Circ_0102231 inactivates the PI3K/AKT signaling pathway by regulating the miR-635/NOVA2 pathway to promote the progression of non-small cell lung cancer.
Circular RNAs (circRNAs) are involved in the malignant development of tumors. However, the mechanism of circ_0102231 in non-small cell lung cancer (NSCLC) has rarely been discussed and reported. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of circ_0102231, miR-635 and NOVA alternative splicing regulator 2 (NOVA2) in NSCLC tissues and cells. Western blot was applied to detect the protein expression. Cell proliferation was monitored by cell counting kit-8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) experiments. The angiogenesis ability of cells was tested by angiogenesis assay. Flow cytometry was used to analyze cell apoptosis. The relationship between circ_0102231 and NOVA2 or miR-635 was analyzed by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. An in vivo transplanted tumor model was established to confirm the effect of circ_0102231 on tumor formation. Circ_0102231 was abnormally upregulated in NSCLC tissues and correlated with clinical stage. Silencing of circ_0102231 inhibited cell proliferation and angiogenesis but significantly promoted the apoptosis of NSCLC cells. There were target binding sites between circ_0102231 and miR-635, miR-635 and NOVA2. Importantly, circ_0102231 acted as a sponge for miR-635, increased the expression of NOVA2, and activated the PI3K/AKT signaling pathway. Finally, silencing of circ_0102231 also had obvious antitumor effects in vivo. Circ_0102231 increased the expression of NOVA2 by interacting with miR-635 to promote the malignant progression of NSCLC.


TodaysBaby Quality Improvement: Safe Sleep Teaching and Role Modeling in 8 US Maternity Units.
Nursing education and role modeling can increase adherence to safe sleep practices. Eight US hospital maternity units with variable baseline approaches to education participated in a national multicenter nursing quality improvement (QI) intervention to promote safe sleep practices. The goals at participating maternity units were to (1) increase the rate of mothers who reported receiving safe sleep information from nurses to ≥90% and (2) increase the rates of infants observed sleeping supine in a safe environment to ≥90%. A safe sleep QI toolkit, designed for and provided to all sites, included an educational curriculum and tools to use for staff and parent education. Local teams implemented safe sleep education using the tools as plan-do-study-act cycles. After each cycle, audits assessing maternal report of nursing education on safe sleep and inpatient infant sleep position and environment were performed. The QI interventions lasted a median of 160 days (range, 101-273). Mothers reported receiving information on 4 primary safe sleep topics 72% to 95% of the time (a 24%-57% increase over the baseline). Additionally, 93% of infants were observed in a supine sleep position, and 88% of infants were observed in a safe sleep environment (a 24% and 33% increase over baseline, respectively). These rates were sustained up to 12 months later. Implementation of a multisite QI intervention for safe sleep parenting education and role modeling led to increased knowledge of and compliance with safe sleep practices during postpartum hospitalization.


Application of the ABCD2 score to identify cerebrovascular causes of dizziness in the emergency department.
Dizziness can herald a cerebrovascular event. The ABCD(2) score predicts the risk of stroke after transient ischemic attack partly by distinguishing transient ischemic attack from mimics. We evaluated whether this score would also identify cerebrovascular events among emergency department patients with dizziness. We retrospectively identified consecutive adults presenting to a university emergency department with a primary symptom of dizziness, vertigo, or imbalance. Two neurologists independently reviewed medical records to determine whether the presenting symptom was caused by a cerebrovascular event (ischemic stroke, transient ischemic attack, or intracranial hemorrhage). ABCD(2) scores were then assigned using clinical information from the medical record. The ability of the score to discriminate between patients with cerebrovascular events and those with other diagnoses was quantified using the c statistic. Among 907 dizzy patients (mean age, 59 years; 58% female), 37 (4.1%) had a cerebrovascular cause, the majority of which were ischemic strokes (n=24). The median ABCD(2) score was 3 (interquartile range, 3-4). The ABCD(2) score predicted ultimate diagnosis of a cerebrovascular event (c statistic, 0.79; 95% CI, 0.73-0.85). Only 5 of 512 (1.0%) patients with a score of ≤ 3 had a cerebrovascular event compared to 25 of 369 patients (6.8%) with a score of 4 or 5 and 7 of 26 patients (27.0%) with a score of 6 or 7. The ABCD(2) score may provide useful information on dizzy emergency department patients at low-risk for having a cerebrovascular diagnosis and may aid frontline providers in acute management if validated prospectively.


Drug interactions in the management of HIV infection.
The availability of antiretroviral therapy has significantly reduced the morbidity and mortality of HIV infection. In addition, improved treatment of opportunistic infections and comorbidities common to patients with HIV is further prolonging the lives of patients. Improvement in the treatment of HIV has led to a significant increase in the number of medications which caregivers are able to utilise to manage HIV/AIDS. Antiretroviral medications, as well as many of the drugs used in the management of opportunistic infections and primary care (e.g., macrolide antibiotics, azole antifungals, cholesterol-lowering medications), are particularly prone to drug interactions. The interpretation of clinically significant interactions is complicated by the rate at which new information on drug metabolism and transport is becoming available. Management of drug interactions in HIV is further confounded by conflicting study results and differences between documented and theoretical inter-actions. The mechanisms and significance of interactions involving antiretrovirals, drugs used for opportunistic infections, and other medications commonly used in HIV patients will be reviewed.


Identification of potential core genes at single-cell level contributing to pathogenesis of pancreatic ductal adenocarcinoma through bioinformatics analysis.
Pancreatic ductal adenocarcinoma (PDAC) prognosis has not improved over the last decades because of the lack of effective diagnostic and therapeutic methods in the early stage of the disease. Several gene expression profiles were downloaded from the Expression Omnibus (GEO) database. We calculated the differentially expressed mRNAs (DEGs) and miRNAs (DEmiRs). Then, we constructed a miRNA-mRNA regulatory network by using the miRWalk database. For the DEGs regulated by DEmiRs, we introduced GEPIA to confirm these DEGs' expression and effect on overall survival. We used other GEO datasets and mRNA-miRNA target databases to validate these DEGs and their relationship with DEmiRs. All these potential core DEGs regulated by DEmiRs were also analyzed at the single-cell level to confirm their cell type source. CCNB2 and KCNN4, which were regulated by several micro RNAs, showed relatively high expression levels in PDAC patients and significant association with worse overall survival. Furthermore, we identified many DEGs at single-cell level and found that 10 oncogenes were significantly upregulated in type 2 ductal cell type, thereby further demonstrating that type 2 ductal cells might be major sources of malignant cells and are valuable therapeutic targets in PDAC. Our data added some new insights into the molecular mechanism of PDAC and may be helpful for finding potential biomarkers for diagnosis. These discovery at single-cell level may also be useful for developing new therapeutic targets for PDAC patients.


Testing DAYCENT model simulations of corn yields and nitrous oxide emissions in irrigated tillage systems in Colorado.
Agricultural soils are responsible for the majority of nitrous oxide (N(2)O) emissions in the USA. Irrigated cropping, particularly in the western USA, is an important source of N(2)O emissions. However, the impacts of tillage intensity and N fertilizer amount and type have not been extensively studied for irrigated systems. The DAYCENT biogeochemical model was tested using N(2)O, crop yield, soil N and C, and other data collected from irrigated cropping systems in northeastern Colorado during 2002 to 2006. DAYCENT uses daily weather, soil texture, and land management information to simulate C and N fluxes between the atmosphere, soil, and vegetation. The model properly represented the impacts of tillage intensity and N fertilizer amount on crop yields, soil organic C (SOC), and soil water content. DAYCENT N(2)O emissions matched the measured data in that simulated emissions increased as N fertilization rates increased and emissions from no-till (NT) tended to be lower on average than conventional-till (CT). However, the model overestimated N(2)O emissions. Lowering the amount of N(2)O emitted per unit of N nitrified from 2 to 1% helped improve model fit but the treatments receiving no N fertilizer were still overestimated by more than a factor of 2. Both the model and measurements showed that soil NO(3)(-) levels increase with N fertilizer addition and with tillage intensity, but DAYCENT underestimated NO(3)(-) levels, particularly for the treatments receiving no N fertilizer. We suggest that DAYCENT could be improved by reducing the background nitrification rate and by accounting for the impact of changes in microbial community structure on denitrification rates.


Natural human plasmacytoid dendritic cells induce antigen-specific T-cell responses in melanoma patients.
Vaccination against cancer by using dendritic cells has for more than a decade been based on dendritic cells generated ex vivo from monocytes or CD34(+) progenitors. Here, we report on the first clinical study of therapeutic vaccination against cancer using naturally occurring plasmacytoid dendritic cells (pDC). Fifteen patients with metastatic melanoma received intranodal injections of pDCs activated and loaded with tumor antigen-associated peptides ex vivo. In vivo imaging showed that administered pDCs migrated and distributed over multiple lymph nodes. Several patients mounted antivaccine CD4(+) and CD8(+) T-cell responses. Despite the limited number of administered pDCs, an IFN signature was observed after each vaccination. These results indicate that vaccination with naturally occurring pDC is feasible with minimal toxicity and that in patients with metastatic melanoma, it induces favorable immune responses.


Bifurcatriol, a New Antiprotozoal Acyclic Diterpene from the Brown Alga Bifurcaria bifurcata.
Linear diterpenes that are commonly found in brown algae are of high chemotaxonomic and ecological importance. This study reports bifurcatriol (1), a new linear diterpene featuring two stereogenic centers isolated from the Irish brown alga Bifurcariabifurcata. The gross structure of this new natural product was elucidated based on its spectroscopic data (IR, 1D and 2D-NMR, HRMS). Its absolute configuration was identified by experimental and computational vibrational circular dichroism (VCD) spectroscopy, combined with the calculation of 13C-NMR chemical shielding constants. Bifurcatriol (1) was tested for in vitro antiprotozoal activity towards a small panel of parasites (Plasmodium falciparum, Trypanosoma brucei rhodesiense, T. cruzi, and Leishmania donovani) and cytotoxicity against mammalian primary cells. The highest activity was exerted against the malaria parasite P. falciparum (IC50 value 0.65 μg/mL) with low cytotoxicity (IC50 value 56.6 μg/mL). To our knowledge, this is the first successful application of VCD and DP4 probability analysis of the calculated 13C-NMR chemical shifts for the simultaneous assignment of the absolute configuration of multiple stereogenic centers in a long-chain acyclic natural product.


