Southwest Oncology Group phase II trial of concurrent carboplatin, etoposide, and radiation for poor-risk stage III non-small-cell lung cancer.
A phase II study was conducted by the Southwest Oncology Group (SWOG) to assess the efficacy and toxicity of concurrent carboplatin, etoposide, and thoracic radiation (XRT) in a defined population of poor-risk patients with stage III non-small-cell lung cancer (NSCLC). Patients with stage III NSCLC were eligible if they were excluded from cisplatin-based protocols because of poor pulmonary or renal function, history of congestive heart failure, hearing loss, peripheral neuropathy, or weight loss. Carboplatin 200 mg/m2 daily intravenously days 1, 3, 29, and 31 and etoposide 50 mg/m2 daily intravenously days 1 through 4 and 29 through 32 were administered. Beginning day 1, XRT was delivered at 1.8 to 2.0 Gy daily to a total dose of 61 Gy. Within a period of 1 year, 63 patients were registered and 60 were eligible. Patient characteristics were age 47 to 79 years, performance status 0 to 1 (82%) and 2 (18%), and stages IIIA (60%) and IIIB (40%) NSCLC. The most common grades 3 and 4 toxicities included leukopenia (50%), thrombocytopenia (23%), and esophagitis (15%). There were no treatment-related deaths. The overall confirmed response rate was 29%, and median overall survival was 13 months (95% confidence interval, 11 to 14 months). The 2-year survival rate was 21%. This chemoradiotherapy regimen is well tolerated in poor-risk patients and yields a median survival similar to that of good-risk patients who received cisplatin-based chemoradiotherapy. This chemoradiotherapy regimen will be compared with XRT alone in poor-risk patients with stage III NSCLC in a randomized phase III trial.


Reovirus activates a caspase-independent cell death pathway.
Virus-induced apoptosis is thought to be the primary mechanism of cell death following reovirus infection. Induction of cell death following reovirus infection is initiated by the incoming viral capsid proteins during cell entry and occurs via NF-κB-dependent activation of classical apoptotic pathways. Prototype reovirus strain T3D displays a higher cell-killing potential than strain T1L. To investigate how signaling pathways initiated by T3D and T1L differ, we methodically analyzed cell death pathways activated by these two viruses in L929 cells. We found that T3D activates NF-κB, initiator caspases, and effector caspases to a significantly greater extent than T1L. Surprisingly, blockade of NF-κB or caspases did not affect T3D-induced cell death. Cell death following T3D infection resulted in a reduction in cellular ATP levels and was sensitive to inhibition of the kinase activity of receptor interacting protein 1 (RIP1). Furthermore, membranes of T3D-infected cells were compromised. Based on the dispensability of caspases, a requirement for RIP1 kinase function, and the physiological status of infected cells, we conclude that reovirus can also induce an alternate, necrotic form of cell death described as necroptosis. We also found that induction of necroptosis requires synthesis of viral RNA or proteins, a step distinct from that necessary for the induction of apoptosis. Thus, our studies reveal that two different events in the reovirus replication cycle can injure host cells by distinct mechanisms. Virus-induced cell death is a determinant of pathogenesis. Mammalian reovirus is a versatile experimental model for identifying viral and host intermediaries that contribute to cell death and for examining how these factors influence viral disease. In this study, we identified that in addition to apoptosis, a regulated form of cell death, reovirus is capable of inducing an alternate form of controlled cell death known as necroptosis. Death by this pathway perturbs the integrity of host membranes and likely triggers inflammation. We also found that apoptosis and necroptosis following viral infection are activated by distinct mechanisms. Our results suggest that host cells can detect different stages of viral infection and attempt to limit viral replication through different forms of cellular suicide. While these death responses may aid in curbing viral spread, they can also exacerbate tissue injury and disease following infection.


Garcinoic acid prevents β-amyloid (Aβ) deposition in the mouse brain.
Garcinoic acid (GA or δ-T3-13'COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in β-amyloid (Aβ) metabolism and progression of Alzheimer's disease (AD). In this study, we investigated GA's effects on Aβ oligomer formation and deposition. Specifically, we compared them with those of other vitamin E analogs and the soy isoflavone genistein, a natural agonist of peroxisome proliferator-activated receptor γ (PPARγ) that has therapeutic potential for managing AD. GA significantly reduced Aβ aggregation and accumulation in mouse cortical astrocytes. Similarly to genistein, GA up-regulated PPARγ expression and apolipoprotein E (ApoE) efflux in these cells with an efficacy that was comparable with that of its metabolic precursor δ-tocotrienol and higher than those of α-tocopherol metabolites. Unlike for genistein and the other vitamin E compounds, the GA-induced restoration of ApoE efflux was not affected by pharmacological inhibition of PPARγ activity, and specific activation of pregnane X receptor (PXR) was observed together with ApoE and multidrug resistance protein 1 (MDR1) membrane transporter up-regulation in both the mouse astrocytes and brain tissue. These effects of GA were associated with reduced Aβ deposition in the brain of TgCRND8 mice, a transgenic AD model. In conclusion, GA holds potential for preventing Aβ oligomerization and deposition in the brain. The mechanistic aspects of GA's properties appear to be distinct from those of other vitamin E metabolites and of genistein.


Improvement of the in vitro safety profile and cytoprotective efficacy of amifostine against chemotherapy by PEGylation strategy.
Amifostine, an organic thiophosphate prodrug, has been clinically utilized for selective protection of normal tissues with high expression of alkaline phosphatase from oxidative damage elicited by chemotherapy or radiotherapy. However, the patients receiving amifostine suffer from severe dose-dependent adverse effects. Strategies for improvement of the protective efficacy and toxicity profile of amifostine are urgently required. Here we constructed a PEGylated amifostine (PEG-amifostine) through conjugation of amifostine to the 4-arm PEG (5000 Da) by a mild one-step reaction. The relatively large PEG-amifostine molecules clustered into spherical nanoparticles, resulting in distinct hydrolysis properties, cell uptake profile and antioxidative activity compared with the free small molecules. PEGylation prolonged the hydrolysis time of amifostine, providing sustained transformation to its functional metabolites. PEG-amifostine could be internalized into cells and translocated to acidic organelles in a time-dependent manner. The intrinsic cytotoxicity of amifostine, which is related to the reductive reactivity of its metabolites and their ability to diffuse readily, was attenuated after PEGylation. This modification impeded the interaction between free sulfhydryls and functional biomolecules, providing PEG-amifostine with an improved safety profile in vitro. Moreover, PEG-amifostine showed higher efficiency in the elimination of reactive oxygen species and prevention of cisplatin-induced cytotoxicity compared with free amifostine. Overall, our study for the first time developed a PEGylated form of amifostine which significantly improved the efficacy and decreased the adverse effects of this antioxidant in vitro with great promise for clinical translation. In vivo study is urgently needed to confirm and redeem the cytoprotective effects of the PEG-amifostine in chemotherapy.


Cytoplasmic interactions of syndecan-4 orchestrate adhesion receptor and growth factor receptor signalling.
Syndecan-4 is a ubiquitous transmembrane proteoglycan that localizes to the focal adhesions of adherent cells and binds to a range of extracellular ligands, including growth factors and extracellular-matrix proteins. Engagement of syndecan-4 is essential for adhesion formation in cells adhering via certain integrins, and for cell proliferation and migration in response to growth factors. The cytoplasmic domain of syndecan-4 interacts with a number of signalling and structural proteins, and both extracellular and cytoplasmic domains are necessary for regulated activation of associated transmembrane receptors. PDZ domain-containing scaffold proteins (syntenin and CASK) bind to the C-terminus of the syndecan-4 cytoplasmic domain and co-ordinate clustering of receptors and connection to the actin cytoskeleton. Syndecan-4 also binds and activates protein kinase Calpha in the presence of phosphatidylinositol 4,5-bisphosphate, and regulates signalling by Rho-family GTPases and focal adhesion kinase. This review discusses the cytoplasmic interactions of syndecan-4 and how they affect cell behaviour as a consequence of the interaction with extracellular ligands. These conclusions also offer an insight into the role of syndecan-4 in vivo, and are consistent with phenotypes generated as a consequence of abnormal syndecan-4 expression in pathologies and gene disruption studies.


The risk of sustained sexual transmission of Zika is underestimated.
Pathogens often follow more than one transmission route during outbreaks-from needle sharing plus sexual transmission of HIV to small droplet aerosol plus fomite transmission of influenza. Thus, controlling an infectious disease outbreak often requires characterizing the risk associated with multiple mechanisms of transmission. For example, during the Ebola virus outbreak in West Africa, weighing the relative importance of funeral versus health care worker transmission was essential to stopping disease spread. As a result, strategic policy decisions regarding interventions must rely on accurately characterizing risks associated with multiple transmission routes. The ongoing Zika virus (ZIKV) outbreak challenges our conventional methodologies for translating case-counts into route-specific transmission risk. Critically, most approaches will fail to accurately estimate the risk of sustained sexual transmission of a pathogen that is primarily vectored by a mosquito-such as the risk of sustained sexual transmission of ZIKV. By computationally investigating a novel mathematical approach for multi-route pathogens, our results suggest that previous epidemic threshold estimates could under-estimate the risk of sustained sexual transmission by at least an order of magnitude. This result, coupled with emerging clinical, epidemiological, and experimental evidence for an increased risk of sexual transmission, would strongly support recent calls to classify ZIKV as a sexually transmitted infection.


High spatial resolution infrared micro-spectroscopy reveals the mechanism of leaf lignin decomposition by aquatic fungi.
Organic carbon is a critical component of aquatic systems, providing energy storage and transfer between organisms. Fungi are a major decomposer group in the aquatic carbon cycle, and are one of few groups thought to be capable of breaking down woody (lignified) tissue. In this work we have used high spatial resolution (synchrotron light source) infrared micro-spectroscopy to study the interaction between aquatic fungi and lignified leaf vein material (xylem) from River Redgum trees (E. camaldulensis) endemic to the lowland rivers of South-Eastern Australia. The work provides spatially explicit evidence that fungal colonisation of leaf litter involves the oxidative breakdown of lignin immediately adjacent to the fungal tissue and depletion of the lignin-bound cellulose. Cellulose depletion occurs over relatively short length scales (5-15 µm) and highlights the likely importance of mechanical breakdown in accessing the carbohydrate content of this resource. Low bioavailability compounds (oxidized lignin and polyphenols of plant origin) remain in colonised leaves, even after fungal activity diminishes, and suggests a possible pathway for the sequestration of carbon in wetlands. The work shows that fungi likely have a critical role in the partitioning of lignified material into a biodegradable fraction that can re-enter the aquatic carbon cycle, and a recalcitrant fraction that enters long-term storage in sediments or contribute to the formation of dissolved organic carbon in the water column.


