but their impact on mortality and end-stage renal disease (ESRD) is less well understood. We aimed at studying the associations between potassium disorders, and mortality and progression to ESRD in a CKD population. Using our electronic health record-based CKD registry, 36,359 patients with eGFR <60 ml/min/1.73 m(2) and potassium levels measured from January 1, 2005 to September 15, 2009 were identified. We examined factors associated with hypokalemia (<3.5 mmol/l) and hyperkalemia (>5.0 mmol/l) using logistic regression models and associations between serum potassium levels (both as continuous and categorical variables) and all-cause mortality or ESRD using Cox-proportional hazards models. Serum potassium <3.5 mmol/l was noted among 3% and >5.0 mmol/l among 11% of the study population. In the multivariable logistic regression analysis, lower eGFR, diabetes and use of ACE inhibitors or Angiotensin-Receptor Blockers were associated with higher odds of having hyperkalemia. Heart failure and African American race were factors associated with higher odds of hypokalemia. After adjustment for covariates including kidney function, serum potassium <4.0 and >5.0 mmol/l were significantly associated with increased mortality risk, but there was no increased risk for progression to ESRD. Time-dependent repeated measures analysis confirmed these findings. When potassium was examined as a continuous variable, there was a U-shaped association between serum potassium levels and mortality. In patients with stage 3-4 CKD, serum potassium levels <4.0 and >5.0 mmol/l are associated with higher mortality but not with ESRD.


The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force.
There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.


How I Diagnose Low-Grade Myelodysplastic Syndromes.
Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms that are often difficult to diagnose due to their pathologic and clinical heterogeneity. The key features of MDS are peripheral blood cytopenias, ineffective hematopoiesis manifesting as morphologic dysplasia, and clonal genetic abnormalities. The most difficult diagnostic dilemmas often arise in low-grade MDS cases (lacking excess blasts), which can be difficult to distinguish from other causes of cytopenia. This distinction requires the integration of information from the peripheral blood (both CBC parameters and morphology), bone marrow morphology, genetic studies, and interrogation of the clinical record to exclude secondary causes. We discuss the approach to the diagnosis of low-grade MDS (cases lacking increased blasts), including a diagnostic algorithm and two illustrative cases. The appropriate use of ancillary studies is important to support or dispute the likelihood of low-grade MDS in conjunction with the findings of morphologic dysplasia. Interpreting the results of cytogenetics and next-generation sequencing can be challenging and must incorporate the emerging knowledge of clonal hematopoiesis of indeterminate potential. The role of pathologists in integrating data from multiple sources in the diagnosis of low-grade MDS is evolving and becoming increasingly complex; in this challenging diagnostic setting, it is important to feel comfortable with uncertainty and maintain a conservative approach.


The transcription factor Cux1 regulates dendritic morphology of cortical pyramidal neurons.
In the murine cerebral cortex, mammalian homologues of the Cux family transcription factors, Cux1 and Cux2, have been identified as restricted molecular markers for the upper layer (II-IV) pyramidal neurons. However, their functions in cortical development are largely unknown. Here we report that increasing the intracellular level of Cux1, but not Cux2, reduced the dendritic complexity of cultured cortical pyramidal neurons. Consistently, reducing the expression of Cux1 promoted the dendritic arborization in these pyramidal neurons. This effect required the existence of the DNA-binding domains, hence the transcriptional passive repression activity of Cux1. Analysis of downstream signals suggested that Cux1 regulates dendrite development primarily through suppressing the expression of the cyclin-dependent kinase inhibitor p27(Kip1), and RhoA may mediate the regulation of dendritic complexity by Cux1 and p27. Thus, Cux1 functions as a negative regulator of dendritic complexity for cortical pyramidal neurons.


Selective [1,4]-Hydrovinylation of 1,3-Dienes with Unactivated Olefins Enabled by Iron Diimine Catalysts.
The selective, intermolecular [1,4]-hydrovinylation of conjugated dienes with unactivated α-olefins catalyzed by α-diimine iron complexes is described. Value-added "skipped" diene products were obtained with exclusive [1,4]-selectivity, and the formation of branched, ( Z)-olefin products was observed with no evidence for alkene isomerization. Mechanistic studies conducted with the well-defined, single-component iron precatalyst (MesDI)Fe(COD) (MesDI = [2,4,6-Me3-C6H2-N═CMe]2); COD = 1,5-cyclooctadiene) provided insights into the origin of the high selectivity. An iron diene complex was identified as the catalyst resting state, and one such isoprene complex, (iPrDI)Fe(η4-C5H8), was isolated and characterized. A combination of single crystal X-ray diffraction, Mößbauer spectroscopy, magnetic measurements, and DFT calculations established that the complex is best described as a high-spin Fe(I) center ( SFe = 3/2) engaged in antiferromagnetic coupling to an α-diimine radical anion ( SDI = -1/2), giving rise to the observed S = 1 ground state. Deuterium-labeling experiments and kinetic analyses of the catalytic reaction provided support for a pathway involving oxidative cyclization of an alkene with the diene complex to generate an iron metallacycle. The observed selectivity can be understood in terms of competing steric interactions in the transition states for oxidative cyclization and subsequent β-hydrogen elimination.