Examining the Potential of Vitamin C Supplementation in Tissue-Engineered Equine Superficial Digital Flexor Tendon Constructs.
Because equine tendinopathies are slow to heal and often recur, therapeutic strategies are being considered that aid tendon repair. Given the success of utilizing vitamin C to promote tenogenesis in other species, we hypothesized that vitamin C supplementation would produce dose-dependent improvements in the tenogenic properties of tendon proper (TP) and peritenon (PERI) cells of the equine superficial digital flexor tendon (SDFT). Equine TP- and PERI-progenitor-cell-seeded fibrin three-dimensional constructs were supplemented with four concentrations of vitamin C. The gene expression profiles of the constructs were assessed with 3'-Tag-Seq and real-time quantitative polymerase chain reaction (RT-qPCR); collagen content and fibril ultrastructure were also analyzed. Moreover, cells were challenged with dexamethasone to determine the levels of cytoprotection afforded by vitamin C. Expression profiling demonstrated that vitamin C had an anti-inflammatory effect on TP and PERI cell constructs. Moreover, vitamin C supplementation mitigated the degenerative pathways seen in tendinopathy and increased collagen content in tendon constructs. When challenged with dexamethasone in two-dimensional culture, vitamin C had a cytoprotective effect for TP cells but not necessarily for PERI cells. Future studies will explore the effects of vitamin C on these cells during inflammation and within the tendon niche in vivo.


Cooperation between c-Met and focal adhesion kinase family members in medulloblastoma and implications for therapy.
We previously showed the involvement of the tyrosine kinase receptor c-Met in medulloblastoma malignancy. The nonreceptor tyrosine kinases focal adhesion kinase (FAK) and Pyk2 are key players in the progression of different cancers. However, their role in medulloblastoma malignancy is not well understood. In this study, using a protein array approach, we found that c-Met induces FAK and Pyk2 phosphorylation in medulloblastoma cells. We therefore studied the interactions between c-Met and FAK/Pyk2 and their implications for medulloblastoma therapy. We found that c-Met activates FAK and Pyk2 in several medulloblastoma cell lines. We also found that FAK and Pyk2 mediate the malignant effects of c-Met on medulloblastoma cell proliferation, migration, and invasion. On the basis of these findings, we hypothesized that combined c-Met and FAK inhibitions would have additive effects on the inhibition of medulloblastoma malignancy. To test this hypothesis, we assessed the effects on medulloblastoma malignancy parameters of single or combined treatments of medulloblastoma cells with c-Met and FAK small-molecule kinase inhibitors. We found a significant increase in the inhibitory effect of both inhibitors on medulloblastoma cell migration and cell invasion as compared with single inhibitions (P < 0.05). In addition, oral gavage treatment with c-Met inhibitor of mice bearing medulloblastoma xenografts significantly reduced in vivo tumor growth. Therefore, combining c-Met inhibitors with FAK inhibitors constitutes a new potential strategy for medulloblastoma therapy. Altogether, our study describes a role for FAK and Pyk2 in medulloblastoma malignancy, uncovers new interactions between c-Met and FAK/Pyk2, and proposes for the first time combining anti-c-Met and anti-FAK inhibitors as a new strategy for medulloblastoma therapy.


The Efficacy and Duration of Protection of Pneumococcal Conjugate Vaccines Against Nasopharyngeal Carriage: A Meta-regression Model.
Pneumococcal conjugate vaccines (PCVs) reduce disease largely through their impact on nasopharyngeal (NP) carriage acquisition of Streptococcus pneumoniae, a precondition for developing any form of pneumococcal disease. We aimed to estimate the vaccine efficacy (VEC) and duration of protection of PCVs against S. pneumoniae carriage acquisition through meta-regression models. We identified intervention studies providing NP carriage estimates among vaccinated and unvaccinated children at any time after completion of a full vaccination schedule. We calculated VEC for PCV7 serotypes, grouped as well as individually, and explored cross-protective efficacy against 6A. Efficacy estimates over time were obtained using a Bayesian meta-logistic regression approach, with time since completion of vaccination as a covariate. We used data from 22 carriage surveys (15 independent studies) from 5 to 64 months after the last PCV dose, including 14,298 children. The aggregate VEC for all PCV7 serotypes 6 months after completion of the vaccination schedule was 57% (95% credible interval: 50-65%), varying by serotype from 38% (19F) to 80%. Our model provides evidence of sustained protection of PCVs for several years, with an aggregate VEC of 42% (95% credible interval: 19-54%) at 5 years, although the waning differed between serotypes. We also found evidence of cross-protection against 6A, with a VEC of 39% 6 months after a complete schedule, decreasing to 0 within 5 years postvaccination. Our results suggest that PCVs confer reasonable protection against acquisition of pneumococcal carriage of the 7 studied serotypes, for several years after vaccination, albeit with differences across serotypes.


Presence of transcription regulatory elements within an intron of the virus-inducible murine TIMP gene.
The expression of the gene for the murine tissue inhibitor of metalloproteinases (TIMP) is induced in response to viruses, growth factors, and phorbol esters. In this report we show that the accumulation of TIMP mRNA after Newcastle disease virus induction is caused by transcriptional activation of the gene. Comparison of the sequences of cDNA and genomic clones along with RNase protection and primer extension analyses revealed that the murine TIMP gene possesses multiple cap sites and that the exon 1 consists exclusively of 5'-noncoding sequences. We observed that DNA regions analogous to those found upstream of the virus-inducible interferon genes are present within intron 1 of the TIMP gene. To investigate the possible role of TIMP intron 1 in gene expression, we used a functional assay based on the transfection of plasmids in which the DNA segment to be tested is placed in proximity to a marker gene driven by the heterologous herpes simplex virus thymidine kinase promoter. Our results indicate that TIMP intron 1 contains DNA sequence elements capable of modulating the activity of a heterologous promoter in two different ways: (i) by enhancing constitutive expression and (ii) by conferring virus inducibility. These results suggest that intron 1 may be involved in the transcriptional regulation of TIMP gene expression.


Tests for inbreeding and outbreeding depression and estimation of population differentiation in the bird-pollinated shrub Grevillea mucronulata.
Plants show patterns of spatial genetic differentiation reflecting gene flow mediated by pollen and seed dispersal and genotype × environment interactions. If patterns of genetic structure are determined largely by gene flow then they may be useful in predicting the likelihood of inbreeding or outbreeding depression but should be less useful if there is strong site-specific selection. For many Australian plants little is known about either their population genetics or the effects on mating systems of variation in pollen transfer distances. Experimental pollinations were used to compare the reproductive success of bird-adapted Grevillea mucronulata plants mated with individuals from a range of spatial scales. A hierarchical survey of microsatellite DNA variation was also conducted to describe the scale of population differentiation for neutral markers. The effects of four pollen treatments on reproductive performance were compared. These treatments were characterized by transfer of pollen from (a) neighbouring adults; (b) an adjacent cluster of adults (30-50 m distant); (c) a distant cluster (>5 km distant); and (d) open pollination. Sets of 17·9 ± 3·3 leaves from each of 15 clusters of plants were genotyped and spatial autocorrelation and F statistics were used to describe patterns of genetic structure. Grevillea mucronulata displayed evidence of both inbreeding and outbreeding depression, with 'intermediate' pollen producing consistently superior outcomes for most aspects of fitness including seed set, seed size, germination and seedling growth. Significant genotypic structuring was detected within clusters (spatial autocorrelation) and among adjacent clusters and clusters separated by >5 km distance (F(ST) = 0·07 and 0·10). The superior outcome of intermediate pollen transfer and genetic differentiation of adjacent clusters suggests that G. mucronulata selection disfavours matings among closely and distantly related neighbours. Moreover, the performance of open-pollinated seedlings was poor, implying that current mating patterns are suboptimal.


Solution-based synthesis of GeTe octahedra at low temperature.
GeTe octahedra were prepared by reaction of equimolar amounts of GeCl2·dioxane and Te(SiEt3)2 in oleylamine, whereas a slight excess of the Te precursor yielded GeTe octahedra decorated with elemental Te nanowires, which can be removed by washing with TOP. The mechanism of the GeTe formation is strongly influenced by the solvent. The expected elimination of Et3SiCl (dehalosilylation) only occurred in aprotic solvents, whereas Te(SiEt3)2 was found to react with primary and secondary amines with formation of silylamines. Temperature-dependent studies on the reaction in oleylamine showed that crystalline GeTe particles are formed at temperatures higher than 140 °C. XRD, SAED, and HRTEM studies proved the formation of rhombohedral GeTe nanoparticles. These findings were confirmed by a single-crystal and powder X-ray analysis. The rhombohedral structure modification was found, and the structure was solved in the acentric space group R3m.


Compartmental analysis: theoretical aspects and application.
The basic equations governing the kinetics of metabolic compartmental systems are presented. The most difficult problem in compartmental analysis is the so-called inverse problem which is the estimation of model parameters from experimental data. Two examples are considered how to tackle this problem. The first example concerns the distribution of isotopic carbon atoms in the citric acid cycle. Starting from a matrix formulation of the problem the major steps are outlined towards an analytical solution for this rather complex system. An application of the theoretical approach to the citric acid cycle of rabbit reticulocytes is given. The second problem deals with the kinetic characterization of biochemical reactions proceeding at the same time in different physiological spaces with different rates. Such a situation is, for example, the infection of red blood cells by malaria parasites. Both the host cell and the parasite possess the complete glycolytic pathway. A theoretical approach is proposed to estimate the flux rates through this pathway separately for each of the two spaces when only the total rates and metabolite concentrations are available as experimental data.


Attentional function and basal forebrain cholinergic neuron morphology during aging in the Ts65Dn mouse model of Down syndrome.
Individuals with Down syndrome (DS) exhibit intellectual disability and develop Alzheimer's disease-like neuropathology during the third decade of life. The Ts65Dn mouse model of DS exhibits key features of both disorders, including impairments in learning, attention and memory, as well as atrophy of basal forebrain cholinergic neurons (BFCNs). The present study evaluated attentional function in relation to BFCN morphology in young (3 months) and middle-aged (12 months) Ts65Dn mice and disomic (2N) controls. Ts65Dn mice exhibited attentional dysfunction at both ages, with greater impairment in older trisomics. Density of BFCNs was significantly lower for Ts65Dn mice independent of age, which may contribute to attentional dysfunction since BFCN density was positively associated with performance on an attention task. BFCN volume decreased with age in 2N but not Ts65Dn mice. Paradoxically, BFCN volume was greater in older trisomic mice, suggestive of a compensatory response. In sum, attentional dysfunction occurred in both young and middle-aged Ts65Dn mice, which may in part reflect reduced density and/or phenotypic alterations in BFCNs.


