The Utility of EEG in Attention Deficit Hyperactivity Disorder: A Replication Study.
The routine use of stimulants in pediatrics has increased dramatically over the past 3 decades and the long-term consequences have yet to be fully studied. Since 1978 there have been 7 articles identifying electroencephalogram (EEG) abnormalities, particularly epileptiform discharges in children with attention deficit hyperactivity disorder (ADHD). Many have studied the prevalence of these discharges in this population with varying results. An article published in 2011 suggests that EEG technology should be considered prior to prescribing stimulants to children diagnosed with ADHD due to a high prevalence of epileptiform discharges. The 2011 study found a higher prevalence (26%) of epileptiform discharges when using 23-hour and sleep-deprived EEGs in comparison with other methods of activation (hyperventilation or photostimulation) and conventional EEG. We sought to replicate the 2011 results using conventional EEG with the added qEEG technologies of automatic spike detection and low-resolution electromagnetic tomography analysis (LORETA) brain mapping. Our results showed 32% prevalence of epileptiform discharges, which suggests that an EEG should be considered prior to prescribing stimulant medications.


Electrically Tunable Magnetism in Magnetic Topological Insulators.
The external controllability of the magnetic properties in topological insulators would be important both for fundamental and practical interests. Here we predict the electric-field control of ferromagnetism in a thin film of insulating magnetic topological insulators. The decrease of band inversion by the application of electric fields results in a reduction of magnetic susceptibility, and hence in the modification of magnetism. Remarkably, the electric field could even induce the magnetic quantum phase transition from ferromagnetism to paramagnetism. We further propose a transistor device in which the dissipationless charge transport of chiral edge states is controlled by an electric field. In particular, the field-controlled ferromagnetism in a magnetic topological insulator can be used for voltage based writing of magnetic random access memories in magnetic tunnel junctions. The simultaneous electrical control of magnetic order and chiral edge transport in such devices may lead to electronic and spintronic applications for topological insulators.


Enhanced Phototherapy by Nanoparticle-Enzyme via Generation and Photolysis of Hydrogen Peroxide.
Light has been widely used for cancer therapeutics such as photodynamic therapy (PDT) and photothermal therapy. This paper describes a strategy called enzyme-enhanced phototherapy (EEPT) for cancer treatment. We constructed a nanoparticle platform by covalent conjugation of glucose oxidase (GOx) to small polymer dots, which could be persistently immobilized into a tumor. While the malignant tumors have high glucose uptake, the GOx efficiently catalyzes the glucose oxidation with simultaneous generation of H2O2. Under light irradiation, the in situ generated H2O2 was photolyzed to produce hydroxyl radical, the most reactive oxygen species, for killing cancer cells. In vitro assays indicated that the cancer cells were destroyed by using a nanoparticle concentration at 0.2 μg/mL and a light dose of ∼120 J/cm2, indicating the significantly enhanced efficiency of the EEPT method when compared to typical PDT that requires a photosensitizer of >10 μg/mL for effective cell killing under the same light dose. Furthermore, remarkable inhibition of tumor growth was observed in xenograft-bearing mice, indicating the promise of the EEPT approach for cancer therapeutics.


Insights into the complexity and functionality of hepatitis C virus NS5A phosphorylation.
The hepatitis C virus nonstructural NS5A protein has roles in genome replication, virus assembly, and modulation of host pathways. NS5A is a phosphoprotein, and it has been proposed that differential phosphorylation could regulate the various roles of the protein. By SDS-PAGE, two forms of NS5A with distinct apparent molecular weights can be observed, referred to as basally phosphorylated and hyperphosphorylated species. However, the sites of phosphorylation on these two species have not been unequivocally identified, hampering our understanding of the function and regulation of NS5A. To address this, we purified tagged NS5A from cells harboring a replicating subgenomic replicon and analyzed the purified protein by mass spectrometry. We identified six peptide fragments containing 12 phosphorylated residues and were able to assign four of these to serines 146, 222, and 225 and threonine 348. A serine-rich peptide fragment spanning residues 221 to 240 was highly phosphorylated. Using mutagenesis, we identified roles for a subset of these phosphoacceptors in virus genome replication. We further showed that phosphorylation at S146 regulates hyperphosphorylation, and by generating a phospho-specific antibody targeted to pS222, we identified that S222 phosphorylation predominates in the hyperphosphorylated species. Last, by introducing phosphomimetic mutations across residues 221 to 240, we demonstrated changes in the mobility of the basally phosphorylated species suggestive of a sequential phosphorylation cascade within this serine-rich cluster. We propose that this regulation could drive a conformational switch between the dimeric structures of NS5A and could also explain the different functions of the protein in the virus life cycle.


Impact of comorbid anxiety disorders on health-related quality of life among patients with major depressive disorder.
This study examined the impact of comorbid anxiety disorders-posttraumatic stress disorder (PTSD), generalized anxiety disorder, and panic disorder-on health-related quality of life among primary care patients enrolled in a collaborative care depression intervention study for the Department of Veterans Affairs (VA). Baseline data were used from 324 participants in the Telemedicine Enhanced Antidepressant Management (TEAM) Study, a multisite randomized effectiveness trial targeting VA primary care patients with depression. Health-related quality of life was measured by using the Quality of Well-Being Scale, self-administered version (QWB-SA) and the mental component summary (MCS-12V) and physical component summary (PCS-12V) of the 12-item Short Form Health Survey for Veterans (SF-12V). A majority of participants (69 percent) had at least one anxiety disorder. Generalized anxiety disorder and PTSD predicted scores on the QWB-SA. PTSD predicted scores on the PCS-12V, but none of the comorbid anxiety disorders predicted scores on the MCS-12V. In addition, social support, depression severity, and the number of chronic medical conditions significantly predicted QWB-SA scores; the number of self-reported chronic physical health conditions and the number of depression episodes significantly predicted PCS-12V scores; and social support and depression severity significantly predicted MCS-12V scores. According to scores on the QWB-SA, generalized anxiety disorder and PTSD comorbid with major depressive disorder impair health-related quality of life above and beyond major depressive disorder alone.


Redox-mediated kick-start of mitochondrial energy metabolism drives resource-efficient seed germination.
Seeds preserve a far developed plant embryo in a quiescent state. Seed metabolism relies on stored resources and is reactivated to drive germination when the external conditions are favorable. Since the switchover from quiescence to reactivation provides a remarkable case of a cell physiological transition we investigated the earliest events in energy and redox metabolism of Arabidopsis seeds at imbibition. By developing fluorescent protein biosensing in intact seeds, we observed ATP accumulation and oxygen uptake within minutes, indicating rapid activation of mitochondrial respiration, which coincided with a sharp transition from an oxidizing to a more reducing thiol redox environment in the mitochondrial matrix. To identify individual operational protein thiol switches, we captured the fast release of metabolic quiescence in organello and devised quantitative iodoacetyl tandem mass tag (iodoTMT)-based thiol redox proteomics. The redox state across all Cys peptides was shifted toward reduction from 27.1% down to 13.0% oxidized thiol. A large number of Cys peptides (412) were redox switched, representing central pathways of mitochondrial energy metabolism, including the respiratory chain and each enzymatic step of the tricarboxylic acid (TCA) cycle. Active site Cys peptides of glutathione reductase 2, NADPH-thioredoxin reductase a/b, and thioredoxin-o1 showed the strongest responses. Germination of seeds lacking those redox proteins was associated with markedly enhanced respiration and deregulated TCA cycle dynamics suggesting decreased resource efficiency of energy metabolism. Germination in aged seeds was strongly impaired. We identify a global operation of thiol redox switches that is required for optimal usage of energy stores by the mitochondria to drive efficient germination.


Concentration of digestible, metabolizable, and net energy and digestibility of energy and nutrients in fermented soybean meal, conventional soybean meal, and fish meal fed to weanling pigs.
Two experiments were conducted to determine the digestibility of energy and nutrients and the concentration of DE, ME, and NE in fermented soybean meal (FSBM), conventional soybean meal (SBM-CV), and fish meal fed to weanling pigs. In Exp. 1, 36 barrows (initial BW: 22.0 ± 3.85 kg) were placed in metabolism cages and allotted to a randomized complete block design with 4 diets and 9 pigs per diet. Feces and urine were collected for 5 d after a 5 d adaptation period. Four diets including a corn-based diet and 3 diets consisting of corn and each of the experimental ingredients (FSBM, SBM-CV, and fish meal) were formulated. Results indicated that the apparent total tract digestibility (ATTD) of GE in corn, FSBM, and SBM-CV was 88.6, 88.2, and 90.3%, respectively, but the ATTD of GE in fish meal (84.0%) was less (P < 0.01) than in the other ingredients. The concentrations of DE, ME, and NE in SBM-CV were 4,553, 4,137, and 2,972 kcal/kg DM. These values were greater (P < 0.01) than the DE, ME, and NE in FSBM (4,296, 3,781, and 2,710 kcal/kg DM), corn (3,951, 3,819, and 2,791 kcal/kg DM), and fish meal (3,827, 3,412, and 2,450 kcal/kg DM). However, FSBM contained more (P < 0.01) DE, ME, and NE than fish meal and more (P < 0.01) DE than corn. The biological value of the protein in fish meal (75.4%) was greater (P < 0.05) than in corn (34.8%) and FSBM (62.8%), and the biological value of protein in SBM-CV (67.1%) was greater (P < 0.05) than in corn but not different from FSBM and fish meal. In Exp. 2, 8 barrows (initial BW: 10.4 ± 0.47 kg) were equipped with a T-cannula in the distal ileum and randomly allotted to a replicated 4 × 4 Latin square design with 4 diets and 4 periods per square. Three diets containing FSBM, SBM-CV, or fish meal as the sole source of AA and a N-free diet were formulated. The standardized ileal digestibility (SID) of all indispensable AA except Lys, Thr, and Trp was greater (P < 0.01) in FSBM than in fish meal. The SID of Met and Val was also greater (P < 0.05) in FSBM than in SBM-CV, but for the remaining indispensable AA, no difference between FSBM and SBM-CV was observed. In conclusion, the concentration of DE, ME, and NE is less in FSBM than in SBM-CV. However, DE, ME, and NE are greater in FSBM than in fish meal, but the SID of most AA is not different between FSBM and SBM-CV although they are greater than in fish meal.


