How much of the difference in life expectancy between Scottish cities does deprivation explain?
Glasgow's low life expectancy and high levels of deprivation are well documented. Studies comparing Glasgow to similarly deprived cities in England suggest an excess of deaths in Glasgow that cannot be accounted for by deprivation. Within Scotland comparisons are more equivocal suggesting deprivation could explain Glasgow's excess mortality. Few studies have used life expectancy, an intuitive measure that quantifies the between-city difference in years. This study aimed to use the most up-to-date data to compare Glasgow to other Scottish cities and to (i) evaluate whether deprivation could account for lower life expectancy in Glasgow and (ii) explore whether the age distribution of mortality in Glasgow could explain its lower life expectancy. Sex specific life expectancy was calculated for 2007-2011 for the population in Glasgow and the combined population of Aberdeen, Dundee and Edinburgh. Life expectancy was calculated for deciles of income deprivation, based on the national ranking of datazones, using the Scottish Index of Multiple Deprivation. Life expectancy in Glasgow overall, and by deprivation decile, was compared to that in Aberdeen, Dundee and Edinburgh combined, and the life expectancy difference decomposed by age using Arriaga's discrete method. Life expectancy for the whole Glasgow population was lower than the population of Aberdeen, Dundee and Edinburgh combined. When life expectancy was compared by national income deprivation decile, Glasgow's life expectancy was not systematically lower, and deprivation accounted for over 90 % of the difference. This was reduced to 70 % of the difference when carrying out sensitivity analysis using city-specific income deprivation deciles. In both analyses life expectancy was not systematically lower in Glasgow when stratified by deprivation. Decomposing the differences in life expectancy also showed that the age distribution of mortality was not systematically different in Glasgow after accounting for deprivation. Life expectancy is not systematically lower across the Glasgow population compared to Aberdeen, Dundee and Edinburgh combined, once deprivation is accounted for. This provides further evidence that tackling deprivation in Glasgow would probably reduce the health inequalities that exist between Scottish cities. The change in the amount of unexplained difference when carrying out sensitivity analysis demonstrates the difficulties in comparing socioeconomic deprivation between populations, even within the same country and when applying an established ecological measure. Although the majority of health inequality between Glasgow and other Scottish cities is explained by deprivation, the difference in the amount of unexplained inequality depending on the relative context of deprivation used demonstrates the challenges associated with attributing mortality inequalities to an independent 'place effect'.


Idiopathic intracranial hypertension and bariatric surgery: a literature review and a presentation of two cases.
There is paucity of data concerning the impact of bariatric surgery on idiopathic intracranial hypertension (IIH). We therefore present the clinical course of two cases that were managed at our centre, which is a regional referral centre for bariatric surgery and present a literature review of patients with IIH who underwent bariatric surgery for the treatment of obesity. Two patients were referred for bariatric surgery who were both morbidly obese and were diagnosed with IIH. One patient underwent bariatric surgery; the other patient's weight was managed conservatively. We followed up both patients for 2 years. PubMed was searched for published studies of patients with IIH undergoing bariatric surgery. The patient that underwent weight loss surgery achieved sustained weight loss from 108kg to 87kg and gross resolution of their symptoms. The patient whose weight was managed conservatively lost weight initially and then put the weight back on. Her IIH symptoms persisted despite CSF shunt therapy. The literature review identified 12 original studies, containing 51 patients. Weight loss after bariatric surgery was reported for 84% of patients and improvement or resolution of IIH symptoms was reported for 84% of patients. In light of the literature review and our experience, bariatric surgery appears to be a potential treatment option for IIH alongside the comorbidities associated with obesity. However, more robust studies are needed.


A fundamental question for complementary medicine: Are there other forces in the natural world besides the physical forces?
Background The integration of conventional and complementary medicine reflects the pluralism in science. Still, a critical issue is the conception of the natural world. Many complementary therapy sys-tems seem to contradict the reductionist-atomistic paradigm that all of natural reality is essential-ly based on the physical interactions of atoms and molecules. Thus, a fundamental question about the natural world is: Do other than the physical forces exist? Methods Elaboration of: the limitations of the reductionist-atomistic paradigm, the existence of specifi-cally Gestalt-forming and Gestalt-maintaining forces in organisms, and implications for the con-cept of matter. Results and Conclusion The assumption that no other than physical forces exist and work in the natural world is not tenable. For example, the formation and maintenance of the functional Gestalt of organisms can-not possibly be explained by molecular processes (e.g. from DNA to RNA and further to amino acids and proteins). The processes on each structural level - from molecules, organelles, cells, organs up to the whole organism - are regulated in regard to the formation of the next higher-level. Specific Gestalt-forming forces exist and can be systematically investigated. Their exist-ence implies an extended conception of matter. The Gestalt-forming forces and the extended concept of matter may be relevant for the scientific assessment of complementary therapy sys-tems.


Molecular characterization of GCD1, a yeast gene required for general control of amino acid biosynthesis and cell-cycle initiation.
The GCD1 gene product of Saccharomyces cerevisiae has been implicated in the coordination of the cell cycle with the general control of amino acid biosynthesis (M. Wolfner et al., J. Mol. Biol. 96:273-290, 1975). Strains containing the gcd1-1 allele constitutively express the amino acid biosynthetic genes at the induced levels normally found only during conditions of amino acid starvation. In addition, gcd1-1 strains do not grow at high temperatures because under these conditions they are unable to proceed beyond the START step of the cell division cycle. We have cloned and sequenced the GCD1 gene and examined various aspects of cellular metabolism in order to elucidate its role(s) in regulating gene expression and the cell cycle. GCD1 encodes a 1.7 kb RNA whose expression is not regulated as a function of amino acid starvation. Overexpression of this RNA does not affect the regulation of amino acid biosynthetic genes or cell growth. GCD1 is an essential gene because cells containing a gcd1-HIS3 disruption are unable to grow. The essential function of GCD1 may be involved in protein synthesis because a gcd1-1 strain incorporates low levels of 35S-methionine into protein when cells are shifted to the restrictive temperature. GCD1 encodes a protein of 511 amino acids whose predicted sequence does not exhibit significant homology to any other known proteins and appears too large to be a ribosomal protein. We suggest that GCD1 encodes a component of the normal protein synthesis machinery that is involved in the translational regulation of GCN4, a protein that coordinately activates the transcription of amino acid biosynthetic genes. GCD1 may also be part of a sensing mechanism in which cells monitor the protein synthesis capacity prior to initiating a new cell division cycle.


A Microplate-Based System as In Vitro Model of Biofilm Growth and Quantification.
We describe a 96-well microtiter plate-based system as an in vitro model for biofilm formation and quantification. Although in vitro assays are artificial systems and thus significantly differ from in vivo conditions, they represent an important tool to evaluate biofilm formation and the effect of compounds on biofilms. Stainings to evaluate the amount of biomass (crystal violet staining) and the number of metabolically active cells (resazurin assay) are discussed and specific attention is paid to the use of this model to quantify persisters in sessile populations.


Intrinsic Multi-Scale Dynamic Behaviors of Complex Financial Systems.
The empirical mode decomposition is applied to analyze the intrinsic multi-scale dynamic behaviors of complex financial systems. In this approach, the time series of the price returns of each stock is decomposed into a small number of intrinsic mode functions, which represent the price motion from high frequency to low frequency. These intrinsic mode functions are then grouped into three modes, i.e., the fast mode, medium mode and slow mode. The probability distribution of returns and auto-correlation of volatilities for the fast and medium modes exhibit similar behaviors as those of the full time series, i.e., these characteristics are rather robust in multi time scale. However, the cross-correlation between individual stocks and the return-volatility correlation are time scale dependent. The structure of business sectors is mainly governed by the fast mode when returns are sampled at a couple of days, while by the medium mode when returns are sampled at dozens of days. More importantly, the leverage and anti-leverage effects are dominated by the medium mode.