Camptothecin-based dendrimersomes for gene delivery and redox-responsive drug delivery to cancer cells.
Combination therapy involving chemotherapeutic drugs and genes is emerging as a promising strategy to provide a synergistic therapeutic effect, to overcome drug resistance while reducing the severe side effects associated with conventional chemotherapeutic drugs. However, the lack of nanomedicines able to simultaneously carry anti-cancer drugs and nucleic acids limits the application of this therapeutic strategy. To overcome this issue, we proposed to synthesize a pro-drug dendrimer by conjugating the PEGylated, positively charged generation 3-diaminobutyric polypropylenimine dendrimer to the anti-cancer drug camptothecin with a redox-sensitive disulphide linkage, and evaluate its efficacy to co-deliver the complexed DNA and camptothecin to cancer cells. This PEGylated pro-drug dendrimer was found to spontaneously self-assemble into cationic (∼3-5 mV) vesicles at pH 7.4, at a critical aggregation concentration of about 200 μg mL-1. These vesicles (dendrimersomes) became smaller (150-200 nm) with increasing dendrimer concentration and remained stable over 7 days. They were able to release about 70% of the conjugated camptothecin in presence of 50 mM glutathione (equivalent to the intracellular environment of tumor tissue). They could also condense more than 85% of the DNA at dendrimer : DNA weight ratios of 5 : 1 and higher. DNA condensation occurred instantly and was found to be stable for at least 24 h. This led to an enhanced cellular uptake of DNA (by up to 1.6-fold) and increased gene transfection (by up to 2.4-fold) in prostate cancer cells in comparison with the unmodified dendrimer. These novel dendrimersomes are therefore promising for single carrier-based combination cancer therapy.


Anomalous dispersion of sulfur in quinidine sulfate, (C(20)H(25)N(2)O(2))(2)SO(4).2H(2)O: Implications for structure analysis.
A Patterson-type map computed with Bijvoet differences squared as coefficients, (F(h) - F(-h))(2), as recommended by Rossmann, readily yielded the position of the S atom. The experiment was performed with Cu Kalpha radiation which is far from the absorption edge for sulfur. The coordinates of the remainder of the 54C, N, and O atoms were derived by means of partial structure development by use of the tangent formula. The latter was used only to effect phase extension, not phase refinement. A main purpose of this experiment was to reaffirm, as first shown in the investigation of the protein crambin by Hendrickson and Teeter, that, in the presence of a large number of lighter atoms, sulfur atoms can be located by use of anomalous dispersion at wave-lengths far from the absorption edge. The space group is P2(1) with a = 26.718(8) A, b = 6.987(3) A, c = 10.857(6) A, and beta = 99.51(4) degrees and contains two quinidyl ions, one sulfate ion, and two water molecules per asymmetric unit. The conformations of the two independent quinidyl ions differ mainly in the torsional angle of the bond between the vinyl side chain and the quinuclidine moiety. The R factor is 4.9% for all 2869 data.


4-Halo-1,2,3-triazolylidenes: stable carbenes featuring halogen bonding.
Synthesis and coordination of 4-halo-1,2,3-triazolylidenes have been developed. These novel ligands featured the character with σ-donation at carbon and a σ-hole at the halogen. Halogen bonding was observed by single crystal X-ray diffraction in their coinage metal complexes. The electronic properties of 4-iodo-1,2,3-triazolylidene were studied by both Ir-CO frequencies of the Tolman electronic parameter (TEP) and Huynh's electronic parameter (HEP) method, which suggested similar electronic properties to those of imidazolylidenes. During HEP tests, an interesting tunability was observed when different electron donors were employed.


Compressive behaviour of anisotropic mycelium-based composites.
Mycelium based composites (MBC) exhibit many properties that make them promising alternatives for less sustainable materials. However, there is no unified approach to their testing. We hypothesise that the two-phase particulate composite model and use of ASTM D1037 could provide a basis for systematisation. An experimental series of MBC were produced using four substrate particle sizes and subjected to compression testing. We report on their effect over Young's modulus and ultimate strength. We extend the study by investigating three anisotropic substrate designs through orientated fibre placement as a strategy for modifying compressive behaviour. We find that the two-phase particulate model is appropriate for describing the mechanical behaviour of MBC and that mechanical behaviour can be modified through anisotropic designs using orientated fibres. We also confirm that fibre orientation and particle size are significant parameters in determining ultimate strength.


Cellular correlates of spontaneous periodic events in the medial entorhinal cortex of the in vitro isolated guinea pig brain.
Periodic potentials characterized by fast oscillations superimposed on a slow complex event are typically observed in cortical structures during sleep and anaesthesia. In the entorhinal cortex (EC) similar spontaneous periodic events (SPEs) have been described both in vivo and in vitro. Simultaneous extracellular and intracellular recordings from superficial neurons of the entorhinal cortex of the isolated Hartley guinea pig brain preparation demonstrated that SPEs recur with a periodicity of 2-10 s and correlate to neuronal firing superimposed on a depolarizing plateau that lasts 0.7-1 s. During SPEs, putative interneurons in all layers discharged high frequency firing (> 100 Hz), whereas no activity was observed in principal neurons of deep entorhinal cortex layers. Linear correlation analysis demonstrated a tight relationship between the fast component of the extracellular SPE and subthreshold oscillatory activity/neuronal firing in both superficial neurons and putative interneurons; firing of deep principal cells was independent from SPEs occurrence. The present study demonstrates that recurrent spontaneous events analogous to periodic activity observed during sleep/anaesthesia are generated in the entorhinal cortex by the interactions between superficial neurons and interneurons.


Granulocyte alkaline phosphatase. Studies of purified enzymes from normal subjects and patients with polycythemia vera.
To characterize the biological changes which result in increased granulocyte alkaline p-nitrophenyl phosphatase activity in patients with polycythemia vera, the enzyme was purified from granule fractions of sucrose homogenates made from dextran-sedimented leukocytes of normal subjects and patients with polycythemia vera. Polycythemic blood yielded 3-10 times as much granulocyte alkaline phosphatase per 10(9) leukocytes as did normal blood. Sodium dodecyl sulfate extracts of granules were purified by DEAE-cellulose chromatography and sucrose gradient centrifugation to apparent homogeneity as judged by polycarylamide disk gel electrophoresis. Granulocyte alkaline phosphatase from normal subjects was purified 6910-fold with a 60% yield and a specific activity of 47 U/mg. Granulocyte alkaline phosphatase from polycythemic patients was purified 1.166-fold with a 50% yield and a specific activity of 70 U/mg. The two enzymes did not differ in molecular weight; both appeared to be about 160,000 daltons by sucrose gradient centrifugation. Both appeared to be zinc metalloenzymes, in that they were specifically inhibited by o-phenanthroline. Their elution requirements when adsorbed to DEAE-cellulose suggested they were lipoproteins although the content of phosphorus was below the threshold of detection. The identity of the two enzymes was suggested by immunological studies in which antibody prepared against purified polycythemia vera enzyme gave a precipitation reaction of identity with another polycythemia vera enzyme and two pools of normal enzyme. It is possible to account for the difference in alkaline phosphatase activity between the granulocytes of patients with polycythemia vera and normal subjects by differences in the quantity of enzyme synthesized.


[Osteosynthesis of articular fractures of the heelbone using a reconstruction plate].
The authors describe in detail this technique which employs a reconstruction plate which can be moulded in all directions. The plate, fashioned in a stereotyped way extemporaneously or even during the pre-operative period, perfectly fits the lateral surface of the calcaneus, curves behind the tuberosity and descends in front to the junction of the lateral and inferior surfaces of the greater apophysis. With its screws anchored in the sustentaculum tali, it supports the previously reduced thalamic body which is itself fixed to the sustentaculum by screws, thereby avoiding further slippage. The very solid union thus obtained allows early weight bearing. This technique allows logical treatment of all types of fractures. Numerous technical details provide surgical guidelines for these technically difficult fractures. The operating protocol may thus be used by all operators. There are plans to market a pre-moulded plate which would further simplify the procedure. Currently, 55 fractures have been treated by this technique. The median interval to weight bearing was 7 days and 6 weeks to walking without crutches (45 cases). The functional results in 34 cases with sufficient follow-up (16 Months) showed 71% satisfactory results (very good, good or quite good), 21% mediocre and 8% poor results.


Elderly-onset rheumatoid arthritis and its association with HLA-DRB1 alleles in Japanese.
To assess the association between HLA-DRB1 and elderly-onset rheumatoid arthritis (RA) (EORA) in Japanese people, we analysed the HLA-DRB1 antigen frequencies of EORA patients. The age at onset distribution of 852 Japanese RA patients was analysed, and EORA was defined as an age at onset of 60 yr or older. Among the 852 RA patients, 120 (14.1%) were EORA patients. Their HLA-DRB1 antigen frequencies were assessed for significant deviation from those of the control (n = 652) and adult-onset RA (AORA; disease onset between 16 and 59 yr; n = 732) groups. The Japanese EORA patients were positively associated with DRB1*0101, *0405 and *1502, and the relative risks were 2.7, 1.9 and 2.2, respectively. The frequency of DRB1*1502 was also significantly higher among the EORA patients than in the AORA patients. The EORA patients showed different trends from the AORA patients in their frequency of HLA-DRB1 alleles, which suggests that EORA may be a different subset from AORA in light of its immunogenetic background.


Binding of C-reactive protein to human polymorphonuclear leukocytes: evidence for association of binding sites with Fc receptors.
The functional similarities between C-reactive protein (CRP) and IgG raised the question as to whether human phagocytes are stimulated by CRP in the same way as by binding of antigen-complexed or aggregated IgG to their Fc receptors. Studies with the use of highly purified 125I-labeled CRP showed specific and saturable binding to human polymorphonuclear leukocytes (PMN) with a KD of 10.5 +/- 5.7 X 10(-8) M only when carried out in heat-inactivated plasma. The number of specific binding sites per cell was estimated at 1 to 3 X 10(6). Competitive inhibition of CRP binding by antigen-complexed or aggregated IgG suggests CRP binding sites to be associated with PMN Fc receptors. Only when assayed in heat-inactivated plasma did CRP binding induce adherence of cells to tissue culture dishes. However, no metabolic and potentially cytotoxic stimulation of PMN was detected during CRP plasma-dependent attachment to surfaces: induction of aggregation, release of secondary granule constituents, and activation of the hexose monophosphate pathway were not observed. These results imply that CRP-PMN interactions is dependent on an additional factor present in heat-inactivated plasma and is followed only by a complement-independent increase in PMN attachment to surfaces. Because CRP was found to be deposited at sites of tissue injury, the CRP-mediated adherence of PMN may be an important step in localizing an inflammatory focus.