A Protocol for the Ethical Assessment of Wild Animal-Visitor Interactions (AVIP) Evaluating Animal Welfare, Education, and Conservation Outcomes.
Due to the popularity of wild animal-visitor interactions (AVIs), there is a need for an ethical assessment of their impact on animal welfare, education, and conservation. The protocol presented in this study is designed to evaluate such interactions on an integrated level, using a transparent analysis of all the aspects involved, including all the stakeholders and the potential conflicts of values. The protocol consists of a six-step process encompassing dedicated data acquisition and a specific ethical assessment. When the protocol was applied to assess a "giraffe feeding" interaction, steps devoted to data acquisition found that animal welfare risks were low, and that visitors described giraffes with emotionally linked descriptors more often after the interaction. The net promoter score, which refers to how likely visitors would recommend to a friend to join the animal-visitor interaction, was 74%. The subsequent ethical assessment, which consisted of a comparison of the results of the previous steps with an ethical matrix highlighting the ideal situation for all stakeholders' interests, allowed the overall identification of the ethical concerns entailed by the interaction. A final ethical checklist of the examined AVI had a "yes" in entries regarding animal welfare, emotional, and conservation mindedness outcomes and ethical assessment.


Augmented Topological Descriptors of Pore Networks for Material Science.
One potential solution to reduce the concentration of carbon dioxide in the atmosphere is the geologic storage of captured CO2 in underground rock formations, also known as carbon sequestration. There is ongoing research to guarantee that this process is both efficient and safe. We describe tools that provide measurements of media porosity, and permeability estimates, including visualization of pore structures. Existing standard algorithms make limited use of geometric information in calculating permeability of complex microstructures. This quantity is important for the analysis of biomineralization, a subsurface process that can affect physical properties of porous media. This paper introduces geometric and topological descriptors that enhance the estimation of material permeability. Our analysis framework includes the processing of experimental data, segmentation, and feature extraction and making novel use of multiscale topological analysis to quantify maximum flow through porous networks. We illustrate our results using synchrotron-based X-ray computed microtomography of glass beads during biomineralization. We also benchmark the proposed algorithms using simulated data sets modeling jammed packed bead beds of a monodispersive material.


Mechanistic analysis of a suicide inactivator of histone demethylase LSD1.
Lysine-specific demethylase 1 (LSD1) is a transcriptional repressor and a flavin-dependent amine oxidase that is responsible for the removal of methyl from lysine 4 of histone H3. In this study, we characterize the mechanism and scope of LSD1 inhibition by a propargylamine-derivatized histone H3 substrate (1). Unlike aziridinyl and cyclopropylamine-derivatized histone H3 peptide substrate analogues, compound 1 appears to covalently modify and irreversibly inactivate LSD1 with high potency. Accompanying this inactivation is a spectroscopic change, which shifts the absorbance maximum to 392 nm. Spectral changes associated with the 1-LSD1 complex and reactivity to decreased pH and sodium borohydride treatment were suggestive of a structure involving a flavin-linked inhibitor conjugate between N5 of the flavin and the terminal carbon of the inhibitor. Using a 13C-labeled inhibitor, NMR analysis of the 1-flavin conjugate was consistent with this structural assignment. Kinetic analysis of the spectroscopic shift induced by 1 showed that the flavin adduct formed in a reaction with kinetic constants similar to those of the LSD1 inactivation process. Taken together, these data support a mechanism of LSD1 inactivation by 1 involving amine oxidation followed by Michael addition to the propargylic imine. We further examined the potential for a biotinylated analogue of 1 (1-Btn) to be used as a tool in affinity pulldown experiments. Using 1-Btn, it was feasible to selectively pull down spiked and endogenous LSD1 from HeLa cell nuclear extracts, setting the stage for activity-based demethylase proteomics.


A role for the membrane in regulating Chlamydomonas flagellar length.
Flagellar assembly requires coordination between the assembly of axonemal proteins and the assembly of the flagellar membrane and membrane proteins. Fully grown steady-state Chlamydomonas flagella release flagellar vesicles from their tips and failure to resupply membrane should affect flagellar length. To study vesicle release, plasma and flagellar membrane surface proteins were vectorially pulse-labeled and flagella and vesicles were analyzed for biotinylated proteins. Based on the quantity of biotinylated proteins in purified vesicles, steady-state flagella appeared to shed a minimum of 16% of their surface membrane per hour, equivalent to a complete flagellar membrane being released every 6 hrs or less. Brefeldin-A destroyed Chlamydomonas Golgi, inhibited the secretory pathway, inhibited flagellar regeneration, and induced full-length flagella to disassemble within 6 hrs, consistent with flagellar disassembly being induced by a failure to resupply membrane. In contrast to membrane lipids, a pool of biotinylatable membrane proteins was identified that was sufficient to resupply flagella as they released vesicles for 6 hrs in the absence of protein synthesis and to support one and nearly two regenerations of flagella following amputation. These studies reveal the importance of the secretory pathway to assemble and maintain full-length flagella.


Linear morphea presenting as acquired unilateral edema.
We describe a 2-year-old African-American boy with a 4-month history of gradually worsening unilateral edema that was initially noted on his left hand and then approximately 2 weeks later on his left lower extremity. In addition, linear hypopigmented patches were noted along the left forearm and leg, with no appreciable scarring or induration. The edema on the left-hand side of his body progressed so that he developed tense bullae on his left hand. Two months later, the hypopigmented patches were indurated and bound-down, especially over the left groin and thigh. A biopsy specimen from this area showed features characteristic of morphea. In this patient, dilated lymphatic channels secondary to the sclerosis of the morphea caused the bullae. Bullous morphea is a rare condition. We were unable to find any reports its occurrence in children under 18 with associated lymphedema. This entity should be included in the differential for acquired unilateral edema in children.


Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma.
The hypervascular nature of hepatocellular carcinoma (HCC) is well characterized. Recent data have suggested that thalidomide possesses antiangiogenic and immunomodulatory activity. Therefore, the authors initiated a study to assess the efficacy and toxicity of thalidomide in patients with advanced HCC as primary and secondary endpoints, respectively. Inclusion criteria were unresectable HCC with bidimentionally measurable disease, age > or = 18 years, Eastern Cooperative Oncology Group performance status < or = 2, and adequate organ function. Thalidomide was administered at a starting dose of 200 mg per day in a 100-mg-per-week dose escalation regimen, up to the maximum tolerated dose or to 800 mg per day. Toxicity was monitored according to the National Cancer Institute Common Toxicity Criteria. Twenty-six of 27 patients were eligible and assessable for toxicity and response. A median daily dose of 300 mg was achieved. One patient experienced near-complete recovery of alpha-fetoprotein levels and a partial radiographic response on computed tomography. Two patients had stable disease during the 16-week study period. The median duration of progression-free survival was 42 days. The overall median survival was 123 days. Fatigue and somnolence were the most common side effects, occurring in 81% and 62% of patients, respectively. No Grade 4 hematologic toxicity was observed. Three patients experienced Grade 4 hepatic toxicity (namely, hyperbilirubinemia). With gradual dose escalation, thalidomide was tolerated in most patients with advanced HCC. However, treatment with thalidomide alone was associated with only a modest response in the treatment of HCC.


Genetic control of programmed cell death (apoptosis) in Drosophila.
Programmed cell death, or apoptosis, is a highly conserved cellular process that has been intensively investigated in nematodes, flies and mammals. The genetic conservation, the low redundancy, the feasibility for high-throughput genetic screens and the identification of temporally and spatially regulated apoptotic responses make Drosophila melanogaster a great model for the study of apoptosis. Here, we review the key players of the cell death pathway in Drosophila and discuss their roles in apoptotic and non-apoptotic processes.


Risk factors for carriage of group B streptococcus in southern Israel.
In southern Israel, a discrepancy between a relatively high prevalence of Group B streptococcus maternal carriage (12.3%) and a very low incidence of neonatal disease (0.1/1,000 live births) has been found despite the fact that no preventive strategy has been implemented. To determine the risk factors for maternal carriage in order to clarify this discrepancy and further examine the different aspects of GBS in southern Israel. Cultures for GBS were obtained from 681 healthy pregnant women, and relevant demographic and obstetric data were collected. The medical records of 86 neonates born to carrier women were retrospectively examined. Statistical analysis was performed using the Pearson chi-square test. Women who were not born in Israel, particularly immigrants from the former USSR, were significantly prone to carry the pathogen compared to native Israeli women (Bedouins and Jews) (P = 0.03). A high GBS transmission rate is expected among immigrants who came from areas with a high prevalence of maternal carriage to one with a low incidence of neonatal disease environment and were not subject to any preventive strategy. Clinical attention should be directed to this issue throughout Israel.


Killing of Actinobacillus actinomycetemcomitans by the human neutrophil myeloperoxidase-hydrogen peroxide-chloride system.
Actinobacillus actinomycetemcomitans is a facultative gram-negative coccobacillus associated with periodontal disease and nonoral infections. This organism is resistant to serum bactericidal mechanisms but is nevertheless killed by human neutrophils under aerobic and anaerobic conditions. Most of the killing attributable to oxidative mechanisms is inhibited by sodium cyanide, which suggests that the myeloperoxidase-hydrogen peroxide-chloride (MPO-H2O2-Cl-) system may be a key factor in the oxidative killing process. In this report, we examine whether the isolated MPO-H2O2-Cl- system is bactericidal against A. actinomycetemcomitans. We found that three major chromatographic forms of MPO were capable of killing A. actinomycetemcomitans at sublethal concentrations of H2O2 and that both catalase-positive and catalase-negative strains of this organism were sensitive to killing by the MPO-H2O2-Cl- system. We conclude that the isolated MPO-H2O2-Cl- system is bactericidal for A. actinomycetemcomitans independent of other neutrophil granule constituents and may be an important component of the oxygen-dependent bactericidal activity of the neutrophil with respect to this periodontopathic organism.