Graphene-Based Nanomaterials for Dental Applications: Principles, Current Advances, and Future Outlook.
With the development of nanotechnology, nanomaterials have been used in dental fields over the past years. Among them, graphene and its derivatives have attracted great attentions, owing to their excellent physicochemical property, morphology, biocompatibility, multi-differentiation activity, and antimicrobial activity. In our review, we summarized the recent progress about their applications on the dentistry. The synthesis methods, structures, and properties of graphene-based materials are discussed. Then, the dental applications of graphene-based materials are emphatically collected and described. Finally, the challenges and outlooks of graphene-based nanomaterials on the dental applications are discussed in this paper, aiming at inspiring more excellent studies.


Immune responses of the Asian onion moth, Acrolepiopsis sapporensis, and their genetic factors from RNA-Seq analysis.
A nonmodel insect, Acrolepiopsis sapporensis, has been analyzed in immune responses. The total hemocytes in the fifth instar larvae were 2.33 × 106 cells/mL. These hemocytes comprised at least five different types and different relative ratios: 47% granulocytes, 26% plasmatocytes, 11% oenocytoid, 8% prohemocytes, and 5% spherulocytes. Upon bacterial challenge, some of the hemocytes exhibited typical hemocyte-spreading behaviors, such as focal adhesion, and filopodial and lamellipodial cytoplasmic extensions. The hemocyte behaviors induced cellular immune responses demonstrated by nodule formation. In addition, the plasma collected from the immune-challenged larvae exhibited humoral immune responses by bacterial growth inhibition along with enhanced phenoloxidase enzyme activity. These cellular and humoral immune responses were further analyzed by determining the immune-associated genes from a transcriptome generated by RNA-Seq. A total of about 12 Gb sequences led to about 218,116 contigs, which were predicted to encode about 46,808 genes. Comparative expression analysis showed 8392 uniquely expressed genes in the immune-challenged larvae. Differentially expressed gene (DEG) analysis among the commonly expressed genes indicated that 782 genes were upregulated and 548 genes were downregulated in the expressions after bacterial challenge. These immune-associated genes included pattern recognition receptors, immune mediation/signaling genes, and various immune effectors. Specifically, the genetic components of the Toll, IMD, and JAK/STAT immune signaling pathways were included in the DEG database. These results demonstrate the immune responses of A. sapporensis larvae and suggest the genes associated with the immune responses in this nonmodel insect.


Adherence of oral streptococci to composite resin of varying surface roughness.
The adherence of oral bacteria to composite resins plays an important role in the development of secondary caries. The present study deals with the adherence to composite resin having various surface roughness of S.oralis, which is frequently isolated from composite resin squares attached to maxillary first molars. available commercial resin was used in this experiment. In vitro bacterial adhesion test was carried out under a sucrose independent conditions. The surface roughness values of each specimen ranged between 0.2 micron and 3.0 microns. No relationship was observed between the surface roughness values and bacterial adhesion because S. oralis adhered firmly to the filler particles of all composite resin surfaces.


Direct Oral Anticoagulants or Standard Anticoagulant Therapy in Fragile Patients with Venous Thromboembolism.
Background The efficacy and safety of the direct oral anticoagulants (DOACs) in fragile patients (age ≥ 75 years and/or creatinine clearance levels ≤ 50 mL/min and/or body weight ≤ 50kg) with venous thromboembolism (VTE) has not been evaluated. Methods We used the RIETE database to compare the rates of the composite of VTE recurrences or major bleeding during anticoagulation in fragile patients with VTE, according to the use of DOACs or standard anticoagulant therapy. Results From January 2013 to April 2018, 24,701 patients were recruited. Of these, 10,054 (41%) were fragile. Initially, 473 fragile patients (4.7%) received DOACs and 8,577 (85%) low-molecular-weight heparin (LMWH). For long-term therapy, 1,298 patients (13%) received DOACs and 5,038 (50%) vitamin K antagonists (VKAs). Overall, 95 patients developed VTE recurrences and 262 had major bleeding. Patients initially receiving DOACs had a lower rate of the composite outcome (hazard ratio [HR]: 0.32; 95% confidence interval [CI]: 0.08-0.88) than those on LMWH. Patients receiving DOACs for long-term therapy had a nonsignificantly lower rate of the composite outcome (HR: 0.70; 95% CI: 0.46-1.03) than those on VKAs. On multivariable analysis, patients initially receiving DOACs had a nonsignificantly lower risk for the composite outcome (HR: 0.36; 95% CI: 0.11-1.15) than those on LMWH, while those receiving DOACs for long-term therapy had a significantly lower risk (HR: 0.61; 95% CI: 0.41-0.92) than those on VKAs. Conclusions Our data suggest that the use of DOACs may be more effective and safe than standard therapy in fragile patients with VTE, a subgroup of patients where the risk for bleeding is particularly high.


Changes in immunological and hematological parameters of female residents exposed to volatile organic compounds in the city of Kaohsiung, Taiwan.
The objective of this study was to assess the effects, if any, of volatile organic compounds (VOCs) in the ambient air of Kaohsiung, Taiwan, on certain hematological and immunological parameters of 153 female study participants. The major source of VOCs was vehicle emissions. The participants were selected from three areas, each area at a different distance from a freeway. Results indicated that total concentrations of VOCs and a subgroup of 25 VOCs (VOC25) ranged from 250 to 335 ppb and 89 to 113 ppb, respectively. The distribution of VOC concentrations did not correlate with distance from the freeway. The participants living in the area with higher VOC concentrations had significantly higher abnormalities of white blood cells (WBC) and hemoglobin (Hb). In addition, IgG and IgA counts were significantly lower for the participants in the area with higher VOCs than for participants in the area with lower VOCs. This finding indicates that VOCs in ambient air may suppress immunological variables.


Patient-reported outcomes in adults with moderate to severe asthma after use of budesonide and formoterol administered via 1 pressurized metered-dose inhaler.
Patient-reported outcomes (PROs) are important for evaluating asthma therapy. To evaluate PROs in adults with moderate to severe persistent asthma receiving budesonide and formoterol administered via 1 pressurized metered-dose inhaler (pMDI). This 12-week, double-blind, double-dummy, placebo-controlled, multicenter study randomized 596 patients 12 years or older to budesonide/formoterol pMDI 160/4.5 microg x 2 inhalations (320/9 microg); budesonide pMDI 160 microg x 2 inhalations (320 microg) + formoterol dry powder inhaler (DPI) 4.5 microg x 2 inhalations (9 microg); budesonide pMDI 160 microg x 2 inhalations (320 microg); formoterol DPI 4.5 microg x 2 inhalations (9 microg); or placebo, each twice daily, after 2 weeks of budesonide pMDI 80 microg x 2 inhalations (160 microg) twice daily. PROs were assessed in 553 patients 18 years or older using the standardized Asthma Quality of Life Questionnaire (AQLQ[S]), Medical Outcomes Survey (MOS) Sleep Scale, Patient Satisfaction With Asthma Medication (PSAM) questionnaire, diary data, and global assessments. Patients receiving budesonide/formoterol reported significantly greater improvements from baseline on the AQLQ(S) and asthma control variables (based on symptoms and rescue medication use; all P < .001) vs placebo. Clinically important improvements (increase of > or = 0.5 points) from baseline to end of treatment in AQLQ(S) overall scores were achieved by 43.6% of patients receiving budesonide/formoterol vs 22.6% of patients receiving placebo (P = .001). The MOS Sleep Scale scores generally showed no differences among treatment groups. Patients receiving budesonide/formoterol had significantly greater PSAM questionnaire scores and better outcomes on physician-patient global assessments at end of treatment vs placebo (all P < or = .001). Significantly greater improvements in health-related quality of life and asthma control and greater treatment satisfaction were observed with budesonide/formoterol pMDI vs placebo.