Two-dimensional germanium monochalcogenide photocatalyst for water splitting under ultraviolet, visible to near-infrared light.
Full utilization of solar energy to split water into hydrogen and oxygen is an efficient way to solve the current energy problem. Graphene-like germanium monochalcogenides (GeS or GeSe) are proposed here as efficient photocatalysts for water splitting under a broad range from ultraviolet, visible to near-infrared light dependent on their thickness. Compared to traditional photocatalysts, GeS and GeSe possess a large intrinsic dipole and introduce an internal electric field directing from Ge surface to S/Se surface, which causes notable band bending. The band bending means they possess favorable band positions located outside the reduction potential and oxidation potential of water, overcoming the restriction of their band gaps. Moreover, multilayer GeS and GeSe further provide a good separation of electrons and holes, which effectively reduces the probability of their recombination and ensures photocatalytic activity with high efficiency.


Lead poisoning in blind children.
Many partially sighted children use the mouth, lips, and tongue as an aid in identifying objects-this has been termed discriminatory pica. Investigation of a case of lead poisoning in a pupil at a residential school for the blind led to the discovery of others with asymptomatic lead poisoning, all of whom had the same habit.All the children recovered without treatment when they abandoned their habit of discrimination by use of the mouth. Authorities responsible for schools for the blind should be aware of this risk.


17Beta-estradiol regulation of T-type calcium channels in gonadotropin-releasing hormone neurons.
T-type calcium channels are responsible for generating low-threshold spikes that facilitate burst firing and neurotransmitter release in neurons. Gonadotropin-releasing hormone (GnRH) neurons exhibit burst firing, but the underlying conductances are not known. Previously, we found that 17beta-estradiol (E2) increases T-type channel expression and excitability of hypothalamic arcuate nucleus neurons. Therefore, we used ovariectomized oil- or E2-treated EGFP (enhanced green fluorescent protein)-GnRH mice to explore the expression and E2 regulation of T-type channels in GnRH neurons. Based on single-cell reverse transcriptase-PCR and real-time PCR quantification of the T-type channel alpha(1) subunits, we found that all three subunits were expressed in GnRH neurons, with expression levels as follows: Cav3.3 > or = Cav3.2 > Cav3.1. The mRNA expression of the three subunits was increased with surge-inducing levels of E2 during the morning. During the afternoon, Cav3.3 mRNA expression remained elevated, whereas Cav3.1 and Cav3.2 were decreased. The membrane estrogen receptor agonist STX increased the expression of Cav3.3 but not Cav3.2 in GnRH neurons. Whole-cell patch recordings in GnRH neurons revealed that E2 treatment significantly augmented T-type current density at both time points and increased the rebound excitation during the afternoon. Although E2 regulated the mRNA expression of all three subunits in GnRH neurons, the increased expression combined with the slower inactivation kinetics of the T-type current indicates that Cav3.3 may be the most important for bursting activity associated with the GnRH/LH (luteinizing hormone) surge. The E2-induced increase in mRNA expression, which depends in part on membrane-initiated signaling, leads to increased channel function and neuronal excitability and could be a mechanism by which E2 facilitates burst firing and cyclic GnRH neurosecretion.


Probiotics for Trauma Patients: Should We Be Taking a Precautionary Approach?
The use of probiotics in the hospital setting is largely understudied and highly controversial. Probiotics are living organisms that, when taken internally, can produce an immunomodulating effect and improve the gastrointestinal (GI) mucosal barrier. Although used for centuries by healthy individuals for GI health, their use in the hospital setting is now gaining wide attention for the prevention of infectious complications such as antibiotic-associated diarrhea, Clostridium difficile infections, multiple-organ dysfunction syndrome, and ventilator-associated pneumonia. However, current understanding of the efficacy of probiotics in the acute care setting is confounded by the inconsistencies in the literature with regard to the strain of probiotic being studied, optimal dosage, and timing and duration of dosing, which make the formulation of clinical practice guidelines difficult. Although the safety of probiotics has been confirmed when used for the prevention and treatment of certain diseases, practitioners remain hesitant to administer them to their patients, citing the lack of high-quality studies clearly demonstrating efficacy and safety. Infection is a cause of late death in trauma patients, but only recently has research been conducted on the use of probiotics specifically for the prevention of hospital-acquired infections in trauma patients. In the face of such limited but promising research, is it reasonable to use probiotics for the prevention of infection in hospitalized trauma patients and improve outcomes? Use of the "precautionary principle" may be useful in this instance.


Analysis of multidrug-resistant bacteria in 3223 patients with hospital-acquired infections (HAI) from a tertiary general hospital in China.
The frequency of antimicrobial resistance has increased globally due to misuse and overuse of antibiotics, and multi-drug resistant (MDR) bacteria are now recognized as a major cause of hospital-acquired infections (HAI). Our aim was to investigate the prevalence, distribution, and antimicrobial susceptibility rates of MDR bacteria in patients with HAI from a tertiary hospital in China. We retrospectively evaluated all patients with a confirmed diagnosis of bacterial infection at a tertiary general hospital in Jining, for the period between January 2012 and December 2014. The following clinical and demographic data were collected: age, sex, specimens, treatment, microbiology results, and antibiotic resistance patterns of isolates. Bacterial identification and susceptibility testing were performed using VITEK 2 COMPACT system. We screened a total of 15,588 patients, out of which 7579 (48.6%) had an HAI. MDR showed 3223 out of 7579 isolates (42.5%). The most frequently isolated MDR bacteria in patients with HAI were extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (n = 1216/3223, 37.7%), MDR Pseudomonas aeruginosa (n = 627/3223, 19.5%) and MDR Acinetobacter baumannii (n = 588/3223, 18.2%). MDR-HAI were more common in males (2074/3223, 64.4%) and in elderly patients (≥60 years; 1196/3223, 37.1%). Sputum was the main source of MDR isolates (2056/3223, 63.8%). Patients with MDR-HAI were predominantly distributed in different types of intensive care units. MDR strains in our study showed resistance to most current antibiotics. Overall, patients with HAI infections attributed to MDR bacteria were widely distributed in our hospital. Enhanced surveillance of MDR bacteria is critical for guiding the rational use of antibiotics and reducing the incidence of HAI.


A solid phase extraction procedure for the determination of Cd(II) and Pb(II) ions in food and water samples by flame atomic absorption spectrometry.
A relatively rapid, accurate and precise solid phase extraction method is presented for the determination of cadmium(II) and lead(II) in various food and water samples. Quantitation is carried out by flame atomic absorption spectrometry (FAAS). The method is based on the retention of the trace metal ions on Dowex Marathon C, a strong acid cation exchange resin. Some important parameters affecting the analytical performance of the method such as pH, flow rate and volume of the sample solution; type, concentration, volume, flow rate of the eluent; and matrix effects on the retention of the metal ions were investigated. Common coexisting ions did not interfere on the separation and determination of the analytes. The detection limits (3 σb) for Cd(II) and Pb(II) were found as 0.13 and 0.18 μg L(-1), respectively, while the limit of quantification values (10 σb) were computed as 0.43 and 0.60 μg L(-1) for the same sequence of the analytes. The precision (as relative standard deviation was lower than 4% at 5 μg L(-1) Cd(II) and 10 μg L(-1) Pb(II) levels, and the preconcentration factor was found to be 250. The accuracy of the proposed procedure was verified by analysing the certified reference materials, SPS-WW2 Batch 108 wastewater level 2 and INCT-TL-1 tea leaves, with the satisfactory results. In addition, for the accuracy of the method the recovery studies (⩾ 95%) were carried out. The method was applied to the determination of the analytes in the various natural waters (lake water, tap water, waste water with boric acid, waste water with H2SO4) and food samples (pomegranate flower, organic pear, radish leaf, lamb meat, etc.), and good results were obtained. While the food samples almost do not contain cadmium, they have included lead at low levels of 0.13-1.12 μg g(-1).


Reflective properties of randomly rough surfaces under large incidence angles.
The reflective properties of randomly rough surfaces at large incidence angles have been reported due to their potential applications in some of the radiative heat transfer research areas. The main purpose of this work is to investigate the formation mechanism of the specular reflection peak of rough surfaces at large incidence angles. The bidirectional reflectance distribution function (BRDF) of rough aluminum surfaces with different roughnesses at different incident angles is measured by a three-axis automated scatterometer. This study used a validated and accurate computational model, the rigorous coupled-wave analysis (RCWA) method, to compare and analyze the measurement BRDF results. It is found that the RCWA results show the same trend of specular peak as the measurement. This paper mainly focuses on the relative roughness at the range of 0.16<σ/λ<5.35. As the relative roughness decreases, the specular peak enhancement dramatically increases and the scattering region significantly reduces, especially under large incidence angles. The RCWA and the Rayleigh criterion results have been compared, showing that the relative error of the total integrated scatter increases as the roughness of the surface increases at large incidence angles. In addition, the zero-order diffractive power calculated by RCWA and the reflectance calculated by Fresnel equations are compared. The comparison shows that the relative error declines sharply when the incident angle is large and the roughness is small.


Psychological adjustment and knowledge about hereditary hemochromatosis in a clinic-based sample: a prospective study.
This study assessed psychological adjustment and quality of life relative to population-based norms and knowledge about hereditary hemochromatosis in a sample of 101 patients who attended a hemochromatosis clinic. Participants were assessed prior to their clinic visit, and two weeks and 12 months after attendance, using self-administered questionnaires. Mean Mental Health Component Scores from the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) (45.3, 95% CI 43.2, 47.4) were as compromised as those found amongst stroke victims (45.9, 95% CI 42.8, 49.0) who had participated in a national health survey. Recall of the genetic testing result was less than optimal, in that only 69.3% of those with genetic testing results knew whether they carried one or two mutations. This study demonstrates that patients would benefit from routine assessment of psychological distress and referral to mental health professionals of those whose levels of distress suggest a need for clinical intervention. Results also show that patients may benefit from strategies aimed at improving recall of genetic testing results.