Assimilation of Satellite-Based Snow Cover and Freeze/Thaw Observations Over High Mountain Asia.
Toward qualifying hydrologic changes in the High Mountain Asia (HMA) region, this study explores the use of a hyper-resolution (1 km) land data assimilation (DA) framework developed within the NASA Land Information System using the Noah Multi-parameterization Land Surface Model (Noah-MP) forced by the meteorological boundary conditions from Modern-Era Retrospective analysis for Research and Applications, Version 2 data. Two different sets of DA experiments are conducted: (1) the assimilation of a satellite-derived snow cover map (MOD10A1) and (2) the assimilation of the NASA MEaSUREs landscape freeze/thaw product from 2007 to 2008. The performance of the snow cover assimilation is evaluated via comparisons with available remote sensing-based snow water equivalent product and ground-based snow depth measurements. For example, in the comparison against ground-based snow depth measurements, the majority of the stations (13 of 14) show slightly improved goodness-of-fit statistics as a result of the snow DA, but only four are statistically significant. In addition, comparisons to the satellite-based land surface temperature products (MOD11A1 and MYD11A1) show that freeze/thaw DA yields improvements (at certain grid cells) of up to 0.58 K in the root-mean-square error (RMSE) and 0.77 K in the absolute bias (relative to model-only simulations). In the comparison against three ground-based soil temperature measurements along the Himalayas, the bias and the RMSE in the 0-10 cm soil temperature are reduced (on average) by 10 and 7%, respectively. The improvements in the top layer of soil estimates also propagate through the deeper soil layers, where the bias and the RMSE in the 10-40 cm soil temperature are reduced (on average) by 9 and 6%, respectively. However, no statistically significant skill differences are observed for the freeze/thaw DA system in the comparisons against ground-based surface temperature measurements at mid-to-low altitude. Therefore, the two proposed DA schemes show the potential of improving the predictability of snow mass, surface temperature, and soil temperature states across HMA, but more ground-based measurements are still required, especially at high-altitudes, in order to document a more statistically significant improvement as a result of the two DA schemes.


Bayesian inference for improved single molecule fluorescence tracking.
Single molecule tracking is widely used to monitor the change in position of lipids and proteins in living cells. In many experiments in which molecules are tagged with a single or small number of fluorophores, the signal/noise ratio may be limiting, the number of molecules is not known, and fluorophore blinking and photobleaching can occur. All these factors make accurate tracking over long trajectories difficult and hence there is still a pressing need to develop better algorithms to extract the maximum information from a sequence of fluorescence images. We describe here a Bayesian-based inference approach, based on a trans-dimensional sequential Monte Carlo method that utilizes both the spatial and temporal information present in the image sequences. We show, using model data, where the real trajectory of the molecule is known, that our method allows accurate tracking of molecules over long trajectories even with low signal/noise ratio and in the presence of fluorescence blinking and photobleaching. The method is then applied to real experimental data.


Pulmonary function following completion of Minimally Invasive Repair for Pectus Excavatum (MIRPE).
Pulmonary function testing remains part of the routine preoperative investigations in patients with pectus excavatum, although there is evidence that reduced exercise capacity is predominantly due to impaired cardiovascular performance rather than ventilatory limitation. To evaluate the change of pulmonary function in patients after completion (metal bar removal) of minimally invasive repair for pectus excavatum compared to the preoperative functional results. All patients who underwent minimally invasive repair for pectus excavatum (MIRPE) between February 2000 and June 2006 and subsequently had their metal bars removed were examined. Pulmonary function tests were performed as part of the routine pre- and postoperative protocol. Vital capacity (VC), forced expiratory volume in one second (FEV1), total lung capacity (TLC), residual volume (RV) and maximal expiratory flow rate at 25 % (MEF25) were evaluated. In addition, comparisons were made between patients with a low (<or= 6) and those with a high (> 6) pectus severity index (PSI) to establish the relative pre- to postoperative change of the above-mentioned lung function parameters. Fifteen patients were included in the study (14 males, 1 female). The median age at surgery was 15.9 years. The metal bar(s) were removed after a median of 37 months following the initial operation. Lung function tests were performed at a median of 32 days preoperatively and 129 days after completion of the procedure. Preoperative lung function values lay below population averages. The majority of patients had either a restrictive, obstructive or combined pulmonary disorder. Improvement was observed in all lung function parameters after metal bar removal compared to preoperative values and was significant for VC, FEV1 and the RV/TLC ratios. With regard to the severity of the deformity, although not statistically significant, patients with a higher PSI (> 6) appeared to benefit particularly from the operation. Our findings indicate that pulmonary function improves in patients after completion of minimally invasive repair of pectus excavatum. However, a review of the literature suggests that, in all probability, following surgery, patients benefit more with regard to enhanced cardiovascular performance than from improved pulmonary limitations. The value of routine testing of pre- and postoperative lung function in patients with pectus excavatum is questionable.


[(18)F]Fluorodeoxyglucose-positron emission tomography screening for lung cancer: a systematic review and meta-analysis.
Although low-dose computed tomography (CT) is a recommended modality for lung cancer screening in high-risk populations, the role of other modalities, such as [(18)F]fluorodeoxyglucose-positron emission tomography (PET), is unclear. We conducted a systematic review to describe the role of PET in lung cancer screening. A systematic review was conducted by reviewing primary studies focusing on PET screening for lung cancer until July 2012. Two independent reviewers identified studies that were compatible for inclusion/exclusion criteria. The analysis was restricted to English and included studies published since 2000. A descriptive analysis was used to summarize the results, and the pooled diagnostic performance of selective PET screening was calculated by weighted average using individual sample sizes. Among the identified studies (n = 3497), 12 studies were included for analysis. None of the studies evaluated the efficacy of primary PET screening specific to lung cancer. Eight studies focused on primary PET screening for all types of cancer; the detection rates of lung cancer were low. Four studies reported evidence of lung cancer screening programs with selective PET, in which the estimated pooled sensitivity and specificity was 83% and 91%, respectively. The role of primary PET screening for lung cancer remains unknown. However, PET has high sensitivity and specificity as a selective screening modality. Further studies must be conducted to evaluate the use of PET or PET/computed tomography screening for high-risk populations, preferably using randomized trials or prospective registration. Our meta-analysis indicates that PET has high sensitivity and specificity as a selective screening modality.


ParkinSong: A Controlled Trial of Singing-Based Therapy for Parkinson's Disease.
Background. Communication impairment is one of the most common symptoms of Parkinson's disease (PD), significantly affecting quality of life. Singing shares many of the neural networks and structural mechanisms used during speech and, thus, has potential for therapeutic application to address speech disorders. Objective. To explore the effects of an interdisciplinary singing-based therapeutic intervention (ParkinSong) on voice and communication in people with PD. Methods. A controlled trial compared the effects of the ParkinSong intervention with an active control condition at 2 dosage levels (weekly vs monthly) over 3 months, on voice, speech, respiratory strength, and voice-related quality-of-life outcomes for 75 people living with PD. The interdisciplinary ParkinSong model comprised high-effort vocal and respiratory tasks, speech exercises, group singing, and social communication opportunities. Results. ParkinSong intervention participants demonstrated significant improvements in vocal intensity (P = .018), maximum expiratory pressure (P = .032), and voice-related quality of life (P = .043) in comparison to controls. Weekly ParkinSong participants increased vocal intensity more than monthly participants (P = .011). Vocal intensity declined in nontreatment control groups. No statistical differences between groups on maximum phonation length or maximum inspiratory pressure were observed at 3 months. Conclusions. ParkinSong is an engaging intervention with the potential to increase loudness and respiratory function in people with mild to moderately severe PD.


Chimeric Theiler's virus with altered tropism for the central nervous system.
Theiler's virus is a neurotropic murine picornavirus which, depending on the strain, causes either an acute encephalitis or a persistent demyelinating disease. Following intracranial inoculation, the demyelinating strains infect sequentially the grey matter of the brain, the grey matter of the spinal cord, and finally the white matter of the spinal cord, where they persist and cause chronic demyelination. The neurovirulent strains cause a generally fatal encephalitis with lytic infection of neurons. The study of chimeric Theiler's viruses, obtained by recombining the genomes of demyelinating and neurovirulent strains, has shown that the viral capsid contains determinants for persistence and demyelination. In this article we describe the recombinant virus R5, in which the capsid protein VP1 and a small portion of protein 2A come from the neurovirulent GDVII strain and the rest of the genome comes from the persistent DA strain. The capsid of virus R5 also contains one mutation at amino acid 34 of VP3 (Asn-->His). Virus R5 does not persist in the central nervous system (CNS) of immunocompetent SJL/J or BALB/c mice. However, it replicates efficiently and persists in the CNS of BALB/c nu/nu mice, showing that its growth in the CNS is not impaired. In BALB/c nu/nu mice, whereas virus DA causes mortality with large amounts of viral antigens in the white matter of the spinal cord, virus R5 does not kill the animals, persists in the neurons of the grey matter of the brain, and never reaches the white matter of the spinal cord. This phenotype is due to the chimerism of the capsid and/or to the mutation in VP3. These results indicate that the capsid plays an important role in the characteristic migration of Theiler's virus within the CNS.


Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death.
Ischemia/reperfusion (I/R) is a pivotal mechanism of liver damage after liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol (CBD), the nonpsychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, and gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor α (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, intercellular adhesion molecule 1 mRNA levels; tissue neutrophil infiltration; nuclear factor κB (NF-κB) activation), stress signaling (p38MAPK and JNK), and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress, and cell death and also attenuated the bacterial endotoxin-triggered NF-κB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecule expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent of classical CB1/2 receptors.