Preparation and research of nano-scale europium (III)-pyromellitic acid powder luminescent material.
The nanoscale luminescent complex of europium (III)-pyromellitic acid was synthesized successfully in the polyvinylpyrrolidone (PVP) matrix by a co-precipitation method. The chemical formula of the synthesized complex was speculated to be PVP/Eu4/3L x 3H2O by elemental analysis, inductively coupled plasma-atomic emission spectroscopy (ICP-AES) and Fourier-transform infrared spectroscopy (FT-IR). The X-ray diffraction (XRD) pattern of PVP/Eu4/3L x 3H2O indicated that it was a new crystalline complex since the diffraction angle, diffraction intensity, and distance of the crystal plane were all different from those of the ligand. It is proved by the thermogravimetric curve that the synthesized nanoscale luminescent complex was stable, ranging from ambient temperature to 479 degrees C in air. The transmission electron microscopy (TEM) image showed that the complex was nanoparticles. The synthesized complex emitted the characteristic red fluorescence of Eu(III) ions under ultraviolet excitation by the photoluminescence analyses. For example, the emission peaks of PVP/Eu4/3L x 3H2O at 578, 591, 612, and 694 nm using 322 nm as exciting wavelength are assigned to the 5D0 --> 7F0, 5D0 --> 7F1, 5D0 --> F2, and 5D0 --> 7F4 electron transitions of the Eu3+ ions, respectively.


Marrow transplantation in the treatment of murine hereditary diseases.
The prospects for analysing the curative potential of mutant stem cells following transfection with wild type genes is severely limited by the number of available animal models that fulfil all the requirements. Appropriate models must have the following characteristics: (1) the wild type stem cells are capable of providing a long-term cure of the mutant; (2) the primary product of the mutated gene is known; (3) the wild type allele is cloned; and (4) the normal gene is capable of being reinserted into mutant bone marrow stem cells where it continues to function when the cells are returned to the mutant environment. My object in this paper is to review stem cell transplantation in Mus musculus with hereditary anomalies, thus identifying the mutant mice that fulfil the first criterion and are potential models for future gene transfection studies.


Relaxation dynamics of phase oscillators with generic heterogeneous coupling.
The coupled phase oscillator model serves as a paradigm that has been successfully used to shed light on the collective dynamics occurring in large ensembles of interacting units. It was widely known that the system experiences a continuous (second-order) phase transition to synchronization by gradually increasing the homogeneous coupling among the oscillators. As the interest in exploring synchronized dynamics continues to grow, the heterogeneous patterns between phase oscillators have received ample attention during the past years. Here, we consider a variant of the Kuramoto model with quenched disorder in their natural frequencies and coupling. Correlating these two types of heterogeneity via a generic weighted function, we systematically investigate the impacts of the heterogeneous strategies, the correlation function, and the natural frequency distribution on the emergent dynamics. Importantly, we develop an analytical treatment for capturing the essential dynamical properties of the equilibrium states. In particular, we uncover that the critical threshold corresponding to the onset of synchronization is unaffected by the location of the inhomogeneity, which, however, does depend crucially on the value of the correlation function at its center. Furthermore, we reveal that the relaxation dynamics of the incoherent state featuring the responses to external perturbations is significantly shaped by all the considered effects, thereby leading to various decaying mechanisms of the order parameters in the subcritical region. Moreover, we untangle that synchronization is facilitated by the out-coupling strategy in the supercritical region. Our study is a step forward in highlighting the potential importance of the inhomogeneous patterns involved in the complex systems, and could thus provide theoretical insights for profoundly understanding the generic statistical mechanical properties of the steady states toward synchronization.


Derivation of a new lamb survival trait for the New Zealand sheep industry.
Previous research identified that a review of the current industry New Zealand lamb survival trait was necessary as its recording accuracy was reliant on farmers notifying their Sheep Improvement Limited bureau of lamb deaths. This paper reports the decision rules and genetic parameters for a new lamb survival trait for the New Zealand sheep industry. These rules define the new lamb survival trait (NEWSUR) using lamb birth fate (BFATE) codes and the presence/absence of lamb weight measurements. Six univariate animal models were tested and used to estimate variance or covariance components and the resulting direct and maternal heritabilities for NEWSUR. The models differed in the way they adjust for the effect of day of birth, the exclusion or inclusion of a litter (dam/year of birth) random effect, and the application or not of a logit transformation of the phenotypes. For both the linear and logistic methods, models including the random effect of litter provided the best fit for NEWSUR according to log-likelihood values. Log-likelihoods for the linear and logistic models cannot be compared; therefore, a cross-validation method was used to assess whether the logit transformation was appropriate by analyzing the predictive ability of the models. The mean square errors were slightly lower for the linear compared with the logistic model, and therefore, the linear model was recommended for industry use. The heritability attributed to direct effects ranged from 2 to 5.5%. A direct heritability of 5.5% resulted from a linear model without litter effect and omitting the effect of day of birth on survival, whereas a direct heritability of 2% resulted from the logistic model fitting a random litter effect. The heritability attributed to maternal genetic effects ranged from 1.9 to 7.7%. A maternal genetic heritability of 7.7% resulted from the logistic model omitting the litter effect, whereas a maternal genetic heritability of 1.9% resulted from the linear model fitting a random litter effect. The addition of the litter random effect substantially decreased the maternal heritabilities in all cases and was recommended for industry use to avoid overestimation of the maternal genetic variance. Sheep Improvement Limited has implemented NEWSUR and the associated genetic evaluation model based on information described in this paper. Industry-wide implementation will enable sheep breeders to produce more accurate genetic evaluations to their commercial clients.