[Histochemical diagnosis of the neurons of cholinergic synaptic transmission].
The authors studied neurons of the medulla oblongata of 5 human fetuses (22-27 weeks of development). Cholinacetyltransferase (CAT) activity was examined by the Berth method. Three neuronal types were diagnosed in the nuclei of the medulla oblongata with regard to CAT localization in the cytoplasm and synapses: (a) cholinergic-cholinoceptive neurons having CAT in the cytoplasm and in the innervating afferent fibers; (b) cholinergic-noncholinoceptive neurons with high CAT content, innervated with noncholinergic afferent fibers; (c) noncholinergic-cholinoceptive neurons carrying cholinergic synapses.


Cyclosporin neurotoxicity with Epstein-Barr virus-associated hemophagocytic syndrome.
In September 2000, a 22-year-old female was admitted to our hospital due to high grade fever, liver enzymes elevation and pancytopenia. Bone marrow aspiration was performed, and hemophagocytosis was present. Epstein-Barr virus (EBV) DNA was positive in her peripheral blood, and we diagnosed the case as EBV-associated hemophagocytic syndrome (EB-VAHS) after excluding other malignancies. The initial therapy including etoposide and dexamethasone was started. As severe leukocytopenia developed, etoposide was stopped and cyclosporin A (CsA) was administered continuously. Four days after administration of CsA, she developed convulsive seizures with loss of consciousness. An MRI demonstrated decreased signal with T1-weighting and high signal with T2-weighting in the subcortical white matter including the posterior lobe. We stopped CsA infusion, and glycerol was administered. Soon the symptom disappeared. When patients developed an episode of convulsive seizure, other diagnostic possibilities were central nervous system (CNS) involvement of hemophagocytosis, EBV encephalitis and acute disseminated encephalomyelitis (ADEM). CsA neurotoxicity must be considered even in the case of EB-VAHS with administration of CsA. As previously reported, Fluid-attenuated Inversion Recovery (FLAIR) imaging improved diagnostic confidence and conspicuity of the T2 hyper intense lesions of CsA neurotoxicity, as well as tacrolimus encephalopathy, typically in the subcortical white matter. Key words; Cyclosporin neurotoxicity; Epstein-Barr virus associated-Hemophagocytic syndrome; Magnetic Resonance Image (MRI).


Diffusivity measurements differentiate benign from malignant lesions in patients with peripheral neuropathy or plexopathy.
Peripheral nerve disorders caused by benign and malignant primary nerve sheath tumors, infiltration or compression of nerves by metastatic disease, and postradiation neuritis demonstrate overlapping features on conventional MR imaging but require vastly different therapeutic approaches. We characterize and compare diffusivities of peripheral nerve lesions in patients undergoing MR neurography for peripheral neuropathy or brachial or lumbosacral plexopathy. Twenty-three patients, referred for MR neurography at our institution between 2003 and 2009 for a peripheral mononeuropathy or brachial or lumbosacral plexopathy and whose examinations included DWI, received a definitive diagnosis, based on biopsy results or clinical and imaging follow-up, for a masslike or infiltrative peripheral nerve or plexus lesion suspicious for tumor. Mean ADC values were determined within each lesion and compared across 3 groups (benign lesions, malignant lesions, and postradiation changes). Both ANOVA and Kruskal-Wallis tests demonstrated a statistically significant difference in ADC values across the 3 groups (P = .000023, P = .00056, respectively). Post hoc pair-wise comparisons showed that the ADC within malignant tumors differed significantly from that within benign tumors and postradiation changes. ADC within benign tumors and postradiation changes did not differ significantly from each other. DWI may be highly effective for the differentiation of benign from malignant peripheral nerve masslike or infiltrative lesions.


A new particle swarm algorithm and its globally convergent modifications.
Particle swarm optimization (PSO) is a population-based optimization technique that can be applied to a wide range of problems. Here, we first investigate the behavior of particles in the PSO using a Monte Carlo method. The results reveal the essence of the trajectory of particles during iterations and the reasons why the PSO lacks a global search ability in the last stage of iterations. Then, we report a novel PSO with a moderate-random-search strategy (MRPSO), which enhances the ability of particles to explore the solution spaces more effectively and increases their convergence rates. Furthermore, a new mutation strategy is used, which makes it easier for particles in hybrid MRPSO (HMRPSO) to find the global optimum and which also seeks a balance between the exploration of new regions and the exploitation of the already sampled regions in the solution spaces. Thirteen benchmark functions are employed to test the performance of the HMRPSO. The results show that the new PSO algorithm performs much better than other PSO algorithms for each multimodal and unimodal function. Furthermore, compared with recent evolutionary algorithms, experimental results empirically demonstrate that the proposed framework yields promising search performance.


Loricate choanoflagellates (Acanthoecida) from warm water seas. VI. Pleurasiga Schiller and Parvicorbicula Deflandre.
The loricate choanoflagellate genera Pleurasiga and Parvicorbicula are taxonomically ambiguous. Pleurasiga because of the uncertainty that relates to the true identity of the type species, and Parvicorbicula because too many newly described species over time have been dumped here in lack of better options. While all species currently allocated to the genus Pleurasiga (with the exception of the type species) are observed in our samples from the global warm water belt, the genus Parvicorbicula is represented by just a few and mostly infrequently recorded taxa. Two new species, viz. Pl. quadrangiella sp. nov. and Pl. minutissima sp. nov., are described here. While the former is closely related to Pl. echinocostata, the latter is reminiscent of Pl. minima. Core species of Pleurasiga and Parvicorbicula deviate from the vast majority of loricate choanoflagellates in having both the anterior and the mid-lorica transverse costae located exterior to the longitudinal costae. In Pl. quadrangiella there is no mid-lorica transverse costa but rather a small posterior transverse costa located inside the longitudinal costae. In Pl. minutissima the mid-lorica transverse costa has extensive costal strip overlaps which reveal patterns of costal strip junctions that deviate from the norm.


Blast transformation in chronic myelomonocytic leukemia: Risk factors, genetic features, survival, and treatment outcome.
Among 274 patients with chronic myelomonocytic leukemia (CMML) and followed for a median of 17.1 months, blast transformation (BT) occurred in 36 (13%). On multivariable analysis, risk factors for BT were presence of circulating blasts (HR 5.7; 95% CI 2.8-11.9) and female gender (HR 2.6; 95% CI 1.3-5.1); the results remained unchanged when analysis was restricted to CMML-1. ASXL1/SRSF2/SF3B1/U2AF1/SETBP1 mutational frequencies were not significantly different between time of CMML diagnosis and BT. Median survival post-BT was 4.7 months (5-year survival 6%) and better with allogeneic stem cell transplant (SCT) (14.3 months vs. 4.3 months for chemotherapy vs. 0.9 months for supportive care; P = 0.03). Neither karyotype nor mutational status was independently associated with risk of BT or post-BT survival. We conclude that female patients with CMML and those with circulating blasts are at a higher risk of BT. Post-BT survival is dismal and our observations suggest consideration of allogeneic SCT prior to BT.


Low T3 syndrome in psychiatric depression.
In euthyroid sick syndrome [non-thyroidal illness (NTI)], a number of investigators have described TSH and serum thyroid hormone abnormalities, low T3, low T3 and T4, increased T4, low TSH, etc. Those cases of NTI where there is only T3 decrease [and normal serum T4, free T4 (FT4), and TSH levels] are specifically referred to as low T3 syndrome. However, the information in regard to low T3 syndrome in psychiatric subjects who are clinically euthyroid and do not have any other systemic illness is scanty. In our facility, since thyroid function is routinely assessed in psychiatric patients at admission, this provided the opportunity to study low T3 syndrome in a large group of psychiatric patients. Out of 250 subjects with major psychiatric depression, 6.4% exhibited low T3 syndrome (mean serum T3 concentration 0.94 nmol/l vs normal mean serum concentration of 1.77 nmol/l). The low T3 levels could not be ascribed to malnutrition or any other illness and the metabolic parameters were all normal. Possible mechanisms contributing to low T3 are discussed. The depression might constitute an illness having the same relation to low T3 as found in the low T3 syndrome previously described in euthyroid sick subjects. The present findings, besides describing low T3 syndrome in psychiatric patients without systemic illnesses, suggest the possibility of subgrouping in clinical psychiatric depression which may have a broader clinical significance.


A new research strategy for integrating studies of paleoclimate, paleoenvironment, and paleoanthropology.
Paleoanthropologists (scientists studying human origins) universally recognize the evolutionary significance of ancient climates and environments for understanding human origins. Even those scientists working in recent phases of human evolution, when modern humans evolved, agree that hunter-gatherer adaptations are tied to the way that climate and environment shape the food and technological resource base. The result is a long tradition of paleoanthropologists engaging with climate and environmental scientists in an effort to understand if and how hominin bio-behavioral evolution responded to climate and environmental change. Despite this unusual consonance, the anticipated rewards of this synergy are unrealized and, in our opinion, will not reach potential until there are some fundamental changes in the way the research model is constructed. Discovering the relation between climate and environmental change to human origins must be grounded in a theoretical framework and a causal understanding of the connection between climate, environment, resource patterning, behavior, and morphology, then move beyond the strict correlative research that continues to dominate the field.