A new socioeconomic status measure for vaccine research in children using individual housing data: a population-based case-control study.
We recently developed HOUSES, an individual housing-based socioeconomic status (SES) measurement for health disparities research. We assessed whether HOUSES was associated with risk of pertussis and pertussis vaccine up-to-date status in children. The study utilized a previous population-based case-control study cohort assembled during the 2004-2005 pertussis outbreak. We collected data on pertussis vaccine status (up-to-date status) at the time of the index date. Using a z-score for housing value, actual square footage, and numbers of bedrooms and bathrooms, HOUSES was formulated in continuous variable and categorized into quartiles. Vaccine up-to-date status was compared among subjects with different SES as measured by HOUSES using a chi-square test and logistic regression models. Of the 391 eligible pediatric subjects (median age of 13.1 years with male sex of 55 %), 363 (93 %) were successfully geocoded to formulate HOUSES index. HOUSES was not associated with the risk of pertussis (p = 0.82). Pertussis vaccine up-to-date statuses were 79, 86, 83, and 94 % for children in the first (the lowest SES), second, third, and fourth quartiles of HOUSES, respectively (p = 0.03). HOUSES as a continuous variable was associated with pertussis vaccine up-to-date status (adjusted OR: 1.15 per increment of one unit of HOUSES, 95 % CI: 1.04-1.27, p = 0.008). While HOUSES is not associated with the risk of pertussis, it predicts vaccine up-to-date status among children with different SES. HOUSES may be a useful tool for vaccine delivery research among children.


Particle Hydrogels Based on Hyaluronic Acid Building Blocks.
The extracellular matrix (ECM) provides tissues with the mechanical support, space, and bioactive signals needed for homeostasis or tissue repair after wounding or disease. Hydrogel based scaffolds that can match the bulk mechanical properties of the target tissue have been extensively explored as ECM mimics. Although the addition of microporosity to hydrogel scaffolds has been shown to enhance cell/tissue-material integration, the introduction of microporosity often involves harsh chemical methods, which limit bioactive signal incorporation and injectability. Particle hydrogels are an emerging platform to generate in situ forming microporous scaffolds. In this approach, μgel particles are annealed to each other to form a bulk scaffold that is porous because of the void space left by the packed microgels. In the present work, we discuss the formation of hyaluronic acid-based microfluidic generated microgels for the generation of a completely biodegradable material. The generation of particle scaffolds requires two orthogonal chemistries, one for microgel generation and one for microgel annealing and scaffold formation. Here we explore three orthogonal annealing chemistries based on an enzymatic reaction, light based radical polymerization, and amine/carboxylic acid based cross-linking to demonstrate the versatility of our particle hydrogels and explore potential physical differences between the approaches. We explore the connectivity of the generated pores, the pore area/void fraction of the resulting scaffold, the mechanical properties of the scaffold, and cell spreading within scaffolds formed with the three different annealing mechanisms.


Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma.
Gastric adenocarcinoma of fundic gland type (GAFG), which is a rare variant of gastric cancer, is reportedly associated with both Wnt/β-catenin signaling activation and guanine nucleotide binding protein, alpha stimulating complex (GNAS) mutations. This study aimed to elucidate potential roles of the Sonic hedgehog (Shh) signaling pathway in GAFG. We performed immunostaining for β-catenin and Shh signal-associated proteins, including Patched (Ptch), Smoothened (Smo), and Glioma-associated oncogene-1 (Gli1), and the direct sequencing of GNAS/BRAF/KRAS in 27 GAFGs, and compared them with 30 conventional gastric adenocarcinomas (CGAs). GAFGs exhibited significantly lower immunoreactivity scores for Ptch, Smo, and Gli1 than CGAs. Moreover, while the Ptch score was significantly lower in the GAFG tumor areas than in the non-neoplastic areas adjacent to GAFG, the score was significantly higher in the CGA tumor areas than in the non-neoplastic areas. Similar trends were observed in the scores for Smo and Gli1. β-Catenin expression and GNAS mutations were found in 22 (81%) and 8 (30%) of the 27 GAFGs respectively. Gli1 expression was significantly associated with mutations in GNAS. GAFG and CGA exhibited distinct Ptch, Smo, and Gli1 expression patterns. Downregulation of the Shh signaling pathway, as well as activation of the Wnt/β-catenin signaling pathway, may therefore be associated with tumorigenesis in GAFG.


The Evolutionary Origins of Hierarchy.
Hierarchical organization-the recursive composition of sub-modules-is ubiquitous in biological networks, including neural, metabolic, ecological, and genetic regulatory networks, and in human-made systems, such as large organizations and the Internet. To date, most research on hierarchy in networks has been limited to quantifying this property. However, an open, important question in evolutionary biology is why hierarchical organization evolves in the first place. It has recently been shown that modularity evolves because of the presence of a cost for network connections. Here we investigate whether such connection costs also tend to cause a hierarchical organization of such modules. In computational simulations, we find that networks without a connection cost do not evolve to be hierarchical, even when the task has a hierarchical structure. However, with a connection cost, networks evolve to be both modular and hierarchical, and these networks exhibit higher overall performance and evolvability (i.e. faster adaptation to new environments). Additional analyses confirm that hierarchy independently improves adaptability after controlling for modularity. Overall, our results suggest that the same force-the cost of connections-promotes the evolution of both hierarchy and modularity, and that these properties are important drivers of network performance and adaptability. In addition to shedding light on the emergence of hierarchy across the many domains in which it appears, these findings will also accelerate future research into evolving more complex, intelligent computational brains in the fields of artificial intelligence and robotics.


Diversity within the Redeye Bass, Micropterus coosae (Perciformes: Centrarchidae) species group, with descriptions of four new species.
The Redeye Bass, Micropterus coosae, was described from the Mobile River basin, Chattahoochee, and Savannah rivers in Alabama and Georgia, USA, by Hubbs and Bailey (1940). At that time the authors recognized significant variation in the Black Warrior River population, and noted that with further study this form may be recognized as a separate taxon. An examination of variation in morphology and mitochondrial DNA supported this observation, and highlighted additional species-level variation, resulting in descriptions of a total of four new species: Micropterus cahabae, new sp., restricted to the Cahaba River system; Micropterus tallapoosae, new sp., restricted to the Tallapoosa River system; Micropterus warriorensis, new sp., from the Black Warrior River system; and Micropterus chattahoochae, new sp., from the Chattahoochee River system. Micropterus coosae is restricted to the Coosa River system. The new species differ from each other and from M. coosae by a combination of pigmentation and scale count characteristics, development of the tooth patch, and divergence within the ND2 gene. While two of these species are relatively common in upland streams within their ranges, M. warriorensis, M. cahabae and M. chattahoochae are uncommon and may warrant protection.


R213I mutation in release factor 2 (RF2) is one step forward for engineering an omnipotent release factor in bacteria Escherichia coli.
The current understanding of the specificity of the bacterial class I release factors (RFs) in decoding stop codons has evolved beyond a simple tripeptide anticodon model. A recent molecular dynamics study for deciphering the principles for specific stop codon recognition by RFs identified Arg-213 as a crucial residue on Escherichia coli RF2 for discriminating guanine in the third position (G3). Interestingly, Arg-213 is highly conserved in RF2 and substituted by Ile-196 in the corresponding position in RF1. Another similar pair is Leu-126 in RF1 and Asp-143 in RF2, which are also conserved within their respective groups. With the hypothesis that replacement of Arg-213 and Asp-143 with the corresponding RF1 residues will reduce G3 discrimination by RF2, we swapped these residues between E. coli RF1 and RF2 by site-directed mutagenesis and characterized their preference for different codons using a competitive peptide release assay. Among these, the R213I mutant of RF2 showed 5-fold improved reading of the RF1-specific UAG codon relative to UAA, the universal stop codon, compared with the wild type (WT). In-depth fast kinetic studies revealed that the gain in UAG reading by RF2 R213I is associated with a reduced efficiency of termination on the cognate UAA codon. Our work highlights the notion that stop codon recognition involves complex interactions with multiple residues beyond the PXT/SPF motifs. We propose that the R213I mutation in RF2 brings us one step forward toward engineering an omnipotent RF in bacteria, capable of reading all three stop codons.


A retrospective review of lower extremity fracture care in patients with spinal cord injury.
To identify circumstances surrounding incident lower extremity fractures (ILEFs) in patients with spinal cord injury (SCI) and to describe the impact of these fractures on service needs and provision of pharmacological therapies for osteoporosis. Retrospective medical record review. Four Veterans Affairs Medical Centers in the USA. One hundred and forty patients with traumatic SCI who sustained an ILEF from 2002 to 2007. Fracture circumstances and use of assistive devices were described using percentages, means, and standard deviations. Fisher's exact test was used to determine the relationship between fracture site, and patient age and duration of SCI. Differences in pharmacological provision of therapies for osteoporosis pre- and post-fracture were examined using exact McNemar's test. One hundred and fifty-five ILEFs were identified in 140 patients. Tibia/fibula and femur fractures were the most common fractures. Fracture site was not related to patient's age or duration of SCI. Almost one-third of all fractures occurred during transfers to and from wheelchairs. Post-fracture, the provision of new or modified assistive devices, primarily wheelchairs, was frequent, occurring in 83% of patients in the year post-fracture. Few patients transferred residence to a nursing home following the fracture. There was a significant difference in the use of pharmacological therapies for osteoporosis in the first year post-fracture compared with the year prior to the fracture (P < 0.01), with significant differences in the volume of prescriptions for calcium supplements (P < 0.01) and bisphosphonates (P = 0.02). Overall, the amount of prescriptions for osteoporosis increased the year post-fracture (56%) from the year pre-fracture (39%); this increase was secondary to increases in prescriptions for calcium supplements (pre = 13%; post = 30%) and bisphosphonates (pre = 2%; post = 7%). We have identified that wheelchair and other transfer activities are a key area that could be a focus of fracture prevention in SCI. The need for new or modified assistive devices and/or wheelchair skills retraining post-fracture should be anticipated. Examination of whether treatments for osteoporosis following a fracture can prevent future osteoporotic fractures is warranted.