Extracellular Vesicles for the Diagnosis of Parkinson's Disease: Systematic Review and Meta-Analysis.
Parkinson's disease (PD) biomarkers are needed by both clinicians and researchers (for diagnosis, identifying study populations, and monitoring therapeutic response). Imaging, genetic, and biochemical biomarkers have been widely studied. In recent years, extracellular vesicles (EVs) have become a promising material for biomarker development. Proteins and molecular material from any organ, including the central nervous system, can be packed into EVs and transported to the periphery into easily obtainable biological specimens like blood, urine, and saliva. We performed a systematic review and meta-analysis of articles (published before November 15, 2022) reporting biomarker assessment in EVs in PD patients and healthy controls (HCs). Biomarkers were analyzed using random effects meta-analysis and the calculated standardized mean difference (Std.MD). Several proteins and ribonucleic acids have been identified in EVs in PD patients, but only α-synuclein (aSyn) and leucine-rich repeat kinase 2 (LRRK2) were reported in sufficient studies (n = 24 and 6, respectively) to perform a meta-analysis. EV aSyn was significantly increased in neuronal L1 cell adhesion molecule (L1CAM)-positive blood EVs in PD patients compared to HCs (Std.MD = 1.84, 95% confidence interval = 0.76-2.93, P = 0.0009). Further analysis of the biological sample and EV isolation method indicated that L1CAM-IP (immunoprecipitation) directly from plasma was the best isolation method for assessing aSyn in PD patients. Upcoming neuroprotective clinical trials immediately need peripheral biomarkers for identifying individuals at risk of developing PD. Overall, the improved sensitivity of assays means they can identify biomarkers in blood that reflect changes in the brain. CNS-derived EVs in blood will likely play a major role in biomarker development in the coming years. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Natural killing of cytomegalovirus-infected fibroblasts by human mononuclear leucocytes.
The ability of human peripheral blood mononuclear (MN) cells to lyse uninfected and cytomegalovirus (CMV) infected human fibroblasts was determined in a 51Cr-release assay. Maximal release was obtained with 6-day infected fibroblasts incubated with MN cells for 24 hr. A linear relationship existed between E/T ratios of 12.5:1 to 100:1 and lysis of CMV-infected targets. Donor immune status had no effect on the magnitude of killing of infected or uninfected targets. Killing was mediated by non-B, predominantly non-T, Fc receptor-bearing cells. Preincubation of effector cells with interferon enhanced killing of both CMV-infected and uninfected fibroblasts, but infected targets were more effectively killed. These results indicated a possible role for natural killer cells in recovery from CMV infection.


Maternal interactive beliefs and style as predictors of language development in preterm and full term children.
Previous research has shown that the quality of mother-child interactions between pre-term children and their mothers tends to be poorer than that of full-term children and their mothers (Forcada-Guex, Pierrehumbert, Borghini, Moessinger & Muller-Nix, 2006). Mothers of pre-term children are less responsive and more intrusive in interactions with their children than mothers of full-term children (Forcada-Guex et al., 2006; Ionio, Lista, Mascheroni, Olivari, Confalonieri, Mastrangelo, Brazzoduro, Balestriero, Banfi, Bonanomi, Bova, Castoldi, Colombo, Introvini & Scelsa, 2017; Laing, McMahon, Ungerer, Taylor, Badawi & Spence, 2010). The current research explored differences between mothers of pre-term and full-term children in terms of interactive beliefs and style, and the potential for language development to be differentially predicted by maternal interactive beliefs and styles in pre-term versus full-term children. Independent t-tests were conducted to compare pre-term and full-term groups in relation to the measures of maternal interactive beliefs and styles. A series of multiple regression analyses were then performed separately for each group to examine the shared and unique contributions of maternal interactive beliefs and styles on full-term versus pre-term children's language development. The results showed that mothers of pre-term children were more intrusive-directive than mothers of full-term children; in contrast, mothers of full-term children were more responsive and supportive-directive in interactions with their children. Moreover, predictors of language development were different in full-term versus pre-term children; in full-term children, maternal supportive beliefs and responsiveness were significant predictors of language development evaluated by both the Bayley Scales of Infant and Toddler Development and the MacArthur Communicative Development Inventory; in the pre-term group, maternal supportive and directive beliefs, as well as supportive and intrusive directiveness, were significant predictors, with the latter being negatively associated with language development indicators. This research can shed light on how to prevent language delay in children and improve mother-child interactions that contribute to language development, which may in turn improve language development in vulnerable children, children born pre-term in particular.


Evolving treatment implementation among HIV-infected pregnant women and their partners: results from a national surveillance study in Italy, 2001-2015.
The current global and national indications for antiretroviral treatment (ART, usually triple combination therapy) in adolescent and adults, including pregnant women, recommend early ART before immunologic decline, pre-exposure chemoprophylaxis (PrEP), and treatment of HIV-negative partners in serodiscordant couples. There is limited information on the implementation of these recommendations among pregnant women with HIV and their partners. The present analysis was performed in 2016, using data from clinical records of pregnant women with HIV, followed between 2001 and 2015 at hospital or university clinics within a large, nationally representative Italian cohort study. The study period was divided in three intervals of five years each (2001-2005, 2006-2010, 2011-2015), and the analysis evaluated temporal trends in rates of HIV diagnosis in pregnancy, maternal antiretroviral treatment at conception, prevalence of HIV infection among partners of pregnant women with HIV, and proportion of seronegative and seropositive male partners receiving antiretroviral treatment. The analysis included 2755 pregnancies in women with HIV. During the three time intervals considered the rate of HIV diagnosis in pregnancy (overall 23.3%), and the distribution of HIV status among male partners (overall 48.7% HIV-negative, 28.6% HIV-positive and 22.8% unknown) remained substantially unchanged. Significant increases were observed in the proportion of women with HIV diagnosed before pregnancy who were on antiretroviral treatment at conception (from 62.0% in 2001-2005 to 81.3% in 2011-2015, P < 0.001), and in the proportion of HIV-positive partners on antiretroviral treatment (from 73.3% in 2001-2005 to 95.8% in 2011-2015, P = 0.002). Antiretroviral treatment was administered in 99.1% of the pregnancies that did not end early because of miscarriage, termination, or intrauterine death, and in 75.3% of those not ending in a live birth. No implementation of antiretroviral treatment was introduced among male HIV-negative partners. The results suggest good implementation of antiretroviral treatment among HIV-positive women and their HIV-positive partners, but no implementation, even in recent years, of Pre-Exposure Prophylaxis (PrEP) among uninfected male partners. Further studies should assess the determinants of this occurrence and clarify the attitudes and the potential barriers to PrEP use.


Prospectively measured red cell folate levels in methotrexate treated patients with rheumatoid arthritis: relation to withdrawal and side effects.
To investigate whether red cell folate (RCF) levels relate to side effects, withdrawals, or disease activity during treatment with the folic acid antagonist methotrexate (MTX) for rheumatoid arthritis (RA). Side effects were recorded monthly, RCF levels were measured by lactoglobulin binding radioassays, and 8 variables for disease activity were measured in a placebo controlled double blind trial of 28 weeks' duration comparing efficacy of MTX (n = 23) and D-penicillamine (n = 23). From Week 20 RCF levels decreased only in the MTX group (p < 0.02), and 5 MTX treated patients withdrew due to side effects. Withdrawals had lower RCF values at Weeks 0 and 9 compared to the remaining patients (p < 0.05). Folate deficiency evolved in 5 patients; 2 of these developed cytopenia. Aberrations in the scheduled dosage increase were related to lower pretreatment values of RCF (p = 0.007). Side effect scores were inversely correlated to RCF values at Weeks 0, 9, and 28 (p < 0.05). RCF levels measured concomitantly with liver enzyme elevation were lower than the remaining values (p < 0.001). When side effects were reported, 96% of concomitantly measured RCF values were below 800 nmol/l. RCF values at entry did not correlate to improvement in any variable for disease activity, or a graded overall improvement. RCF levels decrease during MTX treatment and relate to side effects, withdrawals, liver enzyme elevations and aberrant MTX dosage increase, but not to the therapeutic effect. RCF above 800 nmol/l protects against side effects.