Molecular Mechanisms of Acclimatization to Phosphorus Starvation and Recovery Underlying Full-Length Transcriptome Profiling in Barley (Hordeum vulgare L.).
A lack of phosphorus (P) in plants can severely constrain growth and development. Barley, one of the earliest domesticated crops, is extensively planted in poor soil around the world. To date, the molecular mechanisms of enduring low phosphorus, at the transcriptional level, in barley are still unclear. In the present study, two different barley genotypes (GN121 and GN42)-with contrasting phosphorus efficiency-were used to reveal adaptations to low phosphorus stress, at three time points, at the morphological, physiological, biochemical, and transcriptome level. GN121 growth was less affected by phosphorus starvation and recovery than that of GN42. The biomass and inorganic phosphorus concentration of GN121 and GN42 declined under the low phosphorus-induced stress and increased after recovery with normal phosphorus. However, the range of these parameters was higher in GN42 than in GN121. Subsequently, a more complete genome annotation was obtained by correcting with the data sequenced on Illumina HiSeq X 10 and PacBio RSII SMRT platform. A total of 6,182 and 5,270 differentially expressed genes (DEGs) were identified in GN121 and GN42, respectively. The majority of these DEGs were involved in phosphorus metabolism such as phospholipid degradation, hydrolysis of phosphoric enzymes, sucrose synthesis, phosphorylation/dephosphorylation and post-transcriptional regulation; expression of these genes was significantly different between GN121 and GN42. Specifically, six and seven DEGs were annotated as phosphorus transporters in roots and leaves, respectively. Furthermore, a putative model was constructed relying on key metabolic pathways related to phosphorus to illustrate the higher phosphorus efficiency of GN121 compared to GN42 under low phosphorus conditions. Results from this study provide a multi-transcriptome database and candidate genes for further study on phosphorus use efficiency (PUE).


Relationships between the firing of identified striatal interneurons and spontaneous and driven cortical activities in vivo.
The striatum is comprised of medium-sized spiny projection neurons (MSNs) and several types of interneuron, and receives massive glutamatergic input from the cerebral cortex. Understanding of striatal function requires definition of the electrophysiological properties of neurochemically identified interneurons sampled in the same context of ongoing cortical activity in vivo. To address this, we recorded the firing of cholinergic interneurons (expressing choline acetyltransferase; ChAT) and GABAergic interneurons expressing parvalbumin (PV) or nitric oxide synthase (NOS), as well as MSNs, in anesthetized rats during cortically defined brain states. Depending on the cortical state, these interneurons were partly distinguished from each other, and MSNs, on the basis of firing rate and/or pattern. During slow-wave activity (SWA), ChAT+ interneurons, and some PV+ and NOS+ interneurons, were tonically active; NOS+ interneurons fired prominent bursts but, contrary to investigations in vitro, these were not typical low-threshold spike bursts. Identified MSNs, and other PV+ and NOS+ interneurons, were phasically active. Contrasting with ChAT+ interneurons, whose firing showed poor brain state dependency, PV+ and NOS+ interneurons displayed robust firing increases and decreases, respectively, upon spontaneous or driven transitions from SWA to cortical activation. The firing of most neurons was phase locked to cortical slow oscillations, but only PV+ and ChAT+ interneurons also fired in time with cortical spindle and gamma oscillations. Complementing this diverse temporal coupling, each interneuron type exhibited distinct responses to cortical stimulation. Thus, these striatal interneuron types have distinct temporal signatures in vivo, including relationships to spontaneous and driven cortical activities, which likely underpin their specialized contributions to striatal microcircuit function.


Partner notification methods for African American men being treated for trichomoniasis: a consideration of main men, Second Hitters, and Third Players.
This pilot study sought information on African American men's preferences for partner notification methods for a common sexually transmitted infection called trichomoniasis. Two focus groups of African American men were convened at a public STI clinic where they were being treated for trichomoniasis. The groups identified a sexual hierarchy in men's preferences for methods of partner notification. The hierarchy consisted of main men (Cake Daddies), second men (Second Hitters), and third or fourth men (Third Players), with placement depending on age, income, and social status. Health department employees affirmed the existence of a sexual hierarchy in a separate focus group. Sexual and economic bartering formed the basis of the hierarchy, and the secrecy involved in such arrangements presented a considerable challenge for STI control. Disease intervention specialists who were responsible for contact tracing spoke of cat-and-mouse methods in contacting the men without understanding fully exactly how the hierarchy influenced men's responses to partner notification. The findings suggest that STI control efforts must take the sexual hierarchy and its privacy implications into account if partner notification methods are to be acceptable to African American men.