Future challenges for vection research: definitions, functional significance, measures, and neural bases.
This paper discusses four major challenges facing modern vection research. Challenge 1 (Defining Vection) outlines the different ways that vection has been defined in the literature and discusses their theoretical and experimental ramifications. The term vection is most often used to refer to visual illusions of self-motion induced in stationary observers (by moving, or simulating the motion of, the surrounding environment). However, vection is increasingly being used to also refer to non-visual illusions of self-motion, visually mediated self-motion perceptions, and even general subjective experiences (i.e., "feelings") of self-motion. The common thread in all of these definitions is the conscious subjective experience of self-motion. Thus, Challenge 2 (Significance of Vection) tackles the crucial issue of whether such conscious experiences actually serve functional roles during self-motion (e.g., in terms of controlling or guiding the self-motion). After more than 100 years of vection research there has been surprisingly little investigation into its functional significance. Challenge 3 (Vection Measures) discusses the difficulties with existing subjective self-report measures of vection (particularly in the context of contemporary research), and proposes several more objective measures of vection based on recent empirical findings. Finally, Challenge 4 (Neural Basis) reviews the recent neuroimaging literature examining the neural basis of vection and discusses the hurdles still facing these investigations.


Dynamics of Japanese encephalitis virus transmission among pigs in Northwest Bangladesh and the potential impact of pig vaccination.
Japanese encephalitis (JE) virus infection can cause severe disease in humans, resulting in death or permanent neurologic deficits among survivors. Studies indicate that the incidence of JE is high in northwestern Bangladesh. Pigs are amplifying hosts for JE virus (JEV) and a potentially important source of virus in the environment. The objectives of this study were to describe the transmission dynamics of JEV among pigs in northwestern Bangladesh and estimate the potential impact of vaccination to reduce incidence among pigs. We conducted a comprehensive census of pigs in three JE endemic districts and tested a sample of them for evidence of previous JEV infection. We built a compartmental model to describe JEV transmission dynamics in this region and to estimate the potential impact of pig vaccination. We identified 11,364 pigs in the study area. Previous JEV infection was identified in 30% of pigs with no spatial differences in the proportion of pigs that were seropositive across the study area. We estimated that JEV infects 20% of susceptible pigs each year and the basic reproductive number among pigs was 1.2. The model suggest that vaccinating 50% of pigs each year resulted in an estimated 82% reduction in annual incidence in pigs. The widespread distribution of historic JEV infection in pigs suggests they may play an important role in virus transmission in this area. Future studies are required to understand the contribution of pig infections to JE risk in humans and the potential impact of pig vaccination on human disease.


Short report: Evidence and potential for transmission of human and swine Taenia solium cysticercosis in the Piracuruca region, Piauí, Brazil.
The study conducted in the Cocal dos Alves municipality, located in the Piracuruca region of Piauí State, Brazil in November of 2003 was based on both a socio-behavioral survey and analysis of serum antibodies and parasitic materials. Pig raising is the main economic activity with 91.4% using extensive farming. On the studied population, 54.3% of people did not apply any sanitary measures to wastewater, 45.7% used septic tanks, and 69.1% consumed water without treatment. The data collected indicated the occurrence and active transmission of the taeniasis-cysticercosis complex in the region. One of seven voluntary persons was positive in antibody-ELISA tests using both native and recombinant antigens. Multiplex PCR and DNA sequencing of cyst samples obtained from a pig revealed the presence of the Afro-American genotype of Taenia solium. This study revealed the occurrence of human and porcine cysticercosis in the Piracuruca region of Piauí State, middle-north of Brazil.


Multi-omics analysis of thermal stress response in a zooxanthellate cnidarian reveals the importance of associating with thermotolerant symbionts.
Corals and their endosymbiotic dinoflagellates of the genus Symbiodinium have a fragile relationship that breaks down under heat stress, an event known as bleaching. However, many coral species have adapted to high temperature environments such as the Red Sea (RS). To investigate mechanisms underlying temperature adaptation in zooxanthellate cnidarians we compared transcriptome- and proteome-wide heat stress response (24 h at 32°C) of three strains of the model organism Aiptasia pallida from regions with differing temperature profiles; North Carolina (CC7), Hawaii (H2) and the RS. Correlations between transcript and protein levels were generally low but inter-strain comparisons highlighted a common core cnidarian response to heat stress, including protein folding and oxidative stress pathways. RS anemones showed the strongest increase in antioxidant gene expression and exhibited significantly lower reactive oxygen species (ROS) levels in hospite However, comparisons of antioxidant gene and protein expression between strains did not show strong differences, indicating similar antioxidant capacity across the strains. Subsequent analysis of ROS production in isolated symbionts confirmed that the observed differences of ROS levels in hospite were symbiont-driven. Our findings indicate that RS anemones do not show increased antioxidant capacity but may have adapted to higher temperatures through association with more thermally tolerant symbionts.


Optimization of a novel peptide ligand targeting human carbonic anhydrase IX.
Carbonic anhydrase IX (CA IX) is a hypoxia-regulated transmembrane protein over-expressed in various types of human cancer. Recently, a new peptide with affinity for human carbonic anhydrase IX (CaIX-P1) was identified using the phage display technology. Aim of the present study is to characterize the binding site in the sequence of CaIX-P1, in order to optimize the binding and metabolic properties and use it for targeting purposes. Various fragments of CaIX-P1 were synthesized on solid support using Fmoc chemistry. Alanine scanning was performed for identification of the amino acids crucial for target binding. Derivatives with increased binding affinity were radiolabeled and in vitro studies were carried out on the CA IX positive human renal cell carcinoma cell line SKRC 52 and the CA IX negative human pancreatic carcinoma cell line BxPC3. Metabolic stability was investigated in cell culture medium and human serum. Organ distribution and planar scintigraphy studies were performed in Balb/c nu/nu mice carrying subcutaneously transplanted SKRC 52 tumors. The results of our studies clearly identified amino acids that are important for target binding. Among various fragments and derivatives the ligand CaIX-P1-4-10 (NHVPLSPy) was found to possess increased binding potential in SKRC 52 cells, whereas no binding capacity for BxPC3 cells was observed. Binding of radiolabeled CaIX-P1-4-10 on CA IX positive cells could be inhibited by both the unlabeled and the native CaIX-P1 peptide but not by control peptides. Stability experiments indicated the degradation site in the sequence of CaIX-P1-4-10. Biodistribution studies showed a higher in vivo accumulation in the tumor than in most healthy tissues. Our data reveal modifications in the sequence of the CA IX affine ligand CaIX-P1 that might be favorable for improvement of target affinity and metabolic stability, which are necessary prior to the use of the ligand in clinical approaches.


Living Situation and Physical Activity in the COVID-19 Pandemic Among American Private University Students.
Many university students experienced changes during the COVID-19 pandemic, including potential changes in physical activity (PA) levels and living situation. As PA behaviors in young adulthood help establish life-long habits and future health outcomes, the purpose of this study was to investigate overall change in PA, as well as change in PA due to living situation, among private university students during the COVID-19 pandemic. Private university students (n = 109) between 18 and 25 years of age completed an online survey that included the International Physical Activity Questionnaire - Short Form. T-tests examined changes in overall time spent in PA from before to during the COVID-19 pandemic, and the differences in MET-minute distributions between groups. Students performed significantly less activity during the COVID-19 pandemic than before (t(108) = 3.51, p = .001, d = 0.493), with 70.6% of all students meeting exercise recommendations before the pandemic and 51.4% after. Students living with vs. without a parent/guardian attained similar PA levels (t(107) = -.114, p = .910) before the pandemic (73.1% vs. 69.9%, respectively), but students living with a parent/guardian engaged in significantly less PA (t(107) = 2.04, p = .044, d = 0.475) than those living without a parent/guardian during the pandemic (37.5% vs. 57.1%, respectively). The declines in PA suggest the need for targeted interventions and education among private university students. In order to maximize the health benefits of PA, it is crucial that activity engagement return to at least pre-COVID-19 levels.


Identification of serum regression signs in infantile hemangioma.
Vessel proliferation underlies a number of serious pathological conditions. Infantile Hemangioma (IH) is a low-aggressive vascular tumor, interesting as an in vivo model of spontaneous tumor regression. Identifying mechanisms underlying IH spontaneous regression may then help to elucidate vessel-growth control, strongly deregulated in other serious conditions such as sarcoma, melanoma, diabetic retinopathy. The present study was aimed at identifying early regression indicators within hematological parameters. Thirty-four blood samples were collected from IH diagnosed babies (20-months median age), spontaneously regressing with age. Nineteen serum standard blood-tests were carried out using diagnostic reagents; in addition, serum-expression of 27 cytokine/chemokines was measured. Samples were divided in three age-groups, namely ≤ 12, 13 to 24 and >24 months-age, respectively. Red-cells count, Hemoglobin, Hematocrit, Neutrophils, Lymphocytes, MCP-1 and MIP-1beta were significantly different in the three age-groups, according to one-way ANOVA analysis. The same parameters showed a significant Pearson-correlation with age, supporting the direct link of age with IH-regression. ROC analysis showed that red-cells count, Hemoglobin, Hematocrit, MCP-1 and MIP-1beta levels significantly discriminate IH in the proliferating-phase from IH in the regressing-phase. Such data indicate for the first time that standard hematological tests and cytokine serum-expression values may effectively discriminate proliferating- from regressing-IH, unrevealing early regression signs, and demonstrate that standard blood-tests may have novel unsuspected diagnostic/prognostic relevance in altered vessel-growth conditions.