Bis-N-norgliovictin, a small-molecule compound from marine fungus, inhibits LPS-induced inflammation in macrophages and improves survival in sepsis.
Sepsis is a highly lethal disorder characterized by systemic inflammation, and Toll-like receptor 4 (TLR4) in macrophages plays a crucial role in modulating innate immune response and outcome of sepsis. During the screening of natural products against inflammation, we identified bis-N-norgliovictin, a small-molecule compound isolated from marine-derived fungus, significantly inhibited lipopolysaccharide (LPS, ligand of TLR4)-induced tumor necrosis factor-α (TNF-α) production in RAW264.7 cells. In this study, we evaluated the effect of bis-N-norgliovictin on TLR4-mediated inflammation in mouse macrophages and LPS-induced sepsis model. In RAW264.7 and mouse peritoneal macrophages, bis-N-norgliovictin dose-dependently inhibited LPS-induced production of TNF-α, interleukin-6 (IL-6), interferon-β (IFN-β) and monocyte chemoattractant protein (MCP-1), but without suppressing cell viability. The anti-inflammatory effect was attributed to the down-regulation of TLR4-triggered myeloid differentiation primary response protein 88 (MyD88)-dependent and TIR-containing adapter inducing interferon-β (TRIF)-dependent signaling pathways, including p38 and c-Jun N-terminal kinase (JNK) of mitogen-activated protein kinases (MAPKs), nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3) cascades. Importantly, bis-N-norgliovictin also protected mice against LPS-induced endotoxic shock. Intravenous injection of bis-N-norgliovictin 1h before LPS challenge dose-dependently inhibited LPS-induced increases in serum levels of TNF-α, IL-6, MCP-1 and IL-10, attenuated liver and lung injury and diminished M1 macrophage polarization in liver. Our results demonstrate that bis-N-norgliovictin exhibit potent anti-inflammatory effect both in vitro and in vivo. These findings suggest that bis-N-norgliovictin can be a useful therapeutic candidate for the treatment of sepsis and other inflammatory diseases.


Pulmonary elasticity in children and adolescents.
Static (Cst(L)), dynamic (Cdyn(L)), and "specific lung compliance (CL/TLC, CL/FRC) and the elastic recoil pressure of the lungs (Pst/(L)) were measured in 131 healthy children and the adolescents (age 6 to 17 years) from simultaneous recordings of esophageal pressure and lung volume. Esophageal elastance and vertical esophageal pressure gradients were also studied. Pst(L), measured at different lung volumes (fractional) from the expiratory quasi-static pressure-volume (PV) curves of the lungs, increased significantly with increasing body height, age, and body surface. Cst(L), determined from the midportion of PV curves, and Cdyn(L) measured during normal breathing at frequencies around 20/min also increased significantly with somatic growth. "Specific" Cst(L) decreased with increasing body height, age, and body surface. "Specific" Cdyn(L), esophageal elastance, and the vertical esophageal pressure gradient were independent of body height, age, and body surface, Cdyn(L) was less than Cst(L) mainly in smaller and younger children, and was not considered a valid index of pulmonary elasticity. Values of Pst(L), "specific" Cst(L), and the change of slope of the midportion of PV curves in children and adolescents suggested developmental changes of pulmonary elasticity in man over the age range studied.


Intracranial germ cell tumors in children with and without Down syndrome.
Two Chinese children with Down syndrome affected by intracranial germ cell tumors are described. Because they represent two of eight affected patients in the current series from 1990 to 1996, it is postulated that such occurrence may be more than a coincidental event. Two children with Down syndrome developed germ cell tumors in atypical intracranial sites that affected basal ganglion and cerebellum. The pathology showed germinoma and yolk sac tumor, respectively. These were treated by radical surgical resection and chemotherapy with cisplatin, etoposide, and bleomycin, but without radiotherapy. One patient survived 3 years without radiologic evidence of tumor. The other died from infective complications caused by severe myelosuppression after chemotherapy. Subtle neurologic manifestations in developmentally handicapped patients with intracranial space-occupying lesions could result in delayed diagnosis. Children with Down syndrome suffering from brain tumors may have a higher chance for germ cell tumors. Assay for alpha-fetoprotein and beta-human chorionic gonadotrophin could hasten diagnosis in some cases. This observation and review of literature suggest an increased risk of developing intracranial germ cell tumors in subjects with Down syndrome.


Detection of Wolbachia bacteria in multiple organs and feces of the triatomine insect Rhodnius pallescens (Hemiptera, Reduviidae).
At least two types of Wolbachia bacteria were detected in wild and insectarium-raised Rhodnius pallescens, a natural vector of Trypanosoma cruzi and Trypanosoma rangeli. Wolbachia was detected in all the organs and tissues studied and in the feces, and this provided a methodological advantage for determining the presence of this endosymbiont in this host, obviating the need to kill the specimens. The occurrence of trypanosomatids in wild individuals was also studied.


The antimicrobial properties of different strains of Lactobacillus spp. isolated from kefir.
The characteristics of 58 strains of Lactobacillus spp. isolated from kefir were studied. These strains were tested for adherence to human enterocyte-like Caco-2 cells, resistance to acidic pH and bile acid, antimicrobial activities against enteropathogenic bacteria and inhibition of Salmonella typhimurium attachment to Caco-2 cells. The best probiotic properties were observed in L. acidophilus CYC 10051 and L. kefiranofaciens CYC 10058. L. kefiranofaciens CYC 10058 produced an exopolysaccharide, which revealed that it was closely related to kefiran, a polysaccharide with antitumoral properties. This is the first in vitro study about the antimicrobial characteristics of the Lactobacillus population of kefir.


Porosity of resin filling materials.
Four paste-paste types of resin filling materials and three capsulated products were tested with respect to porosity content and size distribution of the pores. The data were obtained by using an automatic image analyzer. The paste-paste products were inserted into the test cavities by a bulk-packing technique and an injection technique. The results showed that the use of a syringe reduced the porosity content, mainly by the elimination of big pores. The capsulated products were not less porous than the paste-paste materials.


Dependence of tree ring stable isotope abundances and ring width on climate in Finnish oak.
We measured ring widths and isotopic abundances of carbon, oxygen and hydrogen (delta(13)C, delta(18)O and delta(2)H) from the latewood of tree rings of pedunculate oak (Quercus robur L.) in its distributional northern limit in Southern Finland. Ring width was observed to be related to precipitation and relative humidity but not significantly to temperature. delta(13)C and delta(18)O were significantly related to all studied climatic variables, most strongly to cloud cover. Variations in delta(2)H were discovered to be complex combinations of signals from biochemical and physical processes. The results suggest that oaks in Finland can be used as a source of climate information. delta(18)O was discovered to be especially promising as it showed the strongest climate signal and highest common signal between trees. The relationship between climate and ring width indicates that water availability is the main control of ring radial growth. This is supported by the isotope data. High correlation between delta(13)C and delta(18)O time series indicates that photosynthetic carbon assimilation is limited by stomatal control. Therefore, in contrast to the expected temperature limitation, our data indicate that drought limits oak growth more than cold temperatures on the border of its northernmost distribution range.


Development of a transgenic hairy root system in jute (Corchorus capsularis L.) with gusA reporter gene through Agrobacterium rhizogenes mediated co-transformation.
Transgenic hairy root system is important in several recalcitrant plants, where Agrobacterium tumefaciens-mediated plant transformation and generation of transgenic plants are problematic. Jute (Corchorus spp.), the major fibre crop in Indian subcontinent, is one of those recalcitrant plants where in vitro tissue culture has provided a little success, and hence, Agrobacterium-mediated genetic transformation remains to be a challenging proposition in this crop. In the present work, a system of transgenic hairy roots in Corchorus capsularis L. has been developed through genetic transformation by Agrobacterium rhizogenes harbouring two plasmids, i.e. the natural Ri plasmid and a recombinant binary vector derived from the disarmed Ti plasmid of A. tumefaciens. Our findings indicate that the system is relatively easy to establish and reproducible. Molecular analysis of the independent lines of transgenic hairy roots revealed the transfer of relevant transgenes from both the T-DNA parts into the plant genome, indicating the co-transformation nature of the event. High level expression and activity of the gusA reporter gene advocate that the transgenic hairy root system, thus developed, could be applicable as gene expression system in general and for root functional genomics in particular. Furthermore, these transgenic hairy roots can be used in future as explants for plantlet regeneration to obtain stable transgenic jute plants.