Transcriptional activation of the general amino acid permease gene per1 by the histone deacetylase Clr6 Is regulated by Oca2 kinase.
Expression of nitrogen metabolism genes is regulated by the quality of the nitrogen supply. Here, we describe a mechanism for the transcriptional regulation of the general amino acid permease gene per1 in Schizosaccharomyces pombe. We show that when ammonia is used as the nitrogen source, low levels of per1 are transcribed and histones in the coding and surrounding regions of per1 are acetylated. In the presence of proline, per1 transcription is upregulated and initiates from a more upstream site, generating 5'-extended mRNAs. Concomitantly, histones at per1 are deacetylated in a Clr6-dependent manner, suggesting a positive role for Clr6 in transcriptional regulation of per1. Upstream initiation and histone deactylation of per1 are constitutive in cells lacking the serine/threonine kinase oca2, indicating that Oca2 is a repressor of per1. Oca2 interacts with a protein homologous to the Saccharomyces cerevisiae transcriptional activator Cha4 and with Ago1. Loss of Cha4 or Ago1 causes aberrant induction of per1 under noninducing conditions, suggesting that these proteins are also involved in per1 regulation and hence in nitrogen utilization.


On the clinical utility of on-scalp MEG: A modeling study of epileptic activity source estimation.
Epilepsy surgery requires localization of the seizure onset zone (SOZ). Today this can only be achieved by intracranial electroencephalography (iEEG). The iEEG electrode placement is guided by findings from non-invasive modalities that cannot themselves detect SOZ-generated initial seizure activity. On scalp magnetoencephalography (osMEG), with sensors placed on the scalp, demonstrates higher sensitivity than conventional MEG (convMEG) and could potentially detect early seizure activity. Here, we modeled EEG, convMEG and osMEG to compare the modalities' ability to localize SOZ activity and to detect epileptic spikes. We modeled seizure propagation within ten epileptic networks located in the mesial and lateral temporal lobe; basal, dorsal, central and frontopolar frontal lobe; parietal and occipital lobe as well as insula and cingulum. The networks included brain regions often involved in focal epilepsy. 128-channel osMEG, convMEG, EEG and combined osMEG + EEG and convMEG + EEG were modeled, and the SOZ source estimation accuracy was quantified and compared using Student's t-test. OsMEG was significantly (p-value <0.01) better than both convMEG and EEG at detecting the earliest SOZ-generated seizure activity and epileptic spikes, and better at localizing seizure activity from all epileptic networks (p < 0.01). Our modeling results clearly show that osMEG has an unsurpassed potential to detect both epileptic spikes and seizure activity from all simulated anatomical sites. No clinically available non-invasive technique can detect SOZ activity from all brain regions. Our study indicates that osMEG has the potential to become an important clinical tool, improving both non-invasive SOZ localization and iEEG electrode placement accuracy.


Safeguarding against Dementia in Aboriginal and Torres Strait Islander Communities through the Optimisation of Primary Health Care: A Project Protocol.
This protocol describes the methodology and methods for a collaborative project with eight Aboriginal and Torres Strait Islander primary health care (PHC) organisations, across three Australian states and one territory, to increase clinical service performance and access to preventive health and health promotion services for preventing, identifying, treating, and managing dementia risk in Aboriginal and Torres Strait Islander communities. Aboriginal participatory action research (APAR) methodology will be the framework for this project, incorporating continuous quality improvement (CQI), informed by research yarning with stakeholder groups, comprising community members and PHC staff and service providers and data collected from the auditing of client health records and the mapping of existing clinical processes and health services at each partnering PHC organisation. The qualitative and quantitative data will be summarised and discussed with stakeholder groups. Priorities will be identified and broken down into tangible PHC organisation deliverable strategies and programs, which will be co-developed with stakeholder groups and implemented cyclically over 24 months using the Plan, Do, Study, Act model of change. Key project outcome measures include increased clinical service performance and availability of preventive health and health promotion services for safeguarding against dementia. Project implementation will be evaluated for quality and transparency from an Indigenous perspective using an appropriate appraisal tool. The project processes, impact, and sustainability will be evaluated using the RE-AIM framework. A dementia safeguarding framework and accompanying tool kit will be developed from this work to support Aboriginal and Torres Strait Islander PHC organisations to identify, implement, and evaluate dementia safeguarding practice and service improvements on a broader scale.


Quality Characterization of Japanese Medicinal Paeoniae Radix by Metallomic Analysis.
Paeoniae Radix is one of the crude drugs frequently used in traditional Japanese medicine (Kampo medicine). It takes abundant labor and time to cultivate Paeonia lactiflora for medicinal use; high production cost is one of the main reasons why the domestic production of Paeoniae Radix is decreasing in Japan. To promote the production of Paeoniae Radix, we focused on Paeonia cultivars that produce commercially valuable flowers and investigated their possibility for medicinal use. We prepared 28 batches of peony roots derived from P. lactiflora, which were cultivated in Japan; 4 batches were crude drug samples, and 24 batches were cultivar roots. The elements contained in these samples were measured using inductively coupled plasma (ICP)-MS. The obtained data were then analyzed by principal component analysis (PCA) and back propagation artificial neural network (BPANN) analysis. No significant differences were found between the profiles of elements contained in crude drugs and cultivar roots. However, PCA results indicated a high similarity of the multielement fingerprints of crude drugs. Using the PCA results, we also assessed visible cluster trends and found that 5 batches of cultivars also showed fingerprints related to those of crude drugs. We certified this classification by BPANN. From the perspective of metallomics, our findings suggest that these 5 batches of Paeonia cultivars could be alternatives to crude drugs.


The hazards of lack of co-registration of ictal brain SPECT with MRI: A case report of sinusitis mimicking a brainstem seizure focus.
BACKGROUND: Single photon emission computed tomography (SPECT) following injection of radiotracer during a seizure is known as ictal SPECT. Comparison of an ictal SPECT study to a baseline or interictal study can aid identification of a seizure focus. CASE PRESENTATION: A young woman with encephalitis and refractory seizures underwent brain SPECT during a period of frequent seizure-like episodes, and during a seizure-free period. A focal area of increased radiotracer uptake present only when she was experiencing frequent seizure-like episodes was originally localized to the brainstem, but with later computerized co-registration of SPECT to MRI, was found to lie outside the brain, in the region of the sphenoid sinus. CONCLUSION: Low-resolution SPECT images present difficulties in interpretation, which can be overcome through co-registration to higher-resolution structural images.


A Conformationally Constrained Cyclic Acyldepsipeptide Is Highly Effective in Mice Infected with Methicillin-Susceptible and -Resistant Staphylococcus aureus.
Cyclic acyldepsipeptides (ADEPs) are a novel class of antibacterial agents, some of which (e.g., ADEP 4) are highly active against Gram-positive bacteria. The focus of these in vivo studies is ADEP B315, a rationally designed compound that has the most potent in vitro activity of any ADEP analog reported to date. In vivo efficacy experiments were performed using lethal intraperitoneal mice infection models with a methicillin-sensitive S. aureus (MSSA) and a methicillin-resistant (MRSA) strain. The infected mice were treated with ADEP B315, a des-methyl analog of ADEP 4, vancomycin, or the vehicle used for the ADEPs and their survival was assessed daily. A subset of MSSA-infected mice was sacrificed soon after inoculation and the bacterial burden was measured in their livers and spleens. The toxicity of ADEP B315 was assessed in viability assays using human whole blood cultures. In the MSSA experiments, all mice treated with the vehicle succumbed to the infection within 24 hours. All tested compounds were effective in prolonging survival of infected mice (p<0.001). Mice treated with ADEP B315 had a 39% survival rate by 10 days compared to 7% survival in mice treated with a des-methyl ADEP 4 analog (p = 0.017). Survival of the infected mice treated with ADEP B315 was comparable to those treated with vanocmycin (p = 0.12) at the same dose. Further, bacterial burden in the liver and spleen was significantly lower in mice treated with ADEP B315 compared to controls. In the MRSA experiments, ADEP B315 was able to significantly prolong survival compared to mice treated with either the vehicle (p = 0.001) or vancomycin (p = 0.007). ADEP B315 exhibited no significant toxicity in human whole blood cultures at concentrations up to 25 μg/ml. ADEP B315 is safe and can cure mice that have lethal infections of methicillin-sensitive and -resistant strains of S. aureus.


Perspectives on the role of fospropofol in the monitored anesthesia care setting.
Monitored anesthesia care (MAC) is a safe, effective, and appropriate form of anesthesia for many minor surgical procedures. The proliferation of outpatient procedures has heightened interest in MAC sedation agents. Among the most commonly used MAC sedation agents today are benzodiazepines, including midazolam, and propofol. Recently approved in the United States is fospropofol, a prodrug of propofol which hydrolyzes in the body by alkaline phosphatase to liberate propofol. Propofol liberated from fospropofol has unique pharmacological properties, but recently retracted pharmacokinetic (PK) and pharmacodynamic (PD) evaluations make it difficult to formulate clear conclusions with respect to fospropofol's PK/PD properties. In safety and efficacy clinical studies, fospropofol demonstrated dose-dependent sedation with good rates of success at doses of 6.5 mg/kg along with good levels of patient and physician acceptance. Fospropofol has been associated with less pain at injection site than propofol. The most commonly reported side effects with fospropofol are paresthesia and pruritus. Fospropofol is a promising new sedation agent that appears to be well suited for MAC sedation, but further studies are needed to better understand its PK/PD properties as well its appropriate clinical role in outpatient procedures.


Effects of proprotein convertase subtilisin-kexin type 9 inhibitors on inflammatory and hemostatic parameters in post myocardial infarction patients.
Despite progress in treatment, elevated levels of low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) (Lp(a)), represent a significant part of the residual risk. Both are associated with inflammation and the coagulation fibrinolytic system. The purpose of our research was to evaluate the effect of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on lipid parameters and indicators of inflammation, coagulation and fibrinolysis. We included 100 post myocardial infarction (MI) patients with insufficiently controlled LDL-C values despite the maximum dose of statin, and highly elevated Lp(a). Patients received alirocumab or evolocumab (150 mg sc or 140 mg sc every two weeks, respectively), or placebo for 6 months. In patients receiving PCSK9i, a significant decrease in total cholesterol (TC), LDL-C, triglycerides (TG) and Lp(a), and an increase in high density lipoprotein cholesterol (p < 0.001 for all) was found. Before treatment, the concentrations of TC, LDL-C and TG correlated with the concentrations of thrombin activatable fibrinolysis inhibitor (r = 0.41, p < 0.001; r = 0.353, p < 0.001; r = 0.311, p = 0.003, respectively), and plasminogen activator inhibitor-1 (r = 0.302, p = 0.007; r = 0.218, p = 0.049; r = 0.278; p = 0.013, respectively). The concentrations of TC and LDL-C correlated with overall fibrinolytic potential (r = -0.220, p = 0.034; r = -0.207, p = 0.047, respectively). The concentration of TG was related to the concentration of interleukin 6 (r = 0.290, p = 0.004) and interleukin 8 (r = 0.332, p = 0.001). No correlations between Lp(a) and inflammatory or hemostatic variables were found. No associations were found after treatment. Our results show that inflammatory cytokines and fibrinolytic parameters are related to LDL-C and not Lp(a) in post-MI patients before and with neither of them following PCSK9i treatment. The trial registration number: NCT04613167, Date of registration: November 3, 2020.