The uses and abuses of tree thinking in cultural evolution.
Modern phylogenetic methods are increasingly being used to address questions about macro-level patterns in cultural evolution. These methods can illuminate the unobservable histories of cultural traits and identify the evolutionary drivers of trait change over time, but their application is not without pitfalls. Here, we outline the current scope of research in cultural tree thinking, highlighting a toolkit of best practices to navigate and avoid the pitfalls and 'abuses' associated with their application. We emphasize two principles that support the appropriate application of phylogenetic methodologies in cross-cultural research: researchers should (1) draw on multiple lines of evidence when deciding if and which types of phylogenetic methods and models are suitable for their cross-cultural data, and (2) carefully consider how different cultural traits might have different evolutionary histories across space and time. When used appropriately phylogenetic methods can provide powerful insights into the processes of evolutionary change that have shaped the broad patterns of human history. This article is part of the theme issue 'Foundations of cultural evolution'.


The TRPM7 interactome defines a cytoskeletal complex linked to neuroblastoma progression.
Neuroblastoma is the second-most common solid tumor in children and originates from poorly differentiated neural crest-derived progenitors. Although most advanced stage metastatic neuroblastoma patients initially respond to treatment, a therapy resistant pool of poorly differentiated cells frequently arises, leading to refractory disease. A lack of insight into the molecular mechanisms that underlie neuroblastoma progression hampers the development of effective new therapies for these patients. Normal neural crest development and maturation is guided by physical interactions between the cell and its surroundings, in addition to soluble factors such as growth factors. This mechanical crosstalk is mediated by actin-based adhesion structures and cell protrusions that probe the cellular environment to modulate migration, proliferation, survival and differentiation. Whereas such signals preserve cellular quiescence in non-malignant cells, perturbed adhesion signaling promotes de-differentiation, uncontrolled cell proliferation, tissue invasion and therapy resistance. We previously reported that high expression levels of the channel-kinase TRPM7, a protein that maintains the progenitor state of embryonic neural crest cells, are closely associated with progenitor-like features of tumor cells, accompanied by extensive cytoskeletal reorganization and adhesion remodeling. To define mechanisms by which TRPM7 may contribute to neuroblastoma progression, we applied a proteomics approach to identify TRPM7 interacting proteins. We show that TRPM7 is part of a large complex of proteins, many of which function in cytoskeletal organization, cell protrusion formation and adhesion dynamics. Expression of a subset of these TRPM7 interacting proteins strongly correlates with neuroblastoma progression in independent neuroblastoma patient datasets. Thus, TRPM7 is part of a large cytoskeletal complex that may affect the malignant potential of tumor cells by regulating actomyosin dynamics and cell-matrix interactions.


Natural enamel caries: a comparative histological study on biochemical volumes.
This study aimed to test the hypothesis that organic volume is the main variable for explaining the optical properties and predictive degree of diffusion of enamel histological points at zones of natural enamel caries (NEC; surface layer, SL, n = 30, and body of the lesion, BL, n = 58) and normal enamel (NE, n = 131). Molars with either NEC or NE were quantitatively analyzed regarding the mineral, organic and water volumes (considered as effective pore volume), opacity (predicted in 94% of cases by water volume in NEC), and water volume more easily available for diffusion, αd (squared water volume divided by the nonmineral volume; related to permeability). NEC presented lower mineral volumes and higher organic volumes, effective pore volume and opacity than NE. External origin of organic volume in NEC was evidenced by an organic gradient decreasing from the surface inward (R2 = -0.7), which was not detected in teeth with NE only; αd values of the SL and NE were similar and both were lower (p < 0.0001) than that of the BL. Comparing the SL from both NEC and artificial enamel caries (AEC; published data; n = 71), with similar mineral volumes, against developing enamel (published data), AEC showed more effective pore volume (3 times higher), higher αd and opacity than NEC mainly due to differences in organic volumes. Our results reasonably matched widely known features of NEC histological zones, and confirmed the organic volume as the main variable for explaining optical properties and αd (related to permeability).


Pharmacological blocking of the osteoclastic biocorrosion of surgical stainless steel in vitro.
In vitro studies suggest that human osteoclasts (OC) are able to corrode surgical stainless steel 316L (SS). The aim of this study was to investigate whether osteoclastic biocorrosion can be blocked pharmacologically. Human OCs were generated in vitro from peripheral blood monocytic cells (PBMCs) in the presence of OC differentiation cytokines. The osteoclastic viability, differentiation, and resorptive function (on both bone and SS) were assessed using standard colorimetric cell viability assay 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenil)-2H-tetrazolium, inner salt (MTS), fluorescence microscopy, tartrate-resistant acid phosphatase expression (flow cytometry), and scanning electron microscopy. OCs cultured on SS were exposed to nontoxic concentrations of bafilomycin A1, amiloride hydrochloride, or zoledronic acid. The extent of biocorrosion was quantified using atomic emission spectrometry (to measure the concentration of metal ions released into the supernatant) and scanning electron microscopy. PBMCs differentiated into mature and functional OC in the presence of all the drugs used. Osteoclastic resorption of SS was noted with differences in the resorption pattern for all drug treatments. Under the drug treatments, single areas of osteoclastic resorption were larger in size but less abundant when compared with positive controls. None of the drugs used were able to inhibit osteoclastic biocorrosion of SS.


Heparin versus 0.9% sodium chloride locking for prevention of occlusion in central venous catheters in adults.
Intermittent locking of central venous catheters (CVCs) is undertaken to help maintain their patency. There are systematic variations in care: some practitioners use heparin (at different concentrations), whilst others use 0.9% NaCl (normal saline). This review looks at the effectiveness and safety of intermittent locking with heparin compared to 0.9% NaCl to see if the evidence establishes whether one is better than the other. This work is an update of a review first published in 2014. To assess the effectiveness and safety of intermittent locking of CVCs with heparin versus normal saline (NS) in adults to prevent occlusion. The Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (last searched 11 June 2018) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 5). Searches were also carried out in MEDLINE, Embase, CINAHL, and clinical trials databases (11 June 2018). We included randomised controlled trials in adults ≥ 18 years of age with a CVC that compared intermittent locking with heparin at any concentration versus NS. We applied no restriction on language. Two review authors independently selected trials, assessed quality, and extracted data. We contacted trial authors to retrieve additional information, when necessary. We carried out statistical analysis using Review Manager 5 and assessed the overall quality of the evidence supporting assessed outcomes using GRADE. We carried out prespecified subgroup analysis. We identified five new studies for this update (six prior studies were included in the original review), bringing the number of eligible studies to 11, with a total of 2392 participants. We noted differences in methods used by the included studies and variation in heparin concentrations (10 to 5000 IU/mL), time to follow-up (1 to 251.8 days), and the unit of analysis used (participant, catheter, line access).Combined results from these studies showed fewer occlusions with heparin than with NS (risk ratio (RR) 0.70, 95% confidence interval (CI) 0.51 to 0.95; P = 0.02; 1672 participants; 1025 catheters from 10 studies; I² = 14%) and provided very low-quality evidence.We carried out subgroup analysis by unit of analysis (testing for subgroup differences (P = 0.23; I² = 30.3%). When the unit of analysis was the participant, results show no clear differences in all occlusions between heparin and NS (RR 0.79, 95% CI 0.58 to 1.08; P = 0.15; 1672 participants; seven studies). Subgroup analysis using the catheter as the unit of analysis shows fewer occlusions with heparin use (RR 0.53, 95% CI 0.29 to 0.95; P = 0.03; 1025 catheters; three studies). When the unit of analysis was line access, results show no clear differences in occlusions between heparin and NS (RR 1.08, 95% CI 0.84 to 1.40; 770 line accesses; one study).We found no clear differences in the duration of catheter patency (mean difference (MD) 0.44 days, 95% CI -0.10 to 0.99; P = 0.11; 1036 participants; 752 catheters; six studies; low-quality evidence).We found no clear evidence of a difference in the following: CVC-related sepsis (RR 0.74, 95% CI 0.03 to 19.54; P = 0.86; 1097 participants; two studies; low-quality evidence); mortality (RR 0.76, 95% CI 0.44 to 1.31; P = 0.33; 1100 participants; three studies; low-quality evidence); haemorrhage at any site (RR 1.32, 95% CI 0.57 to 3.07; P = 0.52; 1245 participants; four studies; moderate-quality evidence); or heparin-induced thrombocytopaenia (RR 0.21, 95% CI 0.01 to 4.27; P = 0.31; 443 participants; three studies; low-quality evidence).The main reasons for downgrading the quality of evidence were unclear allocation concealment, imprecision, and suspicion of publication bias. Given the very low quality of the evidence, we are uncertain whether intermittent locking with heparin results in fewer occlusions than intermittent locking with NS. Low-quality evidence suggests that heparin may have little or no effect on catheter patency. Although we found no evidence of differences in safety (sepsis, mortality, or haemorrhage), the combined trials are not powered to detect rare adverse events such as heparin-induced thrombocytopaenia.


WITHDRAWN: Day care for pre-school children.
The debate about how, where and by whom young children should be looked after is one which has occupied much social policy and media attention in recent years. Mothers undertake most of the care of young children. Internationally, out-of-home day-care provision ranges widely. These different levels of provision are not simply a response to different levels of demand for day-care, but reflect cultural and economic interests concerning the welfare of children, the need to promote mothers' participation in paid work, and the importance of socialising children into society's values. At a time when a decline in family values is held responsible for a range of social problems, the day-care debate has a special prominence. To quantify the effects of out-of-home day-care for preschool children on educational, health and welfare outcomes for children and their families. Randomised controlled trials of day-care for pre-school children were identified using electronic databases, hand searches of relevant literature, and contact with authors. Studies were included in the review if the intervention involved the provision of non-parental day care for children under 5 years of age, and the evaluation design was that of a randomised or quasi-randomised controlled trial. A total of eight trials were identified after examining 920 abstracts and 19 books. The trials were assessed for methodological quality. Day-care increases children's IQ, and has beneficial effects on behavioural development and school achievement. Long-term follow up demonstrates increased employment, lower teenage pregnancy rates, higher socio-economic status and decreased criminal behaviour. There are positive effects on mothers' education, employment and interaction with children. Effects on fathers have not been examined. Few studies look at a range of outcomes spanning the health, education and welfare domains. Most of the trials combined non-parental day-care with some element of parent training or education (mostly targeted at mothers); they did not disentangle the possible effects of these two interventions. The trials had other significant methodological weaknesses, pointing to the importance of improving on study design in this field. All the trials were carried out in the USA. Day care has beneficial effect on children's development, school success and adult life patterns. To date, all randomised trials have been conducted among disadvantaged populations in the USA. The extent to which the results are generaliseable to other cultures and socioeconomic groups has yet to be evaluated.