Scanning nonlinear dielectric potentiometry.
Measuring spontaneous polarization and permanent dipoles on surfaces and interfaces on the nanoscale is difficult because the induced electrostatic fields and potentials are often influenced by other phenomena such as the existence of monopole fixed charges, screening charges, and contact potential differences. A method based on tip-sample capacitance detection and bias feedback is proposed which is only sensitive to polarization- or dipole-induced potentials, unlike Kelvin probe force microscopy. The feasibility of this method was demonstrated by simultaneously measuring topography and polarization-induced potentials on a reconstructed Si(111)-(7 × 7) surface with atomic resolution.


Neuropathology of vitamin B12 deficiency in the Cd320-/- mouse.
In humans, vitamin B12 deficiency causes peripheral and CNS manifestations. Loss of myelin in the peripheral nerves and the spinal cord (SC) contributes to peripheral neuropathy and motor deficits. The metabolic basis for the demyelination and brain disorder is unknown. The transcobalamin receptor-knockout mouse ( Cd320-/-) develops cobalamin (Cbl) deficiency in the nervous system, with mild anemia. A decreased S-adenosylmethionine: S-adenosylhomocysteine ratio and increased methionine were seen in the brain with no significant changes in neurotransmitter metabolites. The structural pathology in the SC presented as loss of myelin in the axonal tracts with inflammation. The sciatic nerve (SN) showed increased nonuniform, internodal segments suggesting demyelination, and remyelination in progress. Consistent with these changes, the Cd320-/- mouse showed an increased latency to thermal nociception. Further, lower amplitude of compound action potential in the SN suggested that the functional capacity of the heavily myelinated axons were preferentially compromised, leading to loss of peripheral sensation. Although the metabolic basis for the demyelination and the structural and functional alterations of the nervous system in Cbl deficiency remain unresolved, the Cd320-/- mouse provides a unique model to investigate the pathologic consequences of vitamin B12 deficiency. -Arora, K., Sequeira, J. M., Alarcon, J. M., Wasek, B., Arning, E., Bottiglieri, T., Quadros, E. V. Neuropathology of vitamin B12 deficiency in the Cd320-/- mouse.


On means of transport of Danish veterinarians during the last two hundred years.
For almost 20 years the authors have been selecting and editing the material referring to the means of transport which Danish veterinarians used in the 18th, 19th and 20th century. The source material contains memoirs, advertisements from veterinary medical journals, obituaries and other sources, based on which a 210-page book in the Danish language has been published. The article presents an abridged version of this book. In Denmark, the first veterinarians rendered their services at the time when this profession had not yet established itself. They were relatively poor and very often they had to walk even 15 to 20 km per day in order to visit two or three farms, where their professional help was needed. In the first half of the 19th century, the economic situation of Danish veterinarians improved, so they could afford a horse of their own. From the second half of the 19th century, the gig, a light two-wheel vehicle drawn by one horse, was in use. At the end of the 19th century, bicycles and motor-bicycles were slowly gaining ground. The gig, however, continued to be the main means of transport, because it was cheap and safe. In the 20th century, the automobile era began, but World War I prevented the widespread use of cars due to the shortage of petrol, rubber parts and the like. After the war, automobiles came into common use both in medical and veterinary practice. Only in hard winters with much snow, horses and sledges were coming to the fore again. World War II once again created the shortage of petrol and rubber tyres, so horses and gas generators were in demand. After the war, various car models completely dominated the veterinary practice, cars with built-in shelves for medicines, instruments and other medical supplies in particular. The telephone was a great help and of service to veterinarians, because many of long trips to clients were not necessary any more, thanks to the simple communication over the phone. Veterinarians were often among the first owners of the telephone in a town or village, which can still be seen in their valid phone numbers (ending with 01, 02, etc.). Some veterinarians travelled also by train, during the war in particular. When there was much snow, some used skis. Some Danish veterinarians had to accompany exotic animals on their journey from Africa or Thailand, where planes were the main means of transport. In the 19th and 20th century, veterinarians used to accompany animals during their transport at sea, for example from South America to Danish colonies in West India (Tranquebar). After World War II, several veterinarians accompanied animals transported by ships to some of the Baltic harbours in the former USSR. In Denmark, there are many islands with numerous farms, therefore, if required, veterinarians from the continent have to be ready to go to the islands any time, day or night. In such cases boats are the primary means of transport, but planes and helicopters are also used in modern times. In Greenland, veterinary services are provided by veterinarians travelling by ships or boats, helicopters, and sometimes even dog-sledges.


Hepatitis A virus subgenotypes dissemination during a community outbreak in a surrounding region of Rio de Janeiro.
From December 1999 to December 2001, many cases of hepatitis A were notified in the county of Belford Roxo involving individuals aged 0 to 79 years. Serum samples were collected to evaluate the prevalence of anti-hepatitis A virus (HAV) antibodies, to detect HAV-RNA and to correlate with possible risk factors of HAV infection. Serum samples were screened by commercial IgM and total anti-HAV antibody ELISA and HAV-RNA was isolated and subsequently amplified by reverse transcription-polymerase chain reaction (RT-PCR) at VP1/2A region, sequenced and analyzed. Total anti-HAV prevalence was 87.9% (203/231) and IgM anti-HAV prevalence was 38.7% (89/231). Multivariate analysis showed that individuals under 20 years old are risks groups to acquire the infection suggesting that hygienic habits of young subjects are the principal factor of transmission and so they could be the target for vaccine programs. HAV-RNA was amplified from 29 (32.5%) IgM anti-HAV positive patients and 26 samples were sequenced and classified into subgenotypes IB (8 isolates) and IA (18 isolates). Isolates classified into subgenotype IB were identical representing one distinct strain. We could observe both subgenotypes circulating during the study which suggests different sources of infection. Prophylactic measures as vaccination strategies added to improvements in hygienic and sanitary conditions would be highly effective to reduction of infection.


The contraceptive potential of fertilization: a physiological perspective.
Several separate events of the fertilization sequence (sperm capacitation, regulated sperm transport in the oviduct, sperm-cumulus interaction, sperm-zona binding, the acrosome reaction, zona penetration, gamete fusion) represent points at which conception might be preventable. Each is considered variously with reference to its biological significance, what is known about the mechanisms involved, the issues that remain to be resolved, and the prospects for specific inhibition.


Determination of the volume scattering function of aqueous particle suspensions with a laboratory multi-angle light scattering instrument.
We describe a methodology for determining the volume scattering function β(ψ) of aqueous particle suspensions from measurements with a laboratory multi-angle light scattering instrument called DAWN (Wyatt Technology Corporation). In addition to absolute and angular calibration, the key component of the method is the algorithm correcting for reflection errors that reduce the percent error in β(ψ) from as much as ~300% to <13% at backward scattering angles. The method is optimized and tested with simulations of three-dimensional radiative transfer of exact measurement geometry including the key components of the instrument and also validated experimentally using aqueous suspensions of polystyrene beads. Example applications of the method to samples of oceanic waters and comparisons of these measurements with results obtained with other light scattering instruments are presented.