Effects of a N-Maleimide-derivatized Phosphatidylethanolamine on the Architecture and Properties of Lipid Bilayers.
N-maleimide-derivatized phospholipids are often used to facilitate protein anchoring to membranes. In autophagy studies, this is applied to the covalent binding of Atg8, an autophagy protein, to a phosphatidylethanolamine (PE) in the nascent autophagosome. However, the question remains on how closely the N-maleimide PE derivative (PE-mal) mimicks the native PE in the bilayer. In the present paper, spectroscopic and calorimetric techniques have been applied to vesicles containing either PE or PE-mal (together with other phospholipids) to compare the properties of the native and derivatized forms of PE. According to differential scanning calorimetry, and to infrared spectroscopy, the presence of PE-mal did not perturb the fatty acyl chains in the bilayer. Fluorescence spectroscopy and microscopy showed that PE-mal did not alter the bilayer permeability either. However, fluorescence emission polarization of the Laurdan and DPH probes indicated an increased order, or decreased fluidity, in the bilayers containing PE-mal. In addition, the infrared spectral data from the phospholipid phosphate region revealed a PE-mal-induced conformational change in the polar heads, accompanied by increased hydration. Globally considered, the results suggest that PE-mal would be a reasonable substitute for PE in model membranes containing reconstituted proteins.


An Automated Method for Assessing Topographical Structure-Function Agreement in Abnormal Glaucomatous Regions.
To develop an automated/objective method for topographically comparing abnormal regions on optical coherence tomography (OCT) and visual field (VF) tests of eyes with early glaucoma. A custom R program was developed that allows for both visualization and automatic assessment of the topographical agreement between functional (24-2 and/or 10-2 VF) and structural (widefield OCT retinal nerve fiber layer and/or retinal ganglion cell layer) deviation/probability maps. It was optimized using information from 98 eyes: 53 diagnosed as "definitely glaucoma" (DG) and 45 recruited as healthy (H) controls. Different pairs of abnormal VF (P <1%, <2%, <5%) and abnormal OCT (P <5%, <10%, <15%) criteria were evaluated. The percentages of abnormal structure-abnormal function (aS-aF) agreement found in DG eyes and nonagreement found in H eyes were used to define the optimal criteria and number of aS-aF locations for the detection of aS-aF agreement. A criterion of two aS-aF locations with "OCT <10% and VF <5%" on VF pattern deviation (PD) probability and OCT deviation/probability maps yielded high overall agreement (92%) with high aS-aF agreement for the DG eyes (89%) and high aS-aF nonagreement for the H eyes (95%). Total deviation probability maps achieved slightly lower performance than PD maps. The method described here can automatically and objectively evaluate aS-aF agreement with a direct comparison of abnormal regions of function and structure. As glaucoma diagnosis often involves assessing structure-function agreement, this technique can overcome subjectivity in this assessment.


The influence of potato fibre on exocrine pancreatic secretions and on plasma levels of insulin, secretin and cholecystokinin in growing pigs.
The effect of a potato fibre preparation on exocrine pancreatic secretions and on gastrointestinal hormone levels in plasma was studied in three 8 weeks old piglets that were surgically fitted with a jugular vein catheter for blood sampling, a pancreatic duct catheter and a T-shaped duodenal cannula for collection of pancreatic juice. The animals were fed for 2 weeks a control diet (experimental period 1), thereafter for 2 weeks the control diet supplemented with 2% potato fibre (experimental period 2) and for another 2 weeks the control diet again (experimental period 3). Additionally, intraduodenal (i.d.) infusions of the experimental diet, the control diet and potato fibre as well as i.v. infusions of a solution containing cholecystokinin (CCK) and secretin were administered. Potato fibre in the diet evoked in tendency an increase in the volume of secretion of pancreatic juice and a significant increase both in the mean values of the total protein content and total activities of lipase, trypsin and alpha-amylase when compared to the control diet. The i.d. infusion of the control diet, experimental diet and fibre infusate as well as the i.v. administration of the hormone infusate led to a spontaneous secretory response of the exocrine pancreas. Besides gastrointestinal hormones, such as CCK, other factors such as short chain fatty acids may be involved in the regulation of the exocrine pancreas.


Auditory responses and stimulus-specific adaptation in rat auditory cortex are preserved across NREM and REM sleep.
Sleep entails a disconnection from the external environment. By and large, sensory stimuli do not trigger behavioral responses and are not consciously perceived as they usually are in wakefulness. Traditionally, sleep disconnection was ascribed to a thalamic "gate," which would prevent signal propagation along ascending sensory pathways to primary cortical areas. Here, we compared single-unit and LFP responses in core auditory cortex as freely moving rats spontaneously switched between wakefulness and sleep states. Despite robust differences in baseline neuronal activity, both the selectivity and the magnitude of auditory-evoked responses were comparable across wakefulness, Nonrapid eye movement (NREM) and rapid eye movement (REM) sleep (pairwise differences <8% between states). The processing of deviant tones was also compared in sleep and wakefulness using an oddball paradigm. Robust stimulus-specific adaptation (SSA) was observed following the onset of repetitive tones, and the strength of SSA effects (13-20%) was comparable across vigilance states. Thus, responses in core auditory cortex are preserved across sleep states, suggesting that evoked activity in primary sensory cortices is driven by external physical stimuli with little modulation by vigilance state. We suggest that sensory disconnection during sleep occurs at a stage later than primary sensory areas.


Cathepsin G, acid phosphatase, and alpha 1-proteinase inhibitor messenger RNA levels in keratoconus corneas.
Keratoconus is characterized by thinning and scarring of the central region of the cornea. The authors have shown, in corneas obtained from patients with keratoconus, that lysosomal enzyme activities are elevated, whereas levels of protease inhibitors such as alpha 1-proteinase inhibitor (alpha 1-PI) are reduced. This study was undertaken to examine further the gene expression of cathepsin G, acid phosphatase, and alpha 1-PI in keratoconus corneas. Corneal buttons were collected from patients with keratoconus, normal subjects, and patients with other corneal diseases. In situ hybridization was performed on paraffin sections using a tritium-labeled probe for cathepsin G or alpha 1-PI. Competitive polymerase chain reaction (PCR) was used to determine the messenger RNA (mRNA) levels for lysosomal acid phosphatase and alpha 1-PI in epithelial and stromal cells of keratoconus corneas. Silver grains, indicative of positive in situ hybridization products, were observed in all three cell types of normal corneas for both DNA probes. Compared with normal and other diseased controls, the labeling was enhanced for cathepsin G but was diminished for alpha 1-PI in the epithelium of keratoconus corneas. Competitive PCR showed that the mRNA level for acid phosphatase was higher and that the mRNA level for alpha 1-PI was lower in keratoconus corneas. These results indicate that the mRNA level for degradative enzymes in increased and that for alpha 1-PI it is reduced in keratoconus corneas. This study provides the first evidence that the altered expression of multiple enzymes and inhibitors in keratoconus occurs at the gene level. Furthermore, it implicates a possible role of coordinated transcriptional regulation of gene expressions in keratoconus.


Implications of comorbid OCD on PTSD treatment: A case study.
Given the high degree of diagnostic overlap and limited empirical literature surrounding the comorbidity between posttraumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD), appropriately conceptualizing the relationship between the comorbid symptoms and their impact on the treatment process can be challenging. This is especially true when the symptoms of the two disorders become functionally connected, with each symptom set maintaining the other. This article details the case of a veteran with comorbid PTSD and OCD who sought intensive trauma-focused treatment within the U.S. Veterans Health Administration. The dynamic relationship between his PTSD and OCD symptoms is described, along with its impact on trauma-focused treatment and the ability to maintain treatment gains. A novel attempt to integrate empirically based treatment strategies for OCD into intensive PTSD treatment, targeting both sets of symptoms simultaneously, is presented, along with implications for conceptualization and treatment of this comorbidity.


Reduction of tracheal mite parasitism of honey bees by swarming.
Based on population dynamics, tracheal mite (Acarapis woodi) parasitism of colonies of honey bees (Apis mellifera) appears to be, potentially at least, regulatory and stable. Empirical and theoretical considerations suggest, however, that intracolony population dynamics of mite-honey bee worker seem to be unstable in managed situations where honey bee worker population is allowed to grow unchecked. Experimental studies showed that tracheal mite population levels increased in a managed honey bee colony but were impaired in one in which brood rearing was interrupted by loss of the queen. Mite densities but not prevalence were lowered in experimental swarms kept from rearing brood. We propose that swarming reduces mite density within a colony, therefore implicating modern techniques of hive management in the sudden historical appearance of the mite on the Isle of Wight.


Serine Integrase attP Binding and Specificity.
Serine integrases catalyze the site-specific insertion of viral DNA into a host's genome. The minimal requirements and irreversible nature of this integration reaction have led to the use of serine integrases in applications ranging from bacterial memory storage devices to gene therapy. Our understanding of how the integrase proteins recognize the viral (attP) and host (attB) attachment sites is limited, with structural data available for only a Listeria integrase C-terminal domain (CTD) bound to an attP half-site. Here we report quantitative binding and saturation mutagenesis analyses for the Listeria innocua prophage attP site and a new 2.8-Å crystal structure of the CTD•attP half site. We find that Int binds with high affinity to attP (6.9 nM), but the Int CTD binds to attP half-sites with only 7- to 10-fold lower affinity, supporting the idea that free energy is expended to open an Int dimer for attP binding. Despite the 50-bp Int-attP interaction surface, only 20 residues are sensitive to mutagenesis, and of these, only 6 require a specific residue for efficient Int binding and integration activity. One of the integrase DNA-binding domains, the recombinase domain, appears to be primarily non-specific. Several substitutions result in an improved attP site, indicating that higher-efficiency attachment sites can be obtained through site engineering. These findings advance our understanding of serine integrase function and provide important data for efforts towards engineering this family of enzymes for a variety of biotechnology applications.