Results of Liver Transplantation for Hepatocellular Carcinoma in a Multicenter Latin American Cohort Study.
Heterogeneous data has been reported regarding liver transplantation (LT) for hepatocellular carcinoma (HCC) in Latin America. We aimed to describe treatment during waiting list, survival and recurrence of HCC after LT in a multicenter study from Latin America. Patients with HCC diagnosed prior to transplant (cHCC) and incidentally found in the explanted liver (iHCC) were included. Imaging-explanted features were compared in cHCC (non-discordant if pre and post-LT were within Milan, discordant if pre-LT was within and post-LT exceeding Milan). Overall, 435 patients with cHCC and 92 with iHCC were included. At listing, 81% and 91% of cHCC patients were within Milan and San Francisco criteria (UCSF), respectively. Five-year survival and recurrence rates for cHCC within Milan, exceeding Milan/within UCSF and beyond UCSF were 71% and 16%; 66% and 26%; 46% and 55%, respectively. Locoregional treatment prior to LT was performed in 39% of cHCC within Milan, in 53% beyond Milan/within UCSF and in 83% exceeding UCSF (p < 0.0001). This treatment difference was not observed according to AFP values (≤100, 44%; 101-1,000, 39%, and > 1,000 ng/mL 64%; p = 0.12). Discordant imaging-explanted data was observed in 29% of cHCC, showing lower survival HR 2.02 (CI 1.29; 3.15) and higher recurrence rates HR 2.34 when compared to AFP <100 ng/mL. Serum AFP > 1,000 ng/mL at listing was independently associated with a higher 5-year recurrence rate and a HR of 3.24 when compared to AFP <100 ng/mL. Although overall results are comparable to other regions worldwide, pre-LT treatment not only considering imaging data but also AFP values should be contemplated during the next years.


Use of antiepileptics for seizure prophylaxis after traumatic brain injury.
Antiepileptics used for seizure prophylaxis after traumatic brain injury (TBI) are reviewed. Of the 275,000 people who are hospitalized with TBI each year, approximately 5-7% experience a posttraumatic seizure (PTS). According to the latest guidelines issued by the Brain Trauma Foundation and the American Academy of Neurology (AAN) for the management of severe TBI, PTS prophylaxis is recommended only during the first seven days after TBI. Of the available antiepileptic drugs, phenytoin has been the most extensively studied for the prophylaxis of PTS. Phenobarbital, valproate, and carbamazepine have not been as extensively researched, and, given their adverse-effect profiles and pharmacodynamic properties, there is no advantage to using these agents over phenytoin. Levetiracetam has demonstrated comparable efficacy to phenytoin for PTS prophylaxis and is associated with fewer adverse effects and monitoring considerations; it may be a reasonable alternative to phenytoin. However, levetiracetam has been associated with an increased seizure tendency. The Brain Trauma Foundation recommends using phenytoin for early PTS prophylaxis. The guidelines also state that valproate has demonstrated similar efficacy to phenytoin but warn that its use may be associated with increased mortality. The available literature supports the use of antiepileptics for early PTS prophylaxis during the first week after a TBI. Phenytoin has been extensively studied for this indication and is recommended by the AAN and Brain Trauma Foundation guidelines for early PTS prophylaxis. Levetiracetam has demonstrated comparable efficacy to phenytoin for early PTS prophylaxis and may be a reasonable alternative to consider in this patient population.


Surface plasmon polariton absorption modulator.
An electrically controlled ultra-compact surface plasmon polariton absorption modulator (SPPAM) is proposed. The device can be as small as a few micrometers depending on the required extinction ratio and the acceptable loss. The device allows for operation far beyond 100 Gbit/s, being only limited by RC time constants. The absorption modulator comprises a stack of metal/insulator/metal-oxide/metal layers, which support a strongly confined asymmetric surface plasmon polariton (SPP) in the 1.55 μm telecommunication wavelength window. Absorption modulation is achieved by electrically modulating the free carrier density in the intermediate metal-oxide layer. The concept is supported by proof-of-principle experiments.


Effect of N-(Phosphonomethyl)glycine on Carbon Assimilation and Metabolism during a Simulated Natural Day.
The effects of N-(phosphonomethyl)glycine (glyphosate) on the regulation of carbon assimilation, metabolism, and translocation were studied in leaves of sugar beet (Beta vulgaris L., Klein E-type multigerm) under a light regimen that began with gradually increasing irradiance as generally occurs on a natural day. Soon after application, glyphosate caused a marked increase in ribulose bisphosphate and a decrease in phosphoglyceric acid. The response is most simply explained by direct inhibition of ribulose bisphosphate carboxylase activity. The extent of inhibition was small, and the carbon assimilation rate did not decrease. As predicted, photosynthesis declined within an hour after glyphosate was applied to leaves under gradually increasing light. Inhibition resulted from a decrease in ribulose bisphosphate due to depletion of carbon from the photosynthetic carbon reduction cycle. Photoinhibition, a light-dependent limitation of photosynthetic capacity, appeared to be necessary for marked glyphosate-induced inhibition of photosynthesis. As a result, photosynthesis rate increased with irradiance until it exceeded 400 micromoles per square meter per second but then declined as the light level increased beyond 500 micromoles per square meter per second. Glyphosate changed the allocation of newly fixed carbon between starch and sucrose for export. Changes in the levels of ribulose bisphosphate and phosphoglyceric acid produced important effects on the regulation of carbon assimilation and metabolism.


Influence of dilution rate on enzymes of intermediary metabolism in two freshwater bacteria grown in continuous culture.
Two freshwater bacteria, a Pseudomonas sp. and a Spirillum sp., were grown in continuous culture under steady-state conditions in L-lactate-, succinate-, ammonium- or phosphate-limited media. In Pseudomonas sp., NAD-independent and NAD-dependent L-lactate dehydrogenases, aconitase, isocitrate dehydrogenase and glucose 6-phosphate dehydrogenase activities increased up to 10-fold as the dilution rate (D) was decreased from 0.5 to 0.02 h-1, regardless of whether the growth-limiting nutrient was carbon, ammonium or phosphate. In contrast, 2-oxoglutarate dehydrogenase and succinate dehydrogenase activities were not influenced by D, and NADH oxidase activity increased with D. Spirillum sp. gave different results in some respects, but it also exhibited an increase in the activity of several enzymes at low D values. Such increases may emanate from release of catabolite repression, and catabolite repressors for the five enzymes in Pseudomonas sp. showing such increases are probably compounds of carbon, nitrogen and phosphorus. It is likely that increased enzyme syntheses in low D cultures represent the normal physiological state for bacteria in aquatic environments where growth occurs slowly under nutrient limitations. Such increases probably permit a more effective utilization of nutrients present at sub-saturating concentrations.


Photo-Assisted Dietary Method Improves Estimates of Dietary Intake Among People with Sleeve Gastrectomy.
Bariatric operations are effective obesity treatments because of the significant reductions in food intake after surgery, but weight regain remains a problem in a small group of patients after surgery. Estimating food intake is difficult due to dieting status, weight, gender, and challenges with estimating portion size. We aimed to evaluate the use of digital food photography in comparison to conventional methods among patients after sleeve gastrectomy. Participants used a mobile device (mHealth) to photo-document their dietary intake of all food and beverages consumed before and after eating. They also completed a 24 h food recall interview with a dietician. Data from 383 eating occasions were analyzed. Food intake using 24 h recall was reported as 972.5 ± 77 kcal and estimates from photographs were 802.9 ± 63.4 kcal, with a difference of 169.6 ± 451.4 kcal (95% confidence interval (CI) of 41.4 to 297.9 kcal, p = 0.005). There was no difference for protein intake, but carbohydrate intake reported during the 24 h recall was 541.2 ± 298 kcal and estimates from photographs were 395.2 ± 219.6 kcal, with a difference of 145.8 ± 256.3 kcal (95% CI of 73.2 to 218.8 kcal, p = 0.0001). After sleeve gastrectomy, patients reported eating more total calories and calories from carbohydrates compared to estimations using photographs. The implication for patients are that tools such as mHealth might be useful to optimize food intake and calories after sleeve gastrectomy, especially for those patients that may struggle with weight regain after surgery.


Quality of life and psychiatric co‑morbidity in Indian migraine patients: a headache clinic sample.
There is a lack of data from India on the impact of migraine on health-related quality of life (HRQoL) and the extent of psychiatric co-morbidities in migraine. The objectives of the study were to quantify the impairment in HRQoL in migraine patients compared to healthy controls, to compare the prevalence of clinically significant anxiety and depressive symptoms in these groups, and to identify patient and headache characteristics that may predict health-related quality of life. We interviewed 71 consecutive newly diagnosed migraine patients seen in the headache clinic of a tertiary referral center between September and December 2008. Age- and sex-matched healthy subjects (n = 71) were used as controls. Short Form-36, Migraine Disability Assessment Score, and Hospital Anxiety and Depression Scale were administered. Predictors of HRQoL were identified using regression analysis. Migraineurs were significantly impaired in all subscales of the SF-36 compared to controls, with greatest impairments in role physical, general health, and role emotional subscales. Prevalence of clinically significant anxiety (48%) and depressive (41%) symptoms in patients was higher than in healthy controls. Female gender, headache-related disability, and severity of anxiety predicted worse Physical Component Summary scores, while severity of both anxiety and depressive symptoms predicted worse Mental Component Summary scores. HRQoL is significantly reduced in Indian migraine patients compared to healthy controls. Incidence of clinically significant anxiety and depressive symptoms is also much higher in these patients. These findings corroborate well with studies from other parts of the world and suggest that cultural differences do not significantly alter the subjective impact of migraine on quality of life.


Cytosolic phospholipase A2 modulates TLR2 signaling in synoviocytes.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis leading to destruction of cartilage and bone. PLA2 enzymes are key players in inflammation regulating the release of unsaturated fatty acids such as arachidonic acid (AA), a precursor of pro-inflammatory eicosanoids. Several lines of evidence point to toll-like receptors (TLRs) as drivers of synovitis and joint destruction in RA. However, few studies have addressed the implication of PLA2 activity downstream TLR activation in the synovium. Here, we aimed to characterize PLA2 enzyme involvement in TLR2-induced signaling in synovial fibroblast-like cells. TLRs1-7 and a range of sPLA2, iPLA2 and cPLA2 enzymes were found to be transcriptionally expressed in cultured synoviocytes. Activation of TLR2/1 and TLR2/6 led to phosphorylation of cPLA2α at Ser505, and induced AA release and PGE2 production; effects that were attenuated by cPLA2α inhibitors. In contrast, sPLA2 inhibitors did not affect AA or PGE2 release. cPLA2α inhibitors furthermore attenuated TLR-induced expression of IL-6, IL-8 and COX2. COX1/2 inhibitors attenuated TLR2/6-induced IL-6 transcription and protein production comparable to cPLA2α inhibition. Moreover, exogenously PGE2 added alone induced IL-6 production and completely rescued IL-6 transcription when added simultaneously with FSL-1 in the presence of a cPLA2α inhibitor. Our results demonstrate for the first time that cPLA2α is involved in TLR2/1- and TLR2/6-induced AA release, PGE2 production and pro-inflammatory cytokine expression in synoviocytes, possibly through COX/PGE2-dependent pathways. These findings expand our understanding of cPLA2α as a modulator of inflammatory molecular mechanisms in chronic diseases such as RA.