AIMP3 Deletion Induces Acute Radiation Syndrome-like Phenotype in Mice.
Genomes are mostly protected from constant DNA-damaging threats, either internal or external, which ultimately sustain the organism. Herein, we report that AIMP3, a previously demonstrated tumour suppressor, plays an essential role in maintaining genome integrity in adult mice. Upon induction of the temporal systemic deletion of AIMP3 by tamoxifen in adult mice, the animals developed an acute radiation syndrome-like phenotype, typified by scleroderma, hypotrophy of haematopoietic cells and organs, and intestinal failure. Induction of γH2AX, an early marker of DNA double-strand breaks, was observed in the spleen, intestine, and the highly replicating embryonic cortex. In addition, sub-lethal irradiation of AIMP3 mKO mice dramatically affected organ damage and survival. Using isolated MEFs from conditional KO mice or AIMP3 knockdown cells, we confirmed the presence of spontaneously occurring DNA double-strand breaks by COMET assay and γH2AX induction. Furthermore, γH2AX removal was delayed, and homologous DNA repair activity was significantly reduced. Reduction of RPA foci formation and subsequent Rad51 foci formation probably underlie the significant reduction in homologous recombination activity in the absence of AIMP3. Together, our data demonstrate that AIMP3 plays a role in genome stability through the DNA repair process.


Social skills moderate the time-varying association between aggression and peer rejection among children with and without ADHD.
Although childhood aggression is typically associated with peer rejection, some children concurrently employ coercive and socially skilled behavior and successfully avoid negative peer outcomes. However, research on children's dual use of coercive and social behavior has largely employed cross-sectional designs with nonclinical populations and, as a result, little is known about the covariation of aggression with social skills, particularly among high-risk samples. We directly addressed this limitation by testing childhood aggression and social skills as separate time-varying predictors of prospective change in peer rejection in a sample of children with and without attention-deficit/hyperactivity disorder (ADHD). Two hundred and two 5-10-year-old children (M = 7.9 years, SD = 1.2) with and without ADHD were followed prospectively for 6 years. Key constructs, including children's overt aggression, social skills, and peer rejection, were collected at each of the three waves using multiple methods and informants. Controlling for demographic factors and time-varying ADHD symptoms, longitudinal change in child-, parent-, and teacher-reported aggression positively predicted prospective change in parent- and teacher-reported peer rejection. Importantly, predictions were moderated by parent- and teacher-reported social skills, such that aggression inversely predicted peer rejection for children with high social skills. These results demonstrate that social skills meaningfully alter trajectories of peer rejection predicted from cross-time variation in aggression. We discuss the theoretical and empirical implications of these findings within a developmental psychopathology framework, including recommendations for directions for future research.


Stature estimation from long bone lengths in Bulgarians.
The purpose of the present study is to develop a new regression procedure for predicting the stature from the length of the limb long bones taking into account sex- and age-related changes. The statures and lengths of humerus (H), tibia (T) and fibula (Fi) were measured in 416 forensic cases (286 male and 130 female adult Bulgarians). The measurements of the bones and the stature were made on cadavers before autopsy. Stature regression analysis is performed for each of the three bones, as well as for a combination of humerus and tibia. There is a possibility of applying five different procedures with regard of the effect of aging on stature decrease. Resulting models are tested for outliers and heteroskedasticity. Regression parameters, their standard deviations, standard error of the regression. Anova test for model adequacy and the covariance matrix of regression parameters are calculated. The confidence intervals of the error term are determined. Nomograms for a direct application of the results are constructed where it is convenient. The method provides better and more reliable results of stature estimation for the Bulgarian population than other formulae.


Separation of enzymes from Candida boidinii crude extract by continuous flow zone electrophoresis.
Separation of the enzymes formate dehydrogenase, formaldehyde dehydrogenase and methanol oxidase from Candida boidinii crude extract has been explored using continuous flow zone electrophoresis in the VaP-22 and the scaled-up VaP-220 electrophoresis apparatus. Yields up to 95% and purification factors between 3 and 7 were obtained, together with separation of cell debris from the enzymes. Multiple injections of sample were used to obtain a protein throughput of 46.2 mg/h in the VaP-22. A tenfold higher throughput was achieved using the VaP-220. Correlation of the electrophoretic mobility in continuous flow zone electrophoresis with the elution behavior in ion-exchange chromatography confirmed the primary role of net surface charge in the separation of biological molecules. Proteins and enzymes with differences greater than 0.05 M elution molarities in ion-exchange chromatography can be separated. This corresponds to a preparative scale (mg/h or g/h) separation of proteins and enzymes whose difference in apparent electrophoretic mobility is greater than 0.70 x 10(-5) cm2/(V.s).


Exploring the therapeutic potential of jellyfish venom.
The venom of certain jellyfish has long been known to be potentially fatal to humans, but it is only recently that details of the proteomes of these fascinating creatures are emerging. The molecular contents of the nematocysts from several jellyfish species have now been analyzed using proteomic MS approaches and include the analysis of Chironex fleckeri, one of the most venomous jellyfish known. These studies suggest that some species contain toxins related to peptides and proteins found in other venomous creatures. The detailed characterization of jellyfish venom is likely to provide insight into the diversification of toxins and might be a valuable resource in drug design.


Identifying functional networks using endogenous connectivity in gamma band electrocorticography.
Correlations in spontaneous, infra-slow (<0.1 Hz) fluctuations in gamma band (70-100 Hz) signal recorded using electrocorticography (ECoG) reflect the functional organization of the brain, appearing in auditory and visual sensory cortex, motor cortex, and the default mode network (DMN). We have developed a data-driven method using co-modulation in spontaneous, infra-slow, and gamma band power fluctuations in ECoG to characterize the connectivity between cortical areas. A graph spectral clustering algorithm was used to identify networks that appear consistently. These networks were compared with clinical mapping results obtained using electrocortical stimulation (ECS). We identify networks corresponding to motor and visual cortex with good specificity. Anatomic and functional evidence indicates that other networks, such as the DMN, are also identified by this algorithm. These results indicate that it may be possible to map functional cortex using only spontaneous ECoG recordings. In addition, they support the hypothesis that infra-slow co-modulations of gamma band power represent the neurophysiological basis underlying resting-state networks. Methods examining infra-slow co-modulations in gamma band power will be useful for studying changes in brain connectivity in differing behavioral contexts. Our observations can be made in the absence of observable behavior, suggesting that the electrical mapping of functional cortex is feasible without the use of ECS or task-mediated evoked responses.


Illusory Reduplication of One's Own Body: Phenomenology and Classification of Autoscopic Phenomena.
Autoscopic phenomena involve the illusory reduplication of one's own body. The literature on the topic is widely scattered and suffers from considerable terminological and conceptual inconsistencies. This article proposes a classification scheme based on phenomenological criteria. Along with examples of illustrative cases, we outline the main features of autoscopic hallucinations, heautoscopy proper, the feeling of a presence, the out-of-body experience, and negative and inner forms of autoscopic phenomena. We also discuss the need for a differentiation of autoscopic phenomena from reduplicative paramnesias and the misidentification syndromes. Finally, the concept of a neuromatrix (Melzack, 1990) is proposed as a starting point for the understanding of the neuronal mechanisms underlying autoscopic phenomena.