Different metabolic predictors of white-coat and sustained hypertension over a 20-year follow-up period: a population-based study of elderly men.
The clinical significance of white-coat hypertension is still unclear. Moreover, no study has examined metabolic predictors of white-coat versus sustained hypertension. We investigated men (n=602) in a longitudinal population-based cohort who at age 70 years were identified as normotensive, white-coat hypertensive (office blood pressure [BP] > or =140/90 and daytime ambulatory BP <135/85 mm Hg), and sustained hypertensive (office BP > or =140/90 and daytime ambulatory BP > or =135/85 mm Hg). At baseline, when the subjects were aged 50 years, blood glucose, insulin, lipids, and fatty acid composition of the serum cholesterol esters were analyzed. The investigations at age 70 years included determination of insulin sensitivity and target organ damage. At age 50 years, individuals who 20 years later were identified as white-coat hypertensive or sustained hypertensive showed significantly elevated BP, heart rate, and impaired glucose tolerance compared with normotensive subjects but white coat hypertensive subjects were leaner and had a more favorable serum cholesterol ester fatty acid profile than did sustained hypertensive subjects. At age 70 years, both white-coat and sustained hypertensive subjects showed an impaired insulin sensitivity, elevated blood glucose, and increased serum insulin and heart rate compared with normotensive subjects, but left ventricular mass and urinary albumin excretion were increased only in sustained hypertensive subjects. These findings indicate that although metabolic abnormalities and elevated heart rate were consistent over time in both hypertensive groups, a lower body mass index and more favorable dietary fat composition predicted the development of white-coat as opposed to sustained hypertension over 20 years.


Discovery and Optimization of Chromone Derivatives as Novel Selective Phosphodiesterase 10 Inhibitors.
Phosphodiesterase 10 (PDE10) inhibitors have received much attention as promising therapeutic agents for central nervous system (CNS) disorders such as schizophrenia and Huntington's disease. Recently, a hit compound 1 with a novel chromone scaffold has shown moderate inhibitory activity against PDE10A (IC50 = 500 nM). Hit-to-lead optimization has resulted in compound 3e with an improved inhibitory activity (IC50 = 6.5 nM), remarkable selectivity (>95-fold over other PDEs), and good metabolic stability (RLM t1/2 = 105 min) by using an integrated strategy (molecular modeling, chemical synthesis, bioassay, and cocrystal structure). The cocrystal structural information provides insights into the binding pattern of 3e in the PDE10A catalytic domain to highlight the key role of the halogen and hydrogen bonds toward Tyr524 and Tyr693, respectively, thereby resulting in high selectivity against other PDEs. These new observations are of benefit for the rational design of the next generation PDE10 inhibitors for CNS disorders.


Azithromycin Prescribing by Respiratory Pediatricians in Australia and New Zealand for Chronic Wet Cough: A Questionnaire-Based Survey.
Aims: To determine how respiratory pediatricians across Australia and New Zealand prescribe azithromycin for children with chronic wet cough, including recurrent protracted bacterial bronchitis, chronic suppurative lung disease (CSLD) and bronchiectasis. Methods: A prospective web-based questionnaire was emailed to members of the Pediatric Special Interest Group of the Thoracic Society of Australia and New Zealand (TSANZ) between April and May 2018. It comprised eight demographic and 15 clinically focused questions. Results: Of the 73 respiratory pediatricians listed across Australia and New Zealand, 29 (40%) responded and all prescribed azithromycin for chronic wet cough. Twelve (41%) indicated that they would consider prescribing a short-course (2-4 weeks) of azithromycin for children with a chronic wet cough. Although most respondents reported prescribing long-term (>4-weeks) azithromycin for either CSLD (n = 23, 79%) or bronchiectasis (n = 24, 83%), only nine (31%) respondents would commence treatment if in the previous 12-months these children experienced three non-hospitalized exacerbations and just 12 (41%) would do so if there had been two hospitalisations for severe exacerbations during the same period in accordance with the TSANZ national guidelines. A lower threshold for prescribing azithromycin was described for Indigenous children or if co-morbidities were present. None prescribed azithromycin for >24-months. Macrolide-resistance was reported in Streptococcus pneumoniae and Staphylococcus aureus. Conclusion: Although Australian and New Zealand respiratory pediatricians in this survey prescribed azithromycin for chronic wet cough most often in children with either CSLD or bronchiectasis, many did so outside the current national guidelines. Reasons for this need exploring.


Generation of functional antigen-specific T cells in defined genetic backgrounds by retrovirus-mediated expression of TCR cDNAs in hematopoietic precursor cells.
We have developed an alternative to transgenesis for producing antigen-specific T cells in vivo. In this system, clonal naive T cells with defined antigen specificity are generated by retrovirus-mediated expression of T cell antigen receptor cDNAs in RAG1-deficient murine hematopoietic precursor cells. These T cells can be stimulated to proliferate and produce cytokines by exposure to antigen in vitro, and they become activated and expand in vivo after immunization. IL-2-deficient T cells generated by this technique show decreased proliferation and cytokine production, both of which can be rescued by exogenous addition of this growth factor. Thus, retrovirus-mediated expression of T cell antigen receptor cDNAs in hematopoietic precursor cells permits the rapid and efficient analysis of the life history of antigen-specific T cells in different genetic backgrounds and may allow for the long-term production of antigen-specific T cells with different functional properties for prophylactic and therapeutic purposes.


Genetics of diabetes complications.
Chronic hyperglycemia and duration of diabetes are the major risk factors associated with development of micro- and macrovascular complications of diabetes. Although it is believed that hyperglycemia induces damage to the particular cell subtypes, e.g., mesangial cells in the renal glomerulus, capillary endothelial cells in the retina, and neurons and Schwann cells in peripheral nerves, the exact mechanisms underlying these damaging defects are not yet well understood. Clustering of micro- and macrovascular complications in families of patients with diabetes suggests a strong genetic susceptibility. However, until now only a handful number of genetic variants were reported to be associated with either nephropathy (ACE, ELMO1, FRMD3, and AKR1B1) or retinopathy (VEGF, AKR1B1, and EPO), and only a few studies were carried out for genetic susceptibility to cardiovascular diseases (ADIPOQ, GLUL) in patients with diabetes. It is, therefore, obvious that the accumulation of more data from larger studies and better phenotypically characterized cohorts is needed to facilitate genetic discoveries and unravel novel insights into the pathogenesis of diabetic complications.


Phase behaviour of the ternary system: monoolein-water-branched polyethylenimine.
Addition of a branched polymer, polyethyleneimine, significantly alters the organization of a glycerol monooleate (GMO) lipid-water system. We present detailed data over a wide range of compositions (water content from 10 to 40%, relative to GMO and PEI fractions from 0 to 4%) and temperatures (25-80 °C). The PEI molecular weight effects are examined using polymers over a range from 0.8 to 25 kDa. Addition of PEI induces the formation of higher curvature reverse phases. In particular, PEI induces the formation of the Fd3m phase: a discontinuous phase comprising reverse micelles of two different sizes stacked in a cubic AB2 crystal. The formation of the Fd3m phase at room temperature, upon addition of polar, water soluble PEI is unusual, since such phases typically are formed only upon addition of apolar oils. The largest stability window for the Fd3m phase is observed for PEI with a molecular weight = 2 kDa. We discuss how PEI influences the formation and stability of high curvature phases.


Color Doppler US of the scrotum.
Color Doppler ultrasonography (US) is an increasingly important tool in the evaluation of the scrotum, especially in acute scrotal disorders. With this modality, arterial flow is readily detected in the normal spermatic cord and testis but is not seen in the epididymis; venous flow is not seen anywhere in the normal scrotum. Scrotal inflammatory lesions appear as hypervascularity of the epididymis or testis, even though gray-scale findings may be normal or nonspecific. Testicular torsion is demonstrated by an absence or marked decrease in the number of visible vessels. Small tumors (less than 1.5 cm) are hypovascular, and larger tumors (greater than 1.5 cm) are hypervascular. The modality also demonstrates Valsalva maneuver-induced venous flow augmentation in varicoceles and altered flow in testicular tumors. Color Doppler US allows for evaluation of morphologic findings and perfusion and enables accurate diagnosis of most scrotal disorders.


Risk of thyroid cancer associated with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: A population-based cohort study.
To determine the potential association between the use of either glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 (DPP-4) inhibitors, and the risk of thyroid cancer in individuals with type 2 diabetes. This population-based cohort study used claims data from the Korean National Health Insurance Database, 2014-2020. Two distinct cohorts were established to compare each incretin-based drug with sodium-glucose cotransporter-2 (SGLT2) inhibitors, chosen as active comparators because of their previous non-association with thyroid cancer, and their common usage as add-on therapy to metformin along with GLP-1RAs and DPP-4 inhibitors. The first cohort included 21 722 new users of GLP-1RAs and 326 993 new users of SGLT2 inhibitors, whereas the second cohort included 904 300 DPP-4 inhibitor new users and 112 017 SGLT2 inhibitor new users. The outcome was the time to incident thyroid cancer. Weighted Cox proportional models were used to estimate hazard ratios of thyroid cancer incidence associated with incretin-based drugs of interest. The use of GLP-1RAs was not associated with an increased risk of thyroid cancer (weighted hazard ratio 0.98, 95% confidence interval 0.62-1.53) compared with that of SGLT2 inhibitors. Using DPP-4 inhibitors was also not associated with an increased risk of thyroid cancer (0.95, 0.79-1.14) compared with that of SGLT2 inhibitors. No significant effect modifications were observed across subgroup analyses. Sensitivity analyses, including alternative outcome definition analysis of medullary thyroid cancer, were consistent with the primary analysis results. GLP-1RAs and DPP-4 inhibitors were not associated with an increased risk of thyroid cancer in individuals with type 2 diabetes.