Identification of cellular partners of Influenza A virus (H5N1) non-structural protein NS1 by yeast two-hybrid system.
Influenza A virus (IAV) subtype H5N1 is associated with the re-emergence of severe human influenza. The virus is highly virulent and viral non-structural protein 1 (NS1) is believed to play a crucial role in the viral pathogenesis. A screening for human proteins interacting with NS1 was performed by a yeast two-hybrid system (Y2H). Two bait plasmids that expressed DNA binding domain (BD) fused to either RNA binding domain or to effector domain of NS1 were constructed and transformed into yeast. The bait yeast was mated with a prey yeast containing human macrophage cDNA library fused to DNA activation domain. Obtained clones were interacting with interleukin-6 receptor (IL-6R), MHC class I HLA-B, cathepsin B, ubiquitin, and adenosine deaminase acting on RNA (ADAR1). These proteins play important role in the immune response, targeting for proteosomal degradation, and RNA editing. Thus, IAV H5N1 may use NS1 to manipulate these host proteins for its own benefit and in that way confer an unusual severity to the infection.


Hippocampal synaptic pathology in schizophrenia, bipolar disorder and major depression: a study of complexin mRNAs.
Complexin (cx) I and cx II are synaptic proteins preferentially expressed by inhibitory and excitatory hippocampal neurons respectively. We previously reported decreased hippocampal formation cx mRNA and protein expression in schizophrenia, with a greater loss of cx II than cx I. The present in situ hybridization study was both an attempt at replication, and an extension to include bipolar and unipolar mood disorders, using sections from the Stanley Foundation brain series. In schizophrenia, both mRNAs were decreased in some hippocampal subfields, especially CA4, but were preserved in subiculum. The cx II/cx I mRNA ratio was unchanged. In bipolar disorder, the mRNAs were reduced in CA4, subiculum and parahippocampal gyrus, with the deficit in subiculum being diagnostically specific. No alterations in cx mRNAs were found in major depression. Treatment of rats with antipsychotics (haloperidol or chlorpromazine) for 2 weeks had no effect on hippocampal cx mRNAs. These data replicate the finding of decreased cx I and cx II expression in the hippocampus in schizophrenia and show a similar or greater abnormality in bipolar disorder. Non-replication of the cx II > cx I mRNA loss in schizophrenia means that the hypothesis of a preferential involvement of excitatory connections was not supported. The results extend the emerging evidence that altered circuitry may be a component of the neuroanatomy of both schizophrenia and bipolar mood disorder.


Etiopathogenesis of Nephrolithiasis in Ulcerative Colitis Patients with the Ileal Pouch Anal Anastomosis.
Our previous study showed that nephrolithiasis is a common complication in ulcerative colitis patients after ileal pouch anal anastomosis (IPAA). However, the pathogenesis of nephrolithiasis in IPAA patients has not been studied. The aim of this study was to compare urine and serum metabolic compositions in IPAA patients with nephrolithiasis and controls with IPAA and no nephrolithiasis. Using cross-sectional study design, serum and 24-hour urine metabolic compositions were compared between IPAA patients with nephrolithiasis (the study group) and those without (the control group). Urinary supersaturation of calcium oxalate, calcium phosphate, and uric acid was calculated. A total of 40 patients were enrolled in the study. There were no significant differences in serum electrolytes, vitamin D, parathyroid hormone, and kidney function tests between the study (n = 20) and control groups (n = 20). Patients in the study group were found to have a significantly higher 24-hour urine supersaturation of calcium oxalate (8.8 versus 5.0, P = 0.037) and calcium phosphate (0.61 versus 0.27, P = 0.028) as compared with controls. Nineteen (95%) patients in the study group were symptomatic due to nephrolithiasis with several requiring procedural intervention for treatment, including ureteroscopy in 3 (15%) patients, lithotripsy in 5 (25%) patients, and percutaneous surgery in 1 (5%) patient. Ulcerative colitis-IPAA patients are at risk for the development of calcium oxalate and calcium phosphate stones. Nephrolithiasis is symptomatic in a majority of the patients and frequently requires procedural intervention for treatment.


Pornography consumption among adolescent girls in Sweden.
The aims of this study were to describe patterns of pornography consumption, investigate differences between consumers and non-consumers of pornography regarding sexual experiences, health and lifestyle and determine associations between pornography consumption and sexual experiences, health and lifestyle among adolescent girls. The hypotheses were that adolescent girls categorised as pornography consumers would report sexual experiences to a greater extent, and a riskier lifestyle and poorer health, compared with non-consumers. A classroom survey was conducted among 16-year-old girls (N = 393). One-third (30%) consumed pornography. In this group, almost half (43%) had fantasies about trying to copy sexual acts seen in pornography and 39% had tried to copy sexual activities seen in pornography. A higher proportion of pornography-consuming girls reported sexual experiences compared with peers. A third (30%) reported experience of anal sex compared with 15% among non-consuming peers (p = 0.001). Furthermore, peer-relationship problems (17% vs 9%; p = 0.015), use of alcohol (85% vs 69%; p = 0.001) and daily smoking (27% vs 14%; p = 0.002) were reported to a greater extent than in non-consuming peers. Pornography consumption, use of alcohol and daily smoking were associated with experience of casual sex. Pornography-consuming girls reported sexual experiences and a risky lifestyle to a greater extent compared with non-consuming girls. This indicates that pornography consumption may influence sexualisation and lifestyle. This is important to acknowledge when designing and implementing sexual health programmes for adolescents.


Differential role of a persistent seed bank for genetic variation in early vs. late successional stages.
Persistent seed banks are predicted to have an important impact on population genetic processes by increasing effective population size and storing past genetic diversity. Accordingly, persistent seed banks may buffer genetic effects of disturbance, fragmentation and/or selection. However, empirical studies surveying the relationship between aboveground and seed bank genetics under changing environments are scarce. Here, we compared genetic variation of aboveground and seed bank cohorts in 15 populations of the partially cleistogamous Viola elatior in two contrasting early and late successional habitats characterized by strong differences in light-availability and declining population size. Using AFLP markers, we found significantly higher aboveground than seed bank genetic diversity in early successional meadow but not in late successional woodland habitats. Moreover, individually, three of eight woodland populations even showed higher seed bank than aboveground diversity. Genetic differentiation among populations was very strong (фST = 0.8), but overall no significant differentiation could be detected between above ground and seed bank cohorts. Small scale spatial genetic structure was generally pronounced but was much stronger in meadow (Sp-statistic: aboveground: 0.60, seed bank: 0.32) than in woodland habitats (aboveground: 0.11; seed bank: 0.03). Our findings indicate that relative seed bank diversity (i.e. compared to aboveground diversity) increases with ongoing succession and despite decreasing population size. As corroborated by markedly lower small-scale genetic structure in late successional habitats, we suggest that the observed changes in relative seed bank diversity are driven by an increase of outcrossing rates. Persistent seed banks in Viola elatior hence will counteract effects of drift and selection, and assure a higher chance for the species' long term persistence, particularly maintaining genetic variation in declining populations of late successional habitats and thus enhancing success rates of population recovery after disturbance events.


Craniofacial and upper airway profile assessment in North Indian patients with obstructive sleep apnea.
Upper airway imaging can often identify the anatomical risk factors for sleep apnea and provide sufficient insight into the pathophysiology of obstructive sleep apnea (OSA). We conducted a case-control, observational study at a tertiary care hospital in North India. All cases and controls underwent lateral cephalometry and magnetic resonance imaging (MRI) for craniofacial and upper airway evaluation. Only the cases had polysomnography testing for confirmation of OSA and assessing the severity of disease. Forty cases and an equal number of matched controls were recruited. On X-ray cephalometry, it was observed that the cases had a significantly larger hyoid mandibular distance and soft palate length; and shorter mandibular length. The MRI cephalometric variables were significantly different, the soft palate length, tongue length, and submental fat were longer while the retropalatal and retroglossal distance was shorter amongst the cases. A statistically significant positive correlation was found between the cephalometric parameters and the indices of severity of OSA. An increased hyoid mandibular distance and soft palate length, and a decrease in the lower anterior facial height were found to be predictive of severe OSA (Apnea-Hypopnea Index ->30/h). An increased hyoid mandibular distance, soft palate length, and the tongue length and a reduced mandibular length were found to be predictive of need for continuous positive airway pressure (CPAP) pressures of ≥15 cm H2O. There were significant differences between the cephalometric parameters of the Indian OSA patients and patients from other ethnicities reported in the literature. OSA patients had a significantly smaller upper airway compared to age-, sex-, and body mass index-matched controls and cephalometric variables correlated with the indices of OSA severity. The cephalometric assessment was also predictive of severe OSA and the need for higher pressures of CPAP. This indicates the important role of upper airway anatomy in the pathogenesis of OSA.


Optimisation of probe concentration in indirect photometric detection in capillary electrophoresis using highly absorbing dyes.
In indirect photometric detection in capillary electrophoresis, the concentration of the absorbing probe ion in the background electrolyte should be as high as possible in order to increase the dynamic range of the detection method. For relatively low absorptivity probes (epsilon < 2000 L mol(-1)cm(-1)) used under typical conditions (75 microm ID capillary) the maximum probe concentration is normally limited by the separation current. However, for medium (epsilon approximately/= 2000-15000 L mol(-1)cm(-1)) and especially for high (epsilon > 15000 L mol(-1)cm(-1)) absorptivity probes such as dyes, the maximum concentration may be limited by the background absorbance of the electrolyte which must fall within the linearity range of the detector. In this work, it is shown that another practical factor limiting the probe concentration is the adsorption of probe onto the capillary wall at higher concentrations, resulting in unstable baseline and increased noise. Use of a zwitterionic surfactant to suppress adsorption enabled the concentration of a model probe anion (tartrazine) to be increased by a factor of six times (to 3 mM). This resulted in significant improvements in peaks shapes, resolution between peaks, detection sensitivity and linear calibration range for the analyte anions. Baseline separation of a test mixture was maintained up to 7.5 mM total concentration of sample coions injected (13.7 nL) for the 3 mM electrolyte, with detection limits ranging from 0.63 to 0.94 microM. Peak height reproducibility (over 20 consecutive injections) was improved (values ranging from 1.1 to 1.9%) compared with electrolytes containing lower concentrations of the probe. Overall, the optimised, higher concentration probe electrolyte provided the sensitivity benefits of highly absorbing probes with the additional benefits of ruggedness and improved stacking, peak shapes and resolution.