Cross-ecosystem impacts of stream pollution reduce resource and contaminant flux to riparian food webs.
The effects of aquatic contaminants are propagated across ecosystem boundaries by aquatic insects that export resources and contaminants to terrestrial food webs; however, the mechanisms driving these effects are poorly understood. We examined how emergence, contaminant concentration, and total contaminant flux by adult aquatic insects changed over a gradient of bioavailable metals in streams and how these changes affected riparian web-building spiders. Insect emergence decreased 97% over the metal gradient, whereas metal concentrations in adult insects changed relatively little. As a result, total metal exported by insects (flux) was lowest at the most contaminated streams, declining 96% among sites. Spiders were affected by the decrease in prey biomass, but not by metal exposure or metal flux to land in aquatic prey. Aquatic insects are increasingly thought to increase exposure of terrestrial consumers to aquatic contaminants, but stream metals reduce contaminant flux to riparian consumers by strongly impacting the resource linkage. Our results demonstrate the importance of understanding the contaminant-specific effects of aquatic pollutants on adult insect emergence and contaminant accumulation in adults to predict impacts on terrestrial food webs.


Non-specific pleuritis: pathological patterns in benign pleuritis.
A pleural biopsy without granulomatous inflammation or tumour cells is interpreted as 'non-specific pleuritis' (NSP), a diagnosis without any specificity, often frustrating for physicians. However, varying histological features are found in NSPs with unknown significance. The aim of this study was to describe the detailed microscopic features of NSP and correlate them with the underlying aetiology. One hundred patients diagnosed with NSP after pleural biopsy were retrospectively evaluated. A benign cause of pleural effusion was attributed. Histological features evaluated were inflammation, fibrosis, vascular proliferation, haemorrhage, fibrin, oedema and mesothelial hyperplasia. A semi-quantitative scoring was applied. Bacterial-caused and autoimmune disease-associated NSPs showed a higher score followed by viral and drug-induced conditions, while pneumothorax and cardiac-induced NSPs showed a lower score (p<0.0001). The degree of fibrosis was higher in bacterial NSP, and the type of fibrosis was cellular in this group (p=0.006). Vascular proliferation differed between groups (p<0.0001), and was higher in bacterial NSP. Histological findings differ significantly between the varying aetiologies of NSP, and this may be used to suggest the cause of the effusion.


Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies.
The peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPARgamma and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPARgamma(1/)- and RXRalpha(1/)- mice both displayed a significantly enhanced susceptibility to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis compared with their wild-type littermates. A role for the RXR/PPARgamma heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPARgamma agonists. TNBS-induced colitis was significantly reduced by the administration of both PPARgamma and RXR agonists. This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor alpha and interleukin 1beta mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor kappaB DNA binding activity, c-Jun NH(2)-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPARgamma and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPARgamma heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARgamma ligands might hold promise in the clinic due to their synergistic effects.


Catheter Ablation for Long-Standing Persistent Atrial Fibrillation.
Atrial fibrillation (AF) is the most common sustained arrhythmia worldwide and represents a major burden to health care systems. Atrial fibrillation is associated with a 4- to 5-fold increased risk of thromboembolic stroke. The pulmonary veins have been identified as major sources of atrial triggers for AF. This is particularly true in patients with paroxysmal AF but not always the case for those with long-standing persistent AF (LSPAF), in which other locations for ectopic beats have been well recognized. Structures with foci triggering AF include the coronary sinus, the left atrial appendage (LAA), the superior vena cava, the crista terminalis, and the ligament of Marshall. More than 30 studies reporting results on radiofrequency ablation of LSPAF have been published to date. Most of these are observational studies with very different methodologies using different strategies. As a result, there has been remarkable variation in short- and long-term success, which suggests that the optimal ablation technique for LSPAF is still to be elucidated. In this review we discuss the different approaches to LSPAF catheter ablation, starting with pulmonary vein isolation (PVI) through ablation lines in different left atrial locations, the role of complex fractionated atrial electrograms, focal impulses and rotor modulation, autonomic modulation (ganglionated plexi), alcohol ablation, and the future of epicardial mapping and ablation for this arrhythmia. A stepwise ablation approach requires several key ablation techniques, such as meticulous PVI, linear ablation at the roof and mitral isthmus, electrogram-targeted ablation with particular attention to triggers in the coronary sinus and LAA, and discretionary right atrial ablation (superior vena cava, intercaval, or cavotricuspid isthmus lines).


The pattern of disease in the post-infection era: national trends.
Information that can be used to assess trends in the health of the population is limited to the results of irregular surveys of nutritional status and 'I.Q.', to data obtained from the notification of infectious diseases, congenital malformations, blindness and other selected defects, and to mortality rates. The last have been recorded since 1841 and provide the most detailed and useful information, although they are often difficult to interpret because of changes in the nomenclature, classification, methods of diagnosis, and efficacy of treatment of disease states. In the last 40 years, mortality rates have shown progressive reductions at all ages which have continued past the time when improvements in the prevention and treatment of infectious disease might be expected to have produced their principal benefits. Notable differences have emerged between the sexes, the rates continuing to decline in women but remaining more or less stable for a period in middle-aged men. This difference can be attributed to sex differences in life-style, so that until recently the trends in women are likely to have been the better indicators of the effect of toxic agents in the environment. The available data are inadequate to assess possible effects such as alterations in behaviour, but are of some help in regard to teratogenicity and carcinogenicity.


Modulatory effects of 5-fluorouracil on the rhythmic expression of circadian clock genes: a possible mechanism of chemotherapy-induced circadian rhythm disturbances.
The circadian clock system is necessary to adapt endogenous physiological functions to daily variations in environmental conditions. Abnormality in circadian rhythms, such as the sleep-wake cycle and the timing of hormonal secretions, is implicated in various physiological and psychiatrical disorders. Recent molecular studies have revealed that oscillation in the transcription of specific clock genes plays a central role in the generation of 24h cycles of physiology and behavior. It has been noticed that patients receiving chemotherapeutic agents experience disturbances in their behavioral and physical performances, including circadian rhythms. To explore the underlying mechanism of chemotherapeutic agent-induced disturbance of these rhythms, we investigated the influence of 5-fluorouracil (5-FU), one of the most widely used chemotherapeutic agents for the treatment of cancers, on the expression of clock genes. Treatment of cultured NIH3T3 cells with 5-FU for 48 h resulted in a significant reduction of mRNA levels of Period1 (Per1) and Period2 (Per2) without affecting cell viability; however, treatment with the same amount of uracil, a structural analog of 5-FU, had little effect on the expression of clock genes. Consistent with its inhibitory actions, continuous administration of 5-FU (2 mg/kg/h) to mice attenuated the oscillation in the expressions of Per1 and Per2 in the liver and suprachiasmatic nuclei, the center of the mammalian circadian clock. These results reveal a possible pharmacological action by the chemotherapeutic agent 5-FU on the circadian clock mechanism, which is the underlying cause of its adverse effects on 24-h rhythms of physiology and behavior.


The medical home: growing evidence to support a new approach to primary care.
A medical home is a patient-centered, multifaceted source of personal primary health care. It is based on a relationship between the patient and physician, formed to improve the patient's health across a continuum of referrals and services. Primary care organizations, including the American Board of Family Medicine, have promoted the concept as an answer to government agencies seeking political solutions that make quality health care affordable and accessible to all Americans. Standard literature databases, including PubMed, and Internet sites of numerous professional associations, government agencies, business groups, and private health organizations identified over 200 references, reports, and books evaluating the medical home and patient-centered primary care. Evaluations of several patient-centered medical home models corroborate earlier findings of improved outcomes and satisfaction. The peer-reviewed literature documents improved quality, reduced errors, and increased satisfaction when patients identify with a primary care medical home. Patient autonomy and choice also contributes to satisfaction. Although industry has funded case management models demonstrating value superior to traditional fee-for-service reimbursement adoption of the medical home as a basis for medical care in the United States, delivery will require effort on the part of providers and incentives to support activities outside of the traditional face-to-face office visit. Evidence from multiple settings and several countries supports the ability of medical homes to advance societal health. A combination of fee-for-service, case management fees, and quality outcome incentives effectively drive higher standards in patient experience and outcomes. Community/provider boards may be required to safeguard the public interest.


Genomic analysis of detoxification genes in the mosquito Aedes aegypti.
Annotation of the recently determined genome sequence of the major dengue vector, Aedes aegypti, reveals an abundance of detoxification genes. Here, we report the presence of 235 members of the cytochrome P450, glutathione transferase and carboxy/cholinesterase families in Ae. aegypti. This gene count represents an increase of 58% and 36% compared with the fruitfly, Drosophila melanogaster, and the malaria mosquito, Anopheles gambiae, respectively. The expansion is not uniform within the gene families. Secure orthologs can be found across the insect species for enzymes that have presumed or proven biosynthetic or housekeeping roles. In contrast, subsets of these gene families that are associated with general xenobiotic detoxification, in particular the CYP6, CYP9 and alpha esterase families, have expanded in Ae. aegypti. In order to identify detoxification genes associated with resistance to insecticides we constructed an array containing unique oligonucleotide probes for these genes and compared their expression level in insecticide resistant and susceptible strains. Several candidate genes were identified with the majority belonging to two gene families, the CYP9 P450s and the Epsilon GSTs. This 'Ae. aegypti Detox Chip' will facilitate the implementation of insecticide resistance management strategies for arboviral control programmes.