Evaluation of inflammation markers in mitral valve prolapse.
Mitral valve prolapse (MVP) is the most common cause of mitral regurgitation in developed countries. The role of inflammation in the pathogenesis of MVP is still not clear. In this study, we aimed to investigate how inflammatory markers such as monocyte/high-density lipoprotein ratio (MHR), lymphocyte/monocyte ratio (LMR), neutrophil/lymphocyte ratio (NLR), and platelet/neutrophil ratio (PLR) are affected in MVP patients. In this retrospective study, we included 461 patients with MVP and 459 normal echocardiographic patients, matched with gender and age. Inflammatory markers and all variables were compared between the two groups. There were no statistically significant differences in age, sex, or body mass index between the two groups. Neutrophil counts (4,960 [3,900-6,780]. 4,200 [3,800-5,600], p < 0.001), NLR (2.488 [1.72-4.51], 1.857 [1.49-2.38], p < 0.001), MHR (14.9 [11.9-18.6], 12.2 [9.4-17.3], p = 0.003), PLR (122.4 [85-171], 104.4 [85-130], p < 0.001), and CRP (0.71 ± 0.50, 0.67 ± 0.33 p < 0.001) were significantly higher, and LMR (3.75 [2.75-5.09], 4.06 [3.12-4.83] p = 0.016) was significantly lower in the MVP group than the control group, respectively. In logistic regression analysis, NLR (odds ratio [OR]: 1.058 [1.047-1.072]; p < 0.001), LMR (OR: 1.560 [1.211-2.522]; p = 0.027), and PLR (OR: 1.015 [1.012-1.019]; p = 0.003) were found to be independent predictors for MVP presence. These parameters can be used as a simple, low-cost, practical tool to detect inflammation in MVP.


Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.
Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine--choline, trimethylamine N-oxide (TMAO) and betaine--were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.


The pathogenesis, diagnosis, and management of metastatic tumors to the ovary: a comprehensive review.
Secondary tumors of the ovary account for 10-25% of all ovarian malignancies. The most common tumors that give rise to ovarian metastases include breast, colorectal, endometrial, stomach, and appendix cancer. The correct diagnosis of secondary ovarian tumors may be challenging as they are not infrequently misdiagnosed as primary ovarian cancer, particularly in the case of mucinous adenocarcinomas. The distinction from the latter is essential, as it requires different treatment. Immunohistochemistry plays an important role in distinguishing primary ovarian tumors from extra-ovarian metastases and, furthermore, may suggest the primary tumor site. Despite extensive study, some cases remain equivocal even after assessing a broad spectrum of antigens. Therefore, gene expression profiling represents an approach able to further discriminate equivocal findings, and one that has been proven effective in determining the origin of cancer of unknown primary site. The available data concerning secondary ovarian tumors is rather limited owing to the relative heterogeneity of this group and the practical absence of any prospective trials. However, several intriguing questions are encountered in daily practice, including rational diagnostic workup, the role of cytoreductive surgery, and consequent adjuvant chemotherapy. This review seeks to address these issues comprehensively and summarize current knowledge on the epidemiology, pathogenesis, and management of secondary ovarian tumors, including further discussion on the different pathways of metastatisation, metastatic organotropism, and their possible molecular mechanisms.


Motivating Weight Loss Among Black Adults in Relationships: Recommendations for Weight Loss Interventions.
Black men and women have the highest rates of obesity in the United States. Behavioral weight loss programs incorporating intimate partners may be effective in combating obesity among this population. Yet, current participation in these programs is low. Identifying motivations and triggers to weight loss may provide insight in designing programs to increase participation. To determine triggers and motivations for weight loss among Black men and women in committed relationships to inform development of weight loss interventions. Twenty semi-structured interviews, based on an integrated theoretical framework of interdependence and communal coping and the social cognitive theory, were conducted among Black heterosexual couples where one or both individuals intentionally lost ≥5% of their body weight in the last 6 months in a metropolitan region in a southern state. Interviews were transcribed and coded. Themes were identified following multi-rater coding and direct and conventional content analysis. Recommendations were developed from emergent themes. Among individuals with recent weight loss, personal relevancy and awareness (health awareness and self-awareness) were identified as personal triggers for weight loss initiation. Health concerns and appearance were general motivations among the total sample. Emphasizing the impact of weight on daily functioning and quality of life, and increasing awareness of personal weight status and health consequences, may increase weight loss initiation and participation in weight loss programs among Black men and women in committed relationships. Findings also highlight strategies to improve recruitment and retention and guide intervention development and implementation for this population.


Hormone-mediated down-regulation of hepatic glutathione synthesis in the rat.
Our present work characterized the role of hormone-mediated signal transduction pathways in regulating hepatic reduced glutathione (GSH) synthesis. Cholera toxin, dibutyryl cAMP (DBcAMP), and glucagon inhibited GSH synthesis in cultured hepatocytes by 25-43%. Cellular cAMP levels exhibited a lower threshold for stimulation of the GSH efflux than inhibition of its synthesis. The effect of DBcAMP was independent of the type of sulfur amino acid precursor and cellular ATP levels and unassociated with increased GSH mixed disulfide formation or altered GSH/oxidized glutathione ratio. In liver cytosols, addition of DBcAMP and cAMP-dependent protein kinase (A-kinase) inhibited GSH synthesis from substrates (cysteine, ATP, glutamate, and glycine) by approximately 20% which was prevented by the A-kinase inhibitor. However, if only substrates of the second step in GSH synthesis were used (gamma-glutamylcysteine, glycine, and ATP), DBcAMP and A-kinase exerted no inhibitory effect. Phenylephrine, vasopressin, and phorbol ester also inhibited GSH synthesis in cultured cells by approximately 20%, and depleted cell GSH independent of the type of sulfur amino acid precursor. Cellular cysteine level was unchanged despite the significant fall in GSH after glucagon or phenylephrine treatment. Pretreatment with either staurosporine, C-kinase inhibitor, or calmidazolium, a calmodulin inhibitor, partially prevented but, together, completely prevented the inhibitory effect of phenylephrine. The same combination had no effect on the inhibitory effect of glucagon. The effects of hormones were confirmed in both the intact perfused liver and after in vivo administration. Thus, two classes of hormones acting through distinct signal transduction pathways may down-regulate hepatic GSH synthesis by phosphorylation of gamma-glutamylcysteine synthetase.


Low numbers of large microplastics on environmentally-protected Antarctic beaches reveals no widespread contamination: insights into beach sedimentary dynamics.
Microplastics are ubiquitous contaminants of marine ecosystems around the world and Antarctica is no exception. Microplastics can be influenced by sedimentary dynamics mainly on coastal areas where they are more abundant in Antarctica. This study evaluated microplastic contamination in beach environments from two Antarctic Specially Protected Areas, aiming to identify relationships between microplastic numbers and sedimentological parameters on beach sediments. Low numbers of microplastics were found (> 0.5 mm; fibers excluded) - one particle per sample in 4 of 15 samples analyzed - and there is no evidence of widespread contamination. Sedimentological parameters reveal differences between sampled environments, but low numbers of microplastics impaired statistical comparison. All sediment samples are coarse, denoting highenergy depositional environments that are likely little susceptible to microplastic accumulation. Microplastic contamination in the Antarctic coastal ecosystem is heterogeneous, and their detailed characterization assisted by a systematization of methods can improve the understanding of microplastics distribution patterns in the cold coastal ecosystem.


Improvement of restrictive and obstructive pulmonary mechanics following laparoscopic bariatric surgery.
Morbidly obese patients often have impaired respiratory mechanics leading to restrictive and obstructive lung diseases. Weight loss after bariatric surgery has been shown to improve or resolve many obesity-related comorbidities. However, few studies have examined long-term changes in pulmonary mechanics after bariatric surgery. We hypothesize that pulmonary function improves after surgically induced weight loss. We examined the pulmonary function of 104 morbidly obese patients who underwent laparoscopic gastric bypass or gastric banding. Pulmonary studies, including forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC), peak expiratory flow (PEF), and forced expiratory volume at midexpiratory phase (FEV(25-75%)) were measured preoperatively and at 3-month intervals. All results are expressed as a percentage of the baseline values. There were 80 females and 24 males with a mean age of 41 years. The mean body mass index was 48 kg/m(2). The mean percentage of excess body weight loss at 12 months was 54%. At 12 months postoperatively, restrictive pulmonary mechanics significantly improved as demonstrated by an increase in the FEV(1) to 112% of baseline value, increase in the FVC to 109% of baseline value, increase in the PEF to 115% of baseline value, and increase in the FEV(25-75%) to 130% of baseline value. Additionally, the percentage of patients with obstructive lung pattern (FEV(1)/FVC ratio less than 0.8) decreased from 9.6% preoperatively to 1.9% postoperatively (p=0.03). Weight loss after laparoscopic gastric bypass significantly improves restrictive and obstructive respiratory mechanics. The improvements were observed as early as 3 months postoperatively.


Translational applications of glucose metabolism in abdominal aortic aneurysm.
Even though diabetes mellitus is a major risk for cardiovascular events and atherosclerosis-related diseases, it is negatively associated with abdominal aortic aneurysm. The understanding of the mechanisms underlying this negative association could bring new insights to identify prognostic and therapeutic targets. Here we summarize current knowledge of the relationship between glycemic parameters and clinical outcomes of patients with abdominal aortic aneurysm. Translational applications of glucose-targeted approaches as well as their potential interest for clinical practice are discussed in this context.


Bone marrow cell migration to the heart in a chimeric mouse model of acute chagasic disease.
Chagas disease is a public health problem caused by infection with the protozoan Trypanosoma cruzi. There is currently no effective therapy for Chagas disease. Although there is some evidence for the beneficial effect of bone marrow-derived cells in chagasic disease, the mechanisms underlying their effects in the heart are unknown. Reports have suggested that bone marrow cells are recruited to the chagasic heart; however, studies using chimeric mouse models of chagasic cardiomyopathy are rare. The aim of this study was to investigate the migration of bone marrow cells to the heart after T. cruzi infection in a model of chagasic disease in chimeric mice. To obtain chimerical mice, wild-type (WT) C57BL6 mice were exposed to full body irradiation (7 Gy), causing bone marrow ablation. Then, bone marrow cells from green fluorescent protein (GFP)-transgenic mice were infused into the mice. Graft effectiveness was confirmed by flow cytometry. Experimental mice were divided into four groups: (i) infected chimeric (iChim) mice; (ii) infected WT (iWT) mice, both of which received 3 × 104 trypomastigotes of the Brazil strain; (iii) non-infected chimeric (Chim) mice; and (iv) non-infected WT mice. At one-month post-infection, iChim and iWT mice showed first degree atrioventricular block with decreased heart rate and treadmill exercise parameters compared to those in the non-infected groups. iChim mice showed an increase in parasitaemia, myocarditis, and the presence of amastigote nests in the heart tissue compared to iWT mice. Flow cytometry analysis did not detect haematopoietic progenitor cells in the hearts of infected mice. Furthermore, GFP+ cardiomyocytes were not detected in the tissues of chimeric mice.