Patterns of radiation treatment planning for localized prostate cancer in Japan: 2003-05 patterns of care study report.
The purpose of this study is to identify the treatment planning process for Japanese patients with localized prostate cancer. The Patterns of Care Study conducted a random survey of 61 institutions nationwide. Detailed information was collected on prostate cancer patients without distant metastases who were irradiated during the periods 2003-05. Radiation treatment planning and delivery were evaluated in 397 patients who were treated radically with external photon beam radiotherapy. Computed tomography data were used for planning in approximately 90% of the patients. Contrast was rarely used for treatment planning. Simulations and treatments were performed in the supine position in almost all patients. Immobilization devices were used in only 15% of the patients. Verification of the treatment fields using portal films or electric portal imaging devices was performed in most of the patients. However, regular or multiple verifications in addition to initial treatment and/or portal volume changes were performed in only 30% of the patients. Typical beam arrangements for treatment of the prostate consisted of a four-field box. Three-dimensional conformal techniques were applied less frequently in non-academic hospitals than in academic ones. Modernized multileaf collimators with leaf widths < or =10 mm were used in about two-thirds of the patients. Although the total doses given to the prostate were affected by the leaf widths, there were no significant differences between leaf widths of 5 and 10 mm. The results of the survey identified certain patterns in the current treatment planning and delivery processes for localized prostate cancer in Japan.


Does early detection of otitis media with effusion prevent delayed language development?
To consider whether earlier detection of otitis media with effusion (OME) in asymptomatic children in the first 4 years of life prevents delayed language development. MEDLINE and other databases were searched and relevant references from articles reviewed. Critical appraisal and consensus development were in accordance with the methods of the Canadian Task Force on Preventive Health Care. No randomised controlled trials assessing the overall screening for OME and early intervention to prevent delay in acquiring language were identified, although one trial evaluated treatment in a screened population and found no benefit. The "analytic pathway" approach was therefore used, where evidence is evaluated for individual steps in a screening process. The evidence supporting the use of tools for early detection such as tympanometry, microtympanometry, acoustic reflectometry, and pneumatic otoscopy in the first 4 years of life is unclear. Some treatments (mucolytics, antibiotics, steroids) resulted in the short term resolution of effusions as measured by tympanometry. Ventilation tubes resolved effusions and improved hearing. Ventilation tubes in children with hearing loss associated with OME benefited children in the short term, but after 18 months there was no difference in comparison with those assigned to watchful waiting. Most prospective cohort studies that evaluated the association between OME and language development lacked adequate measurement of exposure or outcome, or suffered from attrition bias. Findings with regard to the association were inconsistent. There is insufficient evidence to support attempts at early detection of OME in the first 4 years of life in the asymptomatic child to prevent delayed language development.


Comparison of neurons derived from mouse P19, rat PC12 and human SH-SY5Y cells in the assessment of chemical- and toxin-induced neurotoxicity.
Exposure to chemicals might be toxic to the developing brain. There is a need for simple and robust in vitro cellular models for evaluation of chemical-induced neurotoxicity as a complement to traditional studies on animals. In this study, neuronally differentiated mouse embryonal carcinoma P19 cells (P19 neurons) were compared with human neuroblastoma SH-SY5Y cells and rat adrenal pheochromocytoma PC12 cells for their ability to detect toxicity of methylmercury (MeHg), okadaic acid and acrylamide. Retinoic acid-treated P19 and SH-SY5Y cells and nerve growth factor-stimulated PC12 cells, allowed to differentiate for 6 days, were exposed to MeHg, okadaic acid and acrylamide for 48 h. Cell survival and neurite outgrowth were assessed with the calcein-AM assay and fluorescence detection of antibodies against the cytoskeletal neuron-specific protein βIII-tubulin, respectively. The effects of glutathione (GSH) and the potent inhibitor of GSH synthesis buthionine sulfoximine (BSO) on the MeHg induced-toxicity were assessed using the PrestoBlue™ cell viability assay and the TMRE mitochondrial membrane potential assay. Differentiated P19 cells developed the most extensive neuronal network among the three cell models and were the most sensitive neuronal model to detect neurotoxic effects of the test compounds. MeHg produced a concentration-dependent toxicity in differentiated P19 cells and SH-SY5Y cells, with statistically significant effects at concentrations from 0.1 μM in the P19 neurons and 1 μM in the SH-SY5Y cells. MeHg induced a decrease in the cellular metabolic activity and mitochondrial membrane potential (ΔΨm) in the differentiated P19 cells and SH-SY5Y cells, that were attenuated by GSH. Okadaic acid and acrylamide also showed statistically significant toxicity in the P19 neurons, but not in the SH-SY5Y cells or the P12 cells. P19 neurons are more sensitive to detect cytotoxicity of MeHg, okadaic acid and acrylamide than retinoic acid-differentiated SH-SY5Y cells and nerve growth factor-treated PC12 cells. P19 neurons are at least as sensitive as differentiated SH-SY5Y cells to detect the loss of mitochondrial membrane potential produced by MeHg and the protective effects of extracellular GSH on MeHg toxicity. P19 neurons may be a useful model to study neurotoxic effects of chemicals.


Properties of GexAsySe1-x-y glasses for all-optical signal processing.
We present a systematic study of Ge(x)As(y)Se(1-x-y) bulk chalcogenide glasses to determine the best composition for fabricating all-optical devices. The dependence of physical parameters such as the band-gap, glass transition temperature and third order optical nonlinearity (n(2)) on composition has been studied and a relation between the bond-structure and elevated linear loss levels in high Germanium glasses has been identified. It is found that glasses with 11<x<13 % are most suitable for all-optical devices.


Increased IGF1 levels in relation to heart failure and cardiovascular mortality in an elderly population: impact of ACE inhibitors.
There are conflicting results regarding the association of circulating IGF1 with cardiovascular (CV) morbidity and mortality. We assessed the relationship between IGF1 levels and heart failure (HF), ischemic heart disease (IHD), and CV mortality in an elderly population taking into account the possible impact of angiotensin converting enzyme (ACE) inhibitors. A total of 851 persons aged 66-81 years, in a rural Swedish municipality, were subjected to medical history, clinical examination, electrocardiography, echocardiography, and fasting plasma samples. They were then followed for 8 years. Patients on ACE inhibitors had higher IGF1 levels compared with those without ACE inhibitors. In patients on ACE inhibitors, higher IGF1 values were found in patients with an ejection fraction (EF) <40% compared with EF ≥40%, in patients with higher proBNP levels in quartile 4 vs 1, and in patients with IHD when compared to those without ACE inhibitors (P<0.001). In patients without ACE inhibitors, no relationship was found between IGF1 levels and HF or IHD. In multivariate regression, only ACE inhibitors, ECG changes characteristic for IHD, and gender had a significant impact on IGF1. Patients with higher IGF1 levels in quintiles 4 and 5 compared to quintiles 1 and 2 had a 50% higher risk for CV death (P=0.03). This was significant after adjustment for well-known CV risk factors and ACE inhibitors (P=0.03). Our results show that treatment with ACE inhibitors in an elderly population is associated with increased IGF1 levels, especially in patients with impaired cardiac function or IHD. High IGF1 levels tend to be associated with an increased risk for CV mortality.


Improved recovery from limb ischaemia by delivery of an affinity-isolated heparan sulphate.
Peripheral arterial disease is a major cause of limb loss and its prevalence is increasing worldwide. As most standard-of-care therapies yield only unsatisfactory outcomes, more options are needed. Recent cell- and molecular-based therapies that have aimed to modulate vascular endothelial growth factor-165 (VEGF165) levels have not yet been approved for clinical use due to their uncertain side effects. We have previously reported a heparan sulphate (termed HS7) tuned to avidly bind VEGF165. Here, we investigated the ability of HS7 to promote vascular recovery in a murine hindlimb vascular ischaemia model. HS7 stabilised VEGF165 against thermal and enzyme degradation in vitro, and isolated VEGF165 from serum via affinity-chromatography. C57BL6 mice subjected to unilateral hindlimb ischaemia injury received daily intramuscular injections of respective treatments (n = 8) and were assessed over 3 weeks by laser Doppler perfusion, magnetic resonance angiography, histology and the regain of function. Mice receiving HS7 showed improved blood reperfusion in the footpad by day 7. In addition, they recovered hindlimb blood volume two- to fourfold faster compared to the saline group; the greatest rate of recovery was observed in the first week. Notably, 17% of HS7-treated animals recovered full hindlimb function by day 7, a number that grew to 58% and 100% by days 14 and 21, respectively. This was in contrast to only 38% in the control animals. These results highlight the potential of purified glycosaminoglycan fractions for clinical use following vascular insult, and confirm the importance of harnessing the activity of endogenous pro-healing factors generated at injury sites.