A dual role for integrin-linked kinase and β1-integrin in modulating cardiac aging.
Cardiac performance decreases with age, which is a major risk factor for cardiovascular disease and mortality in the aging human population, but the molecular mechanisms underlying cardiac aging are still poorly understood. Investigating the role of integrin-linked kinase (ilk) and β1-integrin (myospheroid, mys) in Drosophila, which colocalize near cardiomyocyte contacts and Z-bands, we find that reduced ilk or mys function prevents the typical changes of cardiac aging seen in wildtype, such as arrhythmias. In particular, the characteristic increase in cardiac arrhythmias with age is prevented in ilk and mys heterozygous flies with nearly identical genetic background, and they live longer, in line with previous findings in Caenorhabditis elegans for ilk and in Drosophila for mys. Consistent with these findings, we observed elevated β1-integrin protein levels in old compared with young wild-type flies, and cardiac-specific overexpression of mys in young flies causes aging-like heart dysfunction. Moreover, moderate cardiac-specific knockdown of integrin-linked kinase (ILK)/integrin pathway-associated genes also prevented the decline in cardiac performance with age. In contrast, strong cardiac knockdown of ilk or ILK-associated genes can severely compromise cardiac integrity, including cardiomyocyte adhesion and overall heart function. These data suggest that ilk/mys function is necessary for establishing and maintaining normal heart structure and function, and appropriate fine-tuning of this pathway can retard the age-dependent decline in cardiac performance and extend lifespan. Thus, ILK/integrin-associated signaling emerges as an important and conserved genetic mechanism in longevity, and as a new means to improve age-dependent cardiac performance, in addition to its vital role in maintaining cardiac integrity.


Species-specific influence of lithium on the activity of SLC13A5 (NaCT): lithium-induced activation is specific for the transporter in primates.
NaCT (SLC13A5) is a Na(+)-coupled transporter for Krebs cycle intermediates and is expressed predominantly in the liver. Human NaCT is relatively specific for citrate compared with other Krebs cycle intermediates. The transport activity of human NaCT is stimulated by Li(+), whereas that of rat NaCT is inhibited by Li(+). We studied the influence of Li(+) on NaCTs cloned from eight different species. Li(+) stimulated the activity of only NaCTs from primates (human, chimpanzee, and monkey); by contrast, NaCTs from nonprimate species (mouse, rat, dog, and zebrafish) were inhibited by Li(+). Caenorhabditis elegans NaCT was not affected by Li(+). With human NaCT, the Li(+)-induced increase in transport activity was associated with the conversion of the transporter from a low-affinity/high-capacity type to a high-affinity/low-capacity type. H(+) was able to substitute for Li(+) in eliciting the stimulatory effect. The amino acid Phe500 in human NaCT was critical for Li(+)/H(+)-induced stimulation. Mutation of this amino acid to tryptophan (F500W) markedly increased the basal transport activity of human NaCT in the absence of Li(+), but the ability of Li(+) to stimulate the transporter was almost completely lost with this mutant. Substitution of Phe500 with tryptophan in human NaCT converted the transporter from a low-affinity/high-capacity type to a high-affinity/low-capacity type, an effect similar to that of Li(+) on the wild-type NaCT. These studies show that Li(+)-induced activation of NaCT is specific for the transporter in primates and that the region surrounding Phe500 in primate NaCTs is important for the Li(+) effect.


The value from investments in health information technology at the U.S. Department of Veterans Affairs.
We compare health information technology (IT) in the Department of Veterans Affairs (VA) to norms in the private sector, and we estimate the costs and benefits of selected VA health IT systems. The VA spent proportionately more on IT than the private health care sector spent, but it achieved higher levels of IT adoption and quality of care. The potential value of the VA's health IT investments is estimated at $3.09 billion in cumulative benefits net of investment costs. This study serves as a framework to inform efforts to measure and calculate the benefits of federal health IT stimulus programs.