Probing the function of nucleotides in the catalytic cores of the 8-17 and 10-23 DNAzymes by abasic nucleotide and C3 spacer substitutions.
8-17 and 10-23 are the two most comprehensively studied RNA-cleaving DNAzymes to date and have the ability to carry out sequence-specific cleavage of both all-RNA or chimeric RNA/DNA substrates. Mutagenesis studies of 8-17 and 10-23 DNAzymes using alternative natural nucleotides to substitute a given nucleotide in the DNAzyme sequence have found that both DNAzymes are able to tolerate a variety of alterations at many sequence locations. Chemical modification studies employing nucleotides containing nonnatural nucleobases have led to findings that some specific entities of selected nucleobases are irreplaceable by other functional groups. In this work, we set out to carry out a mutagenesis study on both 8-17 and 10-23 by substituting individual nucleotides in their catalytic cores with a baseless (abasic) nucleotide or a baseless/sugarless nucleotide containing only acyclic C3 spacer. We observed that the substitution with an abasic nucleotide or C3 spacer at many locations within the catalytic core of both 8-17 and 10-23 was still able to support a significant level of catalytic activity of each DNAzyme, suggesting that both DNAzymes have considerable structural plasticity to maintain their catalytic functions. We also observed that almost all nucleobases in the catalytic core of each DNAzyme appeared to make either an absolutely essential contribution to the function of each DNAzyme or exhibit a "chaperone-like" activity that is important for the optimal function of each DNAzyme; in contrast, only one sugar ring in 8-17 and four in 10-23 were inferred to make some contribution to the optimal function of the relevant DNAzyme. Finally, our study also raised a possibility that the 10-23 DNAzyme might be a special structural variant of the larger 8-17 DNAzyme family.


Highly divergent ancient gene families in metagenomic samples are compatible with additional divisions of life.
Microbial genetic diversity is often investigated via the comparison of relatively similar 16S molecules through multiple alignments between reference sequences and novel environmental samples using phylogenetic trees, direct BLAST matches, or phylotypes counts. However, are we missing novel lineages in the microbial dark universe by relying on standard phylogenetic and BLAST methods? If so, how can we probe that universe using alternative approaches? We performed a novel type of multi-marker analysis of genetic diversity exploiting the topology of inclusive sequence similarity networks. Our protocol identified 86 ancient gene families, well distributed and rarely transferred across the 3 domains of life, and retrieved their environmental homologs among 10 million predicted ORFs from human gut samples and other metagenomic projects. Numerous highly divergent environmental homologs were observed in gut samples, although the most divergent genes were over-represented in non-gut environments. In our networks, most divergent environmental genes grouped exclusively with uncultured relatives, in maximal cliques. Sequences within these groups were under strong purifying selection and presented a range of genetic variation comparable to that of a prokaryotic domain. Many genes families included environmental homologs that were highly divergent from cultured homologs: in 79 gene families (including 18 ribosomal proteins), Bacteria and Archaea were less divergent than some groups of environmental sequences were to any cultured or viral homologs. Moreover, some groups of environmental homologs branched very deeply in phylogenetic trees of life, when they were not too divergent to be aligned. These results underline how limited our understanding of the most diverse elements of the microbial world remains, and encourage a deeper exploration of natural communities and their genetic resources, hinting at the possibility that still unknown yet major divisions of life have yet to be discovered.


Activation of the AKT and STAT3 pathways and prolonged survival by a mutant EGFR in human lung cancer cells.
To clarify the pathogenic and biological significance of EGFR mutations in lung cancer, we compared the status of ERBB family receptors, their downstream signal transductions and biological phenotypes between lung cancer cell lines with mutant and wild type EGFR. We initially analyzed expression and phosphorylation of ERBB family receptors and their major downstream proteins, AKT, p44/42 MAPK and STAT3, in a series of lung cancer cell lines with or without EGFR mutation. The expression levels of EGFR as well as of ERBB2 and ERBB3 proteins in cells with EGFR mutation tended to be higher than those in cells with wild type EGFR. There was no difference in stability between mutant and wild type EGFR proteins. EGF induced phosphorylation of EGFR, AKT, p44/42 MAPK and STAT3 to various extents, but the level of induction was not associated with the existence of EGFR mutation. These results implied that the activation of AKT, p44/42 MAPK and STAT3 signaling transmitted by EGFR would be critical for the growth and survival of lung cancer cells, but specific features of mutant EGFR in lung cancer cells was not discriminated by these approaches. We therefore performed transfection studies using PC-13 cells with no detectable endogenous EGFR expression. Exogenous expression of wild type and mutant EGFR (delE746-A750) in the cells revealed that only in the mutant EGFR transfected cells, EGFR itself as well as AKT and STAT3 were highly phosphorylated after 24h of serum deprivation. The survival time of mutant EGFR transfected cells was prolonged under serum-free culture conditions, but not under standard culture conditions with 10% serum. These results suggest that cells with a mutant EGFR survive through the activation of the AKT and/or STAT3 pathways, even in low EGF microenvironments. This specific property due to EGFR mutation could be an important step of multistage lung cancer progression.


Different impact of NNRTI and PI-including HAART on bone mineral density loss in HIV-infected patients.
To evaluate the changes in Bone Mineral Density (BMD) and bone remodelling markers in a group of HIV patients treated with HAART and controlled in a long follow-up and to identify possible risk factors for accelerated bone mass loss. In a series of 172 HIV patients treated with HAART a total of 67 patients (44 males and 33 females) underwent repeated bone mineral density measurement by DEXA in lumbar spine and in femur; the patients were classified according to T-score WHO criteria. Serum bone alkaline phosphatase (BAP), by IRMA, and urine pyridinoline/deoxypyridinoline (PYD&DPD), by EIA, were also assayed in all cases. At baseline, 62/67 patients were on HAART, while 5 were naïve; 44.8% were previous intravenous drug users (IVDU), 46.3% heterosexual and 8.9% homosexual, mean age being 40.2 ± 6.5 years, and 23.9% had previous AIDS diagnosis. Fifteen/67 (22.4%) of treated patients had osteoporosis and 25/67 (37.3%) osteopenia in spine and/or femur including 3 naïve, 27/67 (40.3%), including 2 naïve, had normal BMD in both sites. Fifty-one/67 patients were monitored during follow-up (56.8 ± 5.3 months); 27 (52.9%) of these (Group 1), received protease inhibitors (PI) and 24 (47.1%), including naïve, (Group 2) received not nucleoside reverse transcriptase inhibitors (NNRTI) for > 50% of follow-up period. In Group 1 patients, BMD reduction was observed after follow-up in respect of basal condition in both spine and femur, but significantly (p = 0.011) only for the latter. However, mean BMD values remained stable in both sites in Group 2 patients. Basal BAP and PYD&DPD levels were higher in Group 1 than Group 2, but not significantly. Moreover, only PYD&DPD levels at the follow-up evaluation were significantly (p = 0.031) higher in Group 1 than Group 2. Of the remaining 16/67 patients with osteoporosis/osteopenia, 10 received PI and 6 NNRTI and were treated with therapies that could increase bone density, in particular, 9 with Alendronate/Vitamin D/Calcium and 7 with only vitamin D/calcium; these patients were excluded from statistical analysis of 51 Group 1/Group 2 cases. In the 16 patients, after these specific treatments, mean spine and femur BMD increased over time, but significantly only in those cases including alendronate in their protocol. The study showed that in HIV patients on HAART BMD decrease, even osteoporosis, can be present persisting over time, particularly in PI in respect of NNRTI treated patients. The pathogenesis is probably multifactorial, the different antiviral drugs seeming to differently affect bone metabolism. Alendronate/Vitamin D/Calcium therapy can be useful to slow down bone mass loss and also improve osteoporosis/osteopenia conditions, thus, reducing fracture risk also continuing HAART.


Clinical outcomes from a randomised comparison of Microwave Endometrial Ablation with Thermal Balloon endometrial ablation for the treatment of heavy menstrual bleeding.
To compare the clinical outcomes of microwave endometrial ablation and thermal balloon ablation for the treatment of heavy menstrual bleeding. A double blind randomised controlled trial. A UK teaching hospital. Three hundred and twenty women requesting endometrial ablation. Operative data collection and patient completed postal questionnaires were used to ascertain women's satisfaction with outcome, acceptability of each procedure, changes in menstrual symptoms and health related quality of life and additional treatments received. Primary outcomes were satisfaction and menstrual scores 1 year. Secondary outcomes were operative differences, acceptability of treatment and changes in health related quality of life. Both technologies achieved high levels of satisfaction (-1%, 95% CI (-11, 9)). Menstrual scores were also similar (4%, 95% CI (-7, 19)) Microwave had a significantly shorter operating time, reduced usage of antiemetics and opiate analgesia, increased discharge by 6 hours and fewer device failures. Both treatments are acceptable to women, with high levels of satisfaction. Microwave is quicker to perform with faster hospital discharge.


Subclasses of oligodendrocytes populate the mouse hippocampus.
Oligodendrocytes are the myelin-forming cells of the central nervous system that facilitate transmission of axonal electrical impulses. Using transgenic mice expressing 2',3' cyclic nucleotide 3' phosphodiesterase (CNPase)-enhanced green fluorescent protein, a three-dimensional reconstruction tool and analysis, we illustrate that three morphologically different oligodendrocyte types exist in the hippocampus. Those of the ramified type have the most numerous processes, the largest cell body, occupy the largest area and form beaded-like structures, due to mitochondria aggregates, along the processes. Stellar-shaped oligodendrocytes have smaller cell bodies and their processes cover a significantly smaller area. Those of the smooth subtype have a small cell body with at most two processes. In addition to these types, a large number of oligodendrocytes were found that faintly express CNPase-enhanced green fluorescent protein. More than 50% of the faint type colocalized with NG2 and 91% with oligodendrocyte transcription factor-2, whereas 94% of NG2-immunoreactive and 45% of oligodendrocyte transcription factor-2-immunoreactive cells were faintly CNPase-enhanced green fluorescent protein positive. Based on the complexity of the overall structure, the three types probably represent stages of a maturation process such that one subtype can morph into another. Thus, the least complex 'smooth' cell would represent the youngest oligodendrocyte that matures into the stellar type and eventually progresses to become the most complex ramified oligodendrocyte. Investigation of the distribution pattern revealed that the highest density of oligodendrocytes was found in the stratum lacunosum-moleculare and the hilar region. The distribution analysis of oligodendrocyte subclasses revealed a tendency for different cell types to segregate in large non-overlapping areas. This observation suggests that morphologically, and possible functionally, different oligodendrocytes are topographically segregated.