Trait entitlement: A cognitive-personality source of vulnerability to psychological distress.
Psychological entitlement is a personality trait characterized by pervasive feelings of deservingness, specialness, and exaggerated expectations. The present review expands upon this understanding by conceptualizing entitlement as a cognitive-personality vulnerability to psychological distress. A review of research is conducted, and a novel, multipart model is described by which entitlement may be seen as such a vulnerability. First, exaggerated expectations, notions of the self as special, and inflated deservingness associated with trait entitlement present the individual with a continual vulnerability to unmet expectations. Second, entitled individuals are likely to interpret these unmet expectations in ways that foster disappointment, ego threat, and a sense of perceived injustice, all of which may lead to psychological distress indicators such as dissatisfaction across multiple life domains, anger, and generally volatile emotional responses. Furthermore, in the wake of disappointment, ego threat, or perceived injustice, entitled individuals are likely to attempt to bolster their entitled self-concept, leading to a reinforcement of entitled beliefs, thereby initiating the cycle again. At each stage of this process, entitlement presents the individual with the possibility of experiencing distress, predisposes further risk factors for distress (e.g., the subsequent steps in the model), and increases the risk of interpersonal conflict, again leading to distress. A review of relevant empirical data suggests preliminary support for this conceptual model of entitlement. (PsycINFO Database Record


Bone marrow mesenchymal stem cells from patients with aplastic anemia maintain functional and immune properties and do not contribute to the pathogenesis of the disease.
Aplastic anemia is a life-threatening bone marrow failure disorder characterized by peripheral pancytopenia and marrow hypoplasia. The majority of cases of aplastic anemia remain idiopathic, although hematopoietic stem cell deficiency and impaired immune responses are hallmarks underlying the bone marrow failure in this condition. Mesenchymal stem/stromal cells constitute an essential component of the bone marrow hematopoietic microenvironment because of their immunomodulatory properties and their ability to support hematopoiesis, and they have been involved in the pathogenesis of several hematologic malignancies. We investigated whether bone marrow mesenchymal stem cells contribute, directly or indirectly, to the pathogenesis of aplastic anemia. We found that mesenchymal stem cell cultures can be established from the bone marrow of aplastic anemia patients and display the same phenotype and differentiation potential as their counterparts from normal bone marrow. Mesenchymal stem cells from aplastic anemia patients support the in vitro homeostasis and the in vivo repopulating function of CD34(+) cells, and maintain their immunosuppressive and anti-inflammatory properties. These data demonstrate that bone marrow mesenchymal stem cells from patients with aplastic anemia do not have impaired functional and immunological properties, suggesting that they do not contribute to the pathogenesis of the disease.


Improvement of generalization ability for identifying dynamical systems by using universal learning networks.
This paper studies how the generalization ability of models of dynamical systems can be improved by taking advantage of the second order derivatives of the outputs with respect to the external inputs. The proposed method can be regarded as a direct implementation of the well-known regularization technique using the higher order derivatives of the Universal Learning Networks (ULNs). ULNs consist of a number of interconnected nodes where the nodes may have any continuously differentiable nonlinear functions in them and each pair of nodes can be connected by multiple branches with arbitrary time delays. A generalized learning algorithm has been derived for the ULNs, in which both the first order derivatives (gradients) and the higher order derivatives are incorporated. First, the method for computing the second order derivatives of ULNs is discussed. Then, a new method for implementing the regularization term is presented. Finally, simulation studies on identification of a nonlinear dynamical system with noises are carried out to demonstrate the effectiveness of the proposed method. Simulation results show that the proposed method can improve the generalization ability of neural networks significantly, especially in terms that (1) the robust network can be obtained even when the branches of trained ULNs are destructed, and (2) the obtained performance does not depend on the initial parameter values.


Comparative study on the performance of five different Hall effect devices.
Five different Hall Effect sensors were modeled and their performance evaluated using a three dimensional simulator. The physical structure of the implemented sensors reproduces a certain technological fabrication process. Hall voltage, absolute, current-related, voltage-related and power-related sensitivities were obtained for each sensor. The effect of artificial offset was also investigated for cross-like structures. The simulation procedure guides the designer in choosing the Hall cell optimum shape, dimensions and device polarization conditions that would allow the highest performance.


Nanogels from metal-chelating crosslinkers as versatile platforms applied to copper-64 PET imaging of tumors and metastases.
Metals are essential in medicine for both therapy and diagnosis. We recently created the first metal-chelating nanogel imaging agent, which employed versatile, reproducible chemistry that maximizes chelation stability. Here we demonstrate that our metal chelating crosslinked nanogel technology is a powerful platform by incorporating (64)Cu to obtain PET radiotracers. Polyacrylamide-based nanogels were crosslinked with three different polydentate ligands (DTPA, DOTA, NOTA). NOTA-based nanogels stably retained (64)Cu in mouse serum and accumulated in tumors in vivo as detected by PET/CT imaging. Measurement of radioactivity in major organs ex vivo confirmed this pattern, revealing a high accumulation (12.3% ID/g and 16.6% ID/g) in tumors at 24 and 48 h following administration, with lower accumulation in the liver (8.5% ID/g at 24 h) and spleen (5.5% ID/g). Nanogels accumulated even more efficiently in metastases (29.9% and 30.4% ID/g at 24 and 48 h). These metal-chelating nanogels hold great promise for future application as bimodal PET/MRI agents; chelation of β-emitting radionuclides could enable radiation therapy.


Children's antisocial behavior, mental health, drug use, and educational performance after parental incarceration: a systematic review and meta-analysis.
Unprecedented numbers of children experience parental incarceration worldwide. Families and children of prisoners can experience multiple difficulties after parental incarceration, including traumatic separation, loneliness, stigma, confused explanations to children, unstable childcare arrangements, strained parenting, reduced income, and home, school, and neighborhood moves. Children of incarcerated parents often have multiple, stressful life events before parental incarceration. Theoretically, children with incarcerated parents may be at risk for a range of adverse behavioral outcomes. A systematic review was conducted to synthesize empirical evidence on associations between parental incarceration and children's later antisocial behavior, mental health problems, drug use, and educational performance. Results from 40 studies (including 7,374 children with incarcerated parents and 37,325 comparison children in 50 samples) were pooled in a meta-analysis. The most rigorous studies showed that parental incarceration is associated with higher risk for children's antisocial behavior, but not for mental health problems, drug use, or poor educational performance. Studies that controlled for parental criminality or children's antisocial behavior before parental incarceration had a pooled effect size of OR = 1.4 (p < .01), corresponding to about 10% increased risk for antisocial behavior among children with incarcerated parents, compared with peers. Effect sizes did not decrease with number of covariates controlled. However, the methodological quality of many studies was poor. More rigorous tests of the causal effects of parental incarceration are needed, using randomized designs and prospective longitudinal studies. Criminal justice reforms and national support systems might be needed to prevent harmful consequences of parental incarceration for children.


Review on recent advances in the analysis of isolated organelles.
The analysis of isolated organelles is one of the pillars of modern bioanalytical chemistry. This review describes recent developments on the isolation and characterization of isolated organelles both from living organisms and cell cultures. Salient reports on methods to release organelles focused on reproducibility and yield, membrane isolation, and integrated devices for organelle release. New developments on organelle fractionation after their isolation were on the topics of centrifugation, immunocapture, free flow electrophoresis, flow field-flow fractionation, fluorescence activated organelle sorting, laser capture microdissection, and dielectrophoresis. New concepts on characterization of isolated organelles included atomic force microscopy, optical tweezers combined with Raman spectroscopy, organelle sensors, flow cytometry, capillary electrophoresis, and microfluidic devices.


Laparoscopic resection of hilar cholangiocarcinoma.
Surgical resection is the only curative treatment for hilar cholangiocarcinoma. Laparoscopic hepatectomy has been used to treat several types of liver neoplasms. However, technical issues have limited the adoption of laparoscopy for the treatment of hilar cholangiocarcinoma. To date there is only one report of minimally invasive procedure for hilar cholangiocarcinoma in the literature. The present video-assisted procedure shows a laparoscopic resection of hilar cholangiocarcinoma. A 43-year-old woman with progressive jaundice due to left-sided hilar cholangiocarcinoma was referred for treatment. The decision was to perform a laparoscopic left hepatectomy with lymphadenectomy and resection of extrahepatic bile ducts. Biliary reconstruction was performed using the hybrid method. Operative time was 300 minutes with minimum blood loss and no need for blood transfusion. Recovery was uneventful, and the patient was discharged on postoperative Day 7. Pathology revealed a well-differentiated cholangiocarcinoma with negative lymph nodes and clear surgical margins. The patient is well with no signs of the disease 18 months after the procedure. Laparoscopic left hepatectomy with lymphadenectomy is safe and feasible in selected patients and when performed by surgeons with expertise in liver surgery and minimally invasive techniques. The use of a hybrid method may be needed for biliary reconstruction, especially in cases where position and size of remnant bile ducts may jeopardize the anastomosis. Further studies are still needed to confirm the benefit of this approach over conventional surgery for hilar cholangiocarcinoma.


Eudiplozoon nipponicum: morphofunctional adaptations of diplozoid monogeneans for confronting their host.
Monogeneans, in general, show a range of unique adaptations to a parasitic lifestyle, making this group enormously diverse. Due to their unique biological properties, diplozoid monogeneans represent an attractive model group for various investigations on diverse biological interactions. However, despite numerous studies, there are still gaps in our knowledge of diplozoid biology and morphofunctional adaptations. In this study, we provide a comprehensive microscopic analysis of systems/structures involved in niche searching, sensing and self-protection against the host environment, and excretory/secretory processes in Eudiplozoon nipponicum. Freeze-etching enabled us to detect syncytium organisational features not visible by TEM alone, such as the presence of a membrane subjacent to the apical plasma membrane (separated by a dense protein layer) and a lack of basal plasma membrane. We located several types of secretory/excretory vesicles and bodies, including those attached to the superficial membranes of the tegument. Giant unicellular glands were seen accumulating predominantly in the apical forebody and hindbody haptor region. Muscle layer organisation differed from that generally described, with the outer circular and inner longitudinal muscles being basket-like interwoven by diagonal muscles with additional perpendicular muscles anchored to the tegument. Abundant muscles within the tegumentary ridges were detected, which presumably assist in fixing the parasite between the gill lamellae. Freeze-etching, alongside transmission electron and confocal microscopy with tubulin labelling, enabled visualisation of the protonephridia and nervous system, including the peripheral network and receptor innervation. Three types of receptor were identified: 1) uniciliated sensory endings with a subtle (or missing) tegumentary rim, 2) obviously raised uniciliated receptors with a prominent tegumentary rim (packed with massive innervation and muscles) and 3) non-ciliated papillae (restricted to the hindbody lateral region). This study points to specific morphofunctional adaptations that have evolved in diplozoid monogeneans to confront their fish host. We clearly demonstrate that the combination of different microscopic techniques is beneficial and can reveal hidden differences, even in much-studied model organisms such as E. nipponicum.