Autophagy maintains tumour growth through circulating arginine.
Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and to enable survival during starvation1-5. Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect that manifests as starvation intolerance and gradual loss of white adipose tissue, liver glycogen and muscle mass1. Cancer cells also benefit from autophagy. Deletion of essential autophagy genes impairs the metabolism, proliferation, survival and malignancy of spontaneous tumours in models of autochthonous cancer6,7. Acute, systemic deletion of Atg7 or acute, systemic expression of a dominant-negative ATG4b in mice induces greater regression of KRAS-driven cancers than does tumour-specific autophagy deletion, which suggests that host autophagy promotes tumour growth1,8. Here we show that host-specific deletion of Atg7 impairs the growth of multiple allografted tumours, although not all tumour lines were sensitive to host autophagy status. Loss of autophagy in the host was associated with a reduction in circulating arginine, and the sensitive tumour cell lines were arginine auxotrophs owing to the lack of expression of the enzyme argininosuccinate synthase 1. Serum proteomic analysis identified the arginine-degrading enzyme arginase I (ARG1) in the circulation of Atg7-deficient hosts, and in vivo arginine metabolic tracing demonstrated that serum arginine was degraded to ornithine. ARG1 is predominantly expressed in the liver and can be released from hepatocytes into the circulation. Liver-specific deletion of Atg7 produced circulating ARG1, and reduced both serum arginine and tumour growth. Deletion of Atg5 in the host similarly regulated [corrected] circulating arginine and suppressed tumorigenesis, which demonstrates that this phenotype is specific to autophagy function rather than to deletion of Atg7. Dietary supplementation of Atg7-deficient hosts with arginine partially restored levels of circulating arginine and tumour growth. Thus, defective autophagy in the host leads to the release of ARG1 from the liver and the degradation of circulating arginine, which is essential for tumour growth; this identifies a metabolic vulnerability of cancer.


RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes.
Damaged mitochondria generate an excess of superoxide, which may mediate tissue injury in diabetes. We hypothesized that in diabetic nephropathy, advanced glycation end-products (AGEs) lead to increases in cytosolic reactive oxygen species (ROS), which facilitate the production of mitochondrial superoxide. In normoglycemic conditions, exposure of primary renal cells to AGEs, transient overexpression of the receptor for AGEs (RAGE) with an adenoviral vector, and infusion of AGEs to healthy rodents each induced renal cytosolic oxidative stress, which led to mitochondrial permeability transition and deficiency of mitochondrial complex I. Because of a lack of glucose-derived NADH, which is the substrate for complex I, these changes did not lead to excess production of mitochondrial superoxide; however, when we performed these experiments in hyperglycemic conditions in vitro or in diabetic rats, we observed significant generation of mitochondrial superoxide at the level of complex I, fueled by a sustained supply of NADH. Pharmacologic inhibition of AGE-RAGE-induced mitochondrial permeability transition in vitro abrogated production of mitochondrial superoxide; we observed a similar effect in vivo after inhibiting cytosolic ROS production with apocynin or lowering AGEs with alagebrium. Furthermore, RAGE deficiency prevented diabetes-induced increases in renal mitochondrial superoxide and renal cortical apoptosis in mice. Taken together, these studies suggest that AGE-RAGE-induced cytosolic ROS production facilitates mitochondrial superoxide production in hyperglycemic environments, providing further evidence of a role for the advanced glycation pathway in the development and progression of diabetic nephropathy.


Predicting Global Cognitive Decline in the General Population Using the Disease State Index.
Identifying persons at risk for cognitive decline may aid in early detection of persons at risk of dementia and to select those that would benefit most from therapeutic or preventive measures for dementia. In this study we aimed to validate whether cognitive decline in the general population can be predicted with multivariate data using a previously proposed supervised classification method: Disease State Index (DSI). We included 2,542 participants, non-demented and without mild cognitive impairment at baseline, from the population-based Rotterdam Study (mean age 60.9 ± 9.1 years). Participants with significant global cognitive decline were defined as the 5% of participants with the largest cognitive decline per year. We trained DSI to predict occurrence of significant global cognitive decline using a large variety of baseline features, including magnetic resonance imaging (MRI) features, cardiovascular risk factors, APOE-ε4 allele carriership, gait features, education, and baseline cognitive function as predictors. The prediction performance was assessed as area under the receiver operating characteristic curve (AUC), using 500 repetitions of 2-fold cross-validation experiments, in which (a randomly selected) half of the data was used for training and the other half for testing. A mean AUC (95% confidence interval) for DSI prediction was 0.78 (0.77-0.79) using only age as input feature. When using all available features, a mean AUC of 0.77 (0.75-0.78) was obtained. Without age, and with age-corrected features and feature selection on MRI features, a mean AUC of 0.70 (0.63-0.76) was obtained, showing the potential of other features besides age. The best performance in the prediction of global cognitive decline in the general population by DSI was obtained using only age as input feature. Other features showed potential, but did not improve prediction. Future studies should evaluate whether the performance could be improved by new features, e.g., longitudinal features, and other prediction methods.