Confocal imaging of a stratified medium.
The confocal imaging of stratified media (for example, thin-film structures) is investigated. A simple model is introduced for the imaging of a single layer in order to explore the axial resolution attainable. A rigorous model is also described and compared with experimental results from thin surface films. A theoretical treatment of imaging of stratified media with a continuously varying refractive index is presented, and the inverse problem of reconstructing the refractive-index profile from a confocal image is discussed.


Sociodemographic variation in the oral microbiome.
Variations in the oral microbiome are potentially implicated in social inequalities in oral disease, cancers, and metabolic disease. We describe sociodemographic variation of oral microbiomes in a diverse sample. We performed 16S rRNA sequencing on mouthwash specimens in a subsample (n = 282) of the 2013-2014 population-based New York City Health and Nutrition Examination Study. We examined differential abundance of 216 operational taxonomic units, and alpha and beta diversity by age, sex, income, education, nativity, and race/ethnicity. For comparison, we examined differential abundance by diet, smoking status, and oral health behaviors. Sixty-nine operational taxonomic units were differentially abundant by any sociodemographic variable (false discovery rate < 0.01), including 27 by race/ethnicity, 21 by family income, 19 by education, 3 by sex. We found 49 differentially abundant by smoking status, 23 by diet, 12 by oral health behaviors. Genera differing for multiple sociodemographic characteristics included Lactobacillus, Prevotella, Porphyromonas, Fusobacterium. We identified oral microbiome variation consistent with health inequalities, more taxa differing by race/ethnicity than diet, and more by SES variables than oral health behaviors. Investigation is warranted into possible mediating effects of the oral microbiome in social disparities in oral and metabolic diseases and cancers.


On the connection between the transverse tubules and the plasma membrane in frog semitendinosus skeletal muscle. Are caveolae the mouths of the transverse tubule system?
The transverse tubular system (TTS) of skeletal muscle fibers represents the morphological basis for the inward spread of conduction of the electrical signal that triggers muscle contraction. A historical account of the main steps contributing to the elucidation of the structure and function of the TSS has been presented by Huxley (1971). While the localization of the TSS and its association with the sarcoplasmic reticulum (SR) is well documented; there is still a need further to develop our knowledge of the morphology of the connection between the TSS and the plasma membrane. It is generally believed that the TSS opens directly to the extracellular space and that there is continuity between its membrane and the sarcolemma. However, direct observation of such a connection has been clearly shown only for the myotome of fish (Franzini-Armstrong and Porter, 1964). In other muscle fibers, only indirect evidence of the connection has been provided by experiments showing penetration of extracellular tracers into the TSS. These extracellular markers were also observed inside another membrane-bounded compartment consisting of round profiles named "caveolae" (Yamada, 1955) or "pinocytotic vesicles" (Ashurst, 1969). The present study deals with the communication between the TTS, caveolae, and plasma membrane (Peachey, 1965); Ezerman and Ishikawa, 1967; Schiaffino and Margreth, 1968; and Rayns et al., 1968). A detailed study of the caveolae compartment was undertaken with ruthenium red as an electron-dense tracer. As a result of this study, we propose that in certain species the caveolae compartment represents the transitional region in the connection between the TSS and the sarcolemma.


Post-Operative Iron Carboxymaltose May Have an Effect on Haemoglobin Levels in Cardiothoracic Surgical Patients on the ICU - an Observational Pilot Study about Anaemia Treatment with Intravenous Iron.
Post-operative anaemia is associated with increased morbidity and mortality. Positive effects of post-operative intravenous iron (IVI) after elective orthopaedic, abdominal and genitourinary surgery have been reported. The current observational trial investigated the prevalence of post-operative anaemia, the effect of IVI on haemoglobin levels, the use of blood transfusions and diagnoses related to infections. 1,265 patients on five ICUs of Münster University Hospital were screened for post-operative anaemia. On one ICU, patients were screened for iron deficiency and, if indicated, supplemented with 500 mg of ferric carboxymaltose. Primary outcome measures were haemoglobin levels, C-reactive protein, white blood cell count, transfusion requirements, documented infection and antibiotic treatment. Anaemia was prevalent in 86.2% of patients upon ICU admission. 429 patients were screened for iron deficiency anaemia. 95 patients were eligible, 35 were treated with IVI. An increase of +0.4 g/dl in Hb levels 7 days after IVI compared to -0.1 g/dl in non-treated anaemic patients was observed. The number of RBC transfusions, ICD codes related to infections and infectious parameters were similar between groups. Conclusions: IVI treatment was safe and resulted in higher median Hb levels. Randomized controlled trials are required to support the hypotheses of this study.


Astragalus Polysaccharide Protects Neurons and Stabilizes Mitochondrial in a Mouse Model of Parkinson Disease.
BACKGROUND Astragalus polysaccharides (APS) have a very good therapeutic effect in the treatment of neurodegenerative diseases and nerve injury disease. However, research on Parkinson disease (PD) treatment with APS is lacking. MATERIAL AND METHODS The present study was designed to explore the effects of APS on the protection of neurons and mitochondrial in a mouse model of PD using behavioral experiments, and observations of mitochondrial structure and transmembrane potential. RESULTS It was shown that APS could attenuate 1-methyl-4-pheyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor dysfunction (P<0.01), increase the proportion of TH-positive cells (P<0.01), reverse MPTP-induced mitochondrial structural damage, and reduce MPTP-induced high levels of reactive oxygen species (ROS) and increase MPTP-induced decrease in mitochondrial membrane potential. In addition, APS also decreased the bax/bcl2 ratio, and cytochrome-c and caspase-3 protein content (P<0.01) in substantia nigra in our mouse PD model. CONCLUSIONS APS provided a protective effect on neurons and mitochondrial in a mouse PD model.


Retinoblastoma.
Retinoblastoma, a neuroblastic tumor, is the most common primary intraocular malignancy of childhood. Patients usually present with leukokoria (white reflex or white pupil), detected in primary care. The mean age at diagnosis is 12 months for bilateral tumors and 24 months for unilateral tumors. If untreated, almost all patients die of intracranial extension and disseminated disease within two years. However, new diagnostic and treatment methods allow for a high cure rate (93 percent five-year survival in the United States), therefore it is important that primary care physicians recognize the manifestations of this malignancy. Diagnosis is primarily by history and complete ophthalmic examination, with studies including ultrasonography of the eye and imaging of the orbits and brain. Treatment modalities include laser thermotherapy, cryotherapy, radioactive plaques, external beam radiotherapy, chemotherapy, and enucleation. Prospective parents with a family history of retinoblastoma should be referred for genetic counseling. Office evaluation for a red reflex in children should be performed until three years of age. If leukokoria is observed, the patient should be examined by an ophthalmologist within one week.


Cancer Markers Selection Using Network-Based Cox Regression: A Methodological and Computational Practice.
International initiatives such as the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) are collecting multiple datasets at different genome-scales with the aim of identifying novel cancer biomarkers and predicting survival of patients. To analyze such data, several statistical methods have been applied, among them Cox regression models. Although these models provide a good statistical framework to analyze omic data, there is still a lack of studies that illustrate advantages and drawbacks in integrating biological information and selecting groups of biomarkers. In fact, classical Cox regression algorithms focus on the selection of a single biomarker, without taking into account the strong correlation between genes. Even though network-based Cox regression algorithms overcome such drawbacks, such network-based approaches are less widely used within the life science community. In this article, we aim to provide a clear methodological framework on the use of such approaches in order to turn cancer research results into clinical applications. Therefore, we first discuss the rationale and the practical usage of three recently proposed network-based Cox regression algorithms (i.e., Net-Cox, AdaLnet, and fastcox). Then, we show how to combine existing biological knowledge and available data with such algorithms to identify networks of cancer biomarkers and to estimate survival of patients. Finally, we describe in detail a new permutation-based approach to better validate the significance of the selection in terms of cancer gene signatures and pathway/networks identification. We illustrate the proposed methodology by means of both simulations and real case studies. Overall, the aim of our work is two-fold. Firstly, to show how network-based Cox regression models can be used to integrate biological knowledge (e.g., multi-omics data) for the analysis of survival data. Secondly, to provide a clear methodological and computational approach for investigating cancers regulatory networks.


Overview of integrative tools and methods in assessing ecological integrity in estuarine and coastal systems worldwide.
In recent years, several sets of legislation worldwide (Oceans Act in USA, Australia or Canada; Water Framework Directive or Marine Strategy in Europe, National Water Act in South Africa, etc.) have been developed in order to address ecological quality or integrity, within estuarine and coastal systems. Most such legislation seeks to define quality in an integrative way, by using several biological elements, together with physico-chemical and pollution elements. Such an approach allows assessment of ecological status at the ecosystem level ('ecosystem approach' or 'holistic approach' methodologies), rather than at species level (e.g. mussel biomonitoring or Mussel Watch) or just at chemical level (i.e. quality objectives) alone. Increasing attention has been paid to the development of tools for different physico-chemical or biological (phytoplankton, zooplankton, benthos, algae, phanerogams, fishes) elements of the ecosystems. However, few methodologies integrate all the elements into a single evaluation of a water body. The need for such integrative tools to assess ecosystem quality is very important, both from a scientific and stakeholder point of view. Politicians and managers need information from simple and pragmatic, but scientifically sound methodologies, in order to show to society the evolution of a zone (estuary, coastal area, etc.), taking into account human pressures or recovery processes. These approaches include: (i) multidisciplinarity, inherent in the teams involved in their implementation; (ii) integration of biotic and abiotic factors; (iii) accurate and validated methods in determining ecological integrity; and (iv) adequate indicators to follow the evolution of the monitored ecosystems. While some countries increasingly use the establishment of marine parks to conserve marine biodiversity and ecological integrity, there is awareness (e.g. in Australia) that conservation and management of marine ecosystems cannot be restricted to Marine Protected Areas but must include areas outside such reserves. This contribution reviews the current situation of integrative ecological assessment worldwide, by presenting several examples from each of the continents: Africa, Asia, Australia, Europe and North America.


Statistical properties of radio-frequency and envelope-detected signals with applications to medical ultrasound.
Both radio-frequency (rf) and envelope-detected signal analyses have lead to successful tissue discrimination in medical ultrasound. The extrapolation from tissue discrimination to a description of the tissue structure requires an analysis of the statistics of complex signals. To that end, first- and second-order statistics of complex random signals are reviewed, and an example is taken from rf signal analysis of the backscattered echoes from diffuse scatterers. In this case the scattering form factor of small scatterers can be easily separated from long-range structure and corrected for the transducer characteristics, thereby yielding an instrument-independent tissue signature. The statistics of the more economical envelope- and square-law-detected signals are derived next and found to be almost identical when normalized autocorrelation functions are used. Of the two nonlinear methods of detection, the square-law or intensity scheme gives rise to statistics that are more transparent to physical insight. Moreover, an analysis of the intensity-correlation structure indicates that the contributions to the total echo signal from the diffuse scatter and from the steady and variable components of coherent scatter can still be separated and used for tissue characterization. However, this analysis is not system independent. Finally, the statistical methods of this paper may be applied directly to envelope signals in nuclear-magnetic-resonance imaging because of the approximate equivalence of second-order statistics for magnitude and intensity.


Blood Pressure Profiles in Infants With Hypoxic Ischemic Encephalopathy (HIE), Response to Dopamine, and Association With Brain Injury.
Objective: To describe mean arterial blood pressure (MABP), responsiveness to dopamine, and relationship to brain injury in infants with moderate/severe hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). We hypothesized that, when utilized, dopamine would rapidly and effectively increase MABP in treated patients. Methods: Continuous arterial blood pressure measurements were prospectively recorded from infants with moderate/severe HIE undergoing TH in a multi-institutional cohort from 2010 to 2018. Treatment with dopamine was at the discretion of the medical team for hypotension/hypoperfusion. MABP values of treated infants were compared to those obtained at an equivalent time period in control infants receiving TH but not dopamine (24 h after birth). MRI was obtained per unit protocols and included T1/T2/DWI sequences. Injury was classified as no injury/mild injury or moderate/severe injury using a standardized scoring system. Seizures were confirmed with conventional EEG. Results: Eighteen infants were treated with dopamine and were similar to untreated controls (n = 36) with the exception of lower cord gas pH (6.92 ± 0.2 vs. 7.07 ± 0.2, p < 0.05). Dopamine was initiated at a mean of 24 h after birth. MABP was significantly lower in the dopamine group at the start of therapy (39.9 ± 2.0 vs. 49.1 ± 1.3, p < 0.01) and 1 h later (44.3 ± 2.0 vs. 49.8 ± 1.1, p < 0.05). However, after 9 h of treatment, dopamine increased the MABP by an average of 9 mmHg and MABP values were similar to untreated controls for the remainder of the observation period. There were no significant differences in rates of seizures, brain injury, or death. Conclusion: Neonates with moderate/severe HIE treated with dopamine during TH had MABP significantly lower than controls. The majority of infants responded to dopamine monotherapy following adequate volume resuscitation. An association between requirement for dopamine and severity of brain injury was not detected.


Energy landscapes of atomic clusters as black box optimization benchmarks.
We present the energy minimization of atomic clusters as a promising problem class for continuous black box optimization benchmarks. Finding the arrangement of atoms that minimizes a given potential energy is a specific instance of the more general class of geometry optimization or packing problems, which are generally NP-complete. Atomic clusters are a well-studied subject in physics and chemistry. From the large set of available cluster optimization problems, we propose two specific instances: Cohn-Kumar clusters and Lennard-Jones clusters. The potential energies of these clusters are governed by distance-dependent pairwise interaction potentials. The resulting collection of landscapes is composed of smooth and rugged single-funnel topologies, as well as tunable double-funnel topologies. In addition, all problems possess a feature that is not covered by the synthetic functions in current black box optimization test suites: isospectral symmetry. This property implies that any atomic arrangement is uniquely defined by the pairwise distance spectrum, rather than the absolute atomic positions. We hence suggest that the presented problem instances should be included in black box optimization benchmark suites.


Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems.
Heterozygous mutations in the COL1A1 or COL1A2 gene encoding the alpha1 and alpha2 chain of type I collagen generally cause either osteogenesis imperfecta or the arthrochalasis form of Ehlers-Danlos syndrome (EDS). Homozygous or compound heterozygous COL1A2 mutations resulting in complete deficiency of the proalpha2(I) collagen chains are extremely rare and have been reported in only a few patients, albeit with variable phenotypic outcome. The clinical features of the proband, a 6 year old boy, were recorded. Analysis of proalpha and alpha-collagen chains was performed by SDS-polyacrylamide gel electrophoresis using the Laemmli buffer system. Single stranded conformation polymorphism analysis of the proband's DNA was also carried out. In this report we show that complete lack of proalpha2(I) collagen chains can present as a phenotype reminiscent of mild hypermobility EDS during childhood. Biochemical analysis of collagens extracted from skin fibroblasts is a powerful tool to detect the subset of patients with complete absence of proalpha2(I) collagen chains, and in these patients, careful cardiac follow up with ultrasonography is highly recommended because of the risk for cardiac valvular problems in adulthood.


Clinical feature of diagnostic challenging cases for pleural biopsy in patient with malignant pleural mesothelioma.
Pleural biopsy through video-assisted thoracic surgery (VATS pleural biopsy) is the most reliable diagnostic procedure for malignant pleural mesothelioma (MPM). However, definitive diagnosis of MPM is occasionally difficult to establish. This study aims to investigate clinicopathological features of MPM patients who failed diagnosis by the first VATS pleural biopsy. Four hundred consecutive patients with suspected MPM who received VATS pleural biopsy between March 2004 and July 2017 were enrolled in this retrospective study. Patients, whose histological diagnoses were not definitive in the first VATS pleural biopsy, were followed up as atypical mesothelial proliferation (AMP) or non-specific pleuritis (NSP). Re-examination was performed in cases strongly suspected of having MPM. Of the 400 patients, 267 (66.8%) were pathologically diagnosed with MPM, 25 with metastatic carcinoma and 6 with benign pleural disease by the first VATS pleural biopsy. Of the remaining 102 patients diagnosed with AMP or NSP, 10 patients (9.8%) were subsequently diagnosed with MPM. Analysis of the clinical course revealed that only insufficient tissue for diagnosis was obtained via VATS pleural biopsy in all cases and that it was caused by very early stage without visible tumour in 4 patients, intrathoracic inflammation in 4 and desmoplastic MPM in 2. In our review, 9.8% of patients diagnosed with AMP or NSP in first VATS pleural biopsy were subsequently diagnosed with MPM due to insufficient tissue for diagnosis. Definitive diagnosis via VATS pleural biopsy is sometimes challenging in following situation; very early stage, intrathoracic inflammation and desmoplastic MPM.


Gastro-intestinal stromal tumours (GISTs) - the Pretoria experience and a literature review.
To analyse the presentation and management of patients with gastrointestinal stromal tumours (GISTs) at Pretoria hospitals. A retrospective study was done in which all available clinical records of primary c-KIT positive GISTs were analysed. Secondary and tertiary care institutions in Pretoria, including both private and public hospitals. Subjects. The population studied included all individuals treated at Pretoria hospitals from 17 July 2000 to 1 April 2009 who had a GIST confirmed with immunohistochemical c KIT staining. Patients with incomplete or inaccessible clinical records were excluded. Outcome measures. Patient demographics including gender, age and race; presenting symptoms and signs; results of special investigations; and treatment. Fifty-four cases were identified for inclusion in the study. The age of the subjects ranged from 15 to 83 years. The male-to-female ratio was 1.5:1. The organ most commonly affected was the stomach, and abdominal pain and weight loss were the most common presenting symptoms. Seventy-six per cent of the patients were treated surgically, and 24% received Imatinib. GISTs often present late with non-specific symptoms, and are frequently discovered incidentally. Large tumours tend to be malignant.


The pericentriolar lattice of PtK2 cells exhibits temperature and calcium-modulated behavior.
In this study, we demonstrate that manipulations of temperature and free calcium alter the morphology of the centrin-containing pericentriolar lattice of PtK2 cells. Immunofluorescence microscopy reveals that low-temperature incubation (4 degrees C) causes anti-centrin-labeled pericentrosomal spots to coalesce in the peripheral cytoplasm, and fuses small spots into larger spots near the cell center. At electron microscopic resolution, well-formed pericentriolar satellites appear around the centrioles in response to incubation at 4 degrees C. Elevated free calcium enhances these low-temperature-dependent effects. The data suggest that pericentrosomal spots correspond to one or more pericentriolar satellites, and that pericentriolar satellites and centrosomal matrix are interconvertable forms of the same material. Transient elevation of intracellular free calcium at 37 degrees C from a basal level of 3.7 x 10(-8) M to a peak level of 2.0 x 10(-7) M within 30 seconds with ionomycin results in a 35% increase in pericentrosomal spot number throughout the cytoplasm. The number of pericentrosomal spots is 50% larger 2 minutes after ionomycin addition; these spots are also nearer to the cell center as compared to 30 seconds after ionomycin addition. As intracellular free calcium returns to a basal level over 5 minutes, the number of spots and their cellular distribution resume a pretreatment value and pattern. We interpret these observations to indicate movement of pericentrosomal spots toward the cell center in response to the flux in intracellular free calcium. Alternatively, it is possible that no movement has occurred, but that the rise in free calcium has unmasked an epitope responsive to our anti-centrin antiserum. Regardless of the interpretation, we conclude that the pericentriolar lattice exhibits calcium-modulated behavior.