[Cutaneous metastases from adenocarcinoma of unknown primary site].
Metastatic cancer of unknown primary site appears in 5-10% of oncologic patients. The primary tumor is usually discovered at autopsy and only in 27% of patients alive. Metastases from cancer of unknown primary site may be located in the skin and subcutaneous tissue and it is the dermatologist the first in evaluating these patients. We present a case of cutanoeus metastases from moderately-differentiated adenocarcinoma of unknown primary site. The immunohistochemical study revealed positive staining for CEA and negative staining for PSA. The primary tumor could not be identified in spite of the imaging and endoscopic studies performed. Based on these studies we excluded a colorectal or prostatic origin and considered a pancreatic adencarcinoma as the possible primary tumor. Even though a minority of these patients will have a curable disease, the appropriate use of pathological diagnosis and selected imaging studies for an optimal management of patients with a tumor of unknown primary site should not be ignored.


Estimated communication range of social sounds used by bottlenose dolphins (Tursiops truncatus).
Bottlenose dolphins, Tursiops truncatus, exhibit flexible associations in which the compositions of groups change frequently. We investigated the potential distances over which female dolphins and their dependent calves could remain in acoustic contact. We quantified the propagation of sounds in the frequency range of typical dolphin whistles in shallow water areas and channels of Sarasota Bay, Florida. Our results indicated that detection range was noise limited as opposed to being limited by hearing sensitivity. Sounds were attenuated to a greater extent in areas with seagrass than any other habitat. Estimates of active space of whistles showed that in seagrass shallow water areas, low-frequency whistles (7-13 kHz) with a 165 dB source level could be heard by dolphins at 487 m. In shallow areas with a mud bottom, all whistle frequency components of the same whistle could be heard by dolphins travel up to 2 km. In channels, high-frequency whistles (13-19 kHz) could be detectable potentially over a much longer distance (> 20 km). Our findings indicate that the communication range of social sounds likely exceeds the mean separation distances between females and their calves. Ecological pressures might play an important role in determining the separation distances within communication range.


Multiple birth prevalence in The Netherlands. Impact of maternal age and assisted reproductive techniques.
To evaluate the impact of maternal age and use of fertility drugs on multiple birth prevalence from 1970 to 1995 in the Netherlands. A population-based survey was carried out in which data were collected from the Centraal Bureau voor Statistiek, the Institute of Medical Statistics and from all clinics for in vitro fertilization. In the last two decades, the prevalence of multiple births, especially of twin and triplet births, has increased significantly. Three possible explanations for this phenomenon are: (1) introduction of assisted reproductive techniques in combination with fertility drugs; (2) increasing maternal age; and (3) decreasing fecundity with increasing maternal age, resulting in more fertility treatments. A surplus of 1,366 twins was born in 1995 as compared to 1975. The expected excess of twins was 1,368, of which 104 (7.6%) were a result of the increase in total births in 1995, 583 (42.6%) were due to maternal age > 29 years, and, respectively, 330 (24.1%) and 351 (25.7%) twins were due to in vitro fertilization treatment and intrauterine insemination. The delay in achieving pregnancy and the use of fertility-promoting therapies profoundly affect the prevalence of multiple pregnancies in a given country. The general population should be informed of this risk.


Pharmacologic targets on the female urethra.
This article reviews the mechanisms affecting contraction and relaxation of the urethra in order to establish a basis for current and future treatments for urinary incontinence in women. A review of the English literature using MEDLINE was performed between 1970 and 2008 on female urethra pharmacology, urinary incontinence, and mechanisms involved in contraction and relaxation of the female human urethra. alpha-Adrenoceptors (ARs) cause contraction and beta-ARs cause relaxation. Use of selective alpha-agonist and beta-AR blocker agents might have potential for the treatment of stress urinary incontinence. Tolerable doses of cholinergic agonists did not have significant effects on intraurethral pressure. Nitric oxide seems to be the major nonadrenergic-noncholinergic inhibitory transmitter causing relaxation. c-kit-positive interstitial cells seem to regulate urethral tone. The roles of adenosine triphosphate and carbon monoxide have not been fully investigated in humans. Neuropeptides function similarly to the urinary bladder. Prostanoids cause urethral contraction and relaxation depending on their subtypes. Serotonin enhances the strength of urethral sphincteric contractions. The Rho-kinase pathway also appears to be modulating smooth muscle contraction in the urethra. Understanding of the urethral function and pharmacology may lead to the development of promising new agents which might be useful in the management of urinary incontinence in women.


Life Course Trajectories of Maternal Cardiovascular Risk Factors according to Offspring Birthweight: The HUNT Study.
Women with small or large for gestational age offspring are at increased risk of cardiovascular disease later in life. How their cardiovascular risk factors develop across the life course is incompletely known. We linked data from the population-based HUNT Study (1984-2008) and the Medical Birth Registry of Norway (1967-2012) for 22,487 women. Mixed effect models were used to compare cardiovascular risk factor trajectories for women according to first offspring birthweight for gestational age. Women with small for gestational age (SGA) offspring had 1-2 mmHg higher systolic and diastolic blood pressure across the life course, but lower measures of adiposity, compared to women with offspring who were appropriate for gestational age (AGA). In contrast, women with large for gestational age (LGA) offspring had higher measures of adiposity, ~0.1 mmol/l higher non-HDL cholesterol and triglycerides and 0.2 mmol/l higher non-fasting glucose, compared with mothers of AGA offspring. These differences were broadly stable from prior to first pregnancy until 60 years of age. Our findings point to different cardiovascular risk profiles in mothers of SGA versus LGA offspring, where giving birth to SGA offspring might primarily reflect adverse maternal vascular health whereas LGA offspring might reflect the mother's metabolic health.


Structural and optical properties of Nd:YAB-nanoparticle-doped PDMS elastomers for random lasers.
We report the structural and optical properties of Nd:YAB (NdxY1-x Al3(BO3)4)-nanoparticle-doped PDMS elastomer films for random lasing (RL) applications. Nanoparticles with Nd ratios of x = 0.2, 0.4, 0.6, 0.8, and 1.0 were prepared and then incorporated into the PDMS elastomer to control the optical gain density and scattering center content over a wide range. The morphology and thermal stability of the elastomer composites were studied. A systematic investigation of the lasing wavelength, threshold, and linewidth of the laser was carried out by tailoring the concentration and optical gain of the scattering centers. The minimum threshold and linewidth were found to be 0.13 mJ and 0.8 nm for x = 1 and 0.8. Furthermore, we demonstrated that the RL intensity was easily tuned by controlling the degree of mechanical stretching, with strain reaching up to 300%. A strong, repeatable lasing spectrum over ~ 50 cycles of applied strain was observed, which demonstrates the high reproducibility and robustness of the RL. In consideration for biomedical applications that require long-term RL stability, we studied the intensity fluctuation of the RL emission, and confirmed that it followed Lévy-like statistics. Our work highlights the importance of using rare-earth doped nanoparticles with polymers for RL applications.


Minimally invasive surgical clip closure of anorectal fistulas: current status of OTSC Proctology.
OTSC Proctology is a minimally invasive sphincter-preserving technique for the surgical treatment of anorectal fistulas. It is based on a super-elastic Nitinol clip which closes the internal fistula opening to allow healing of the fistula tract. A systematic search of the literature was undertaken to identify publications about OTSC Proctology. All studies and reports identified were reviewed and evaluated to determine the feasibility, efficacy and safety of clip surgery. The assessment of all available studies with a total of more than 200 surgical cases strongly suggests that the clip procedure is safe and effective with a low rate of complications. The technique rendered convincing short and long term results with an overall healing rate of approximately 63%. Best results were achieved when OTSC Proctology was used as first-line treatment (healing rate 74%) and for cryptoglandular fistulas (healing rate 64%). However, its future clinical role for IBD-associated recurrent and anorecto-vaginal fistulas remains to be determined, due to a relatively low number of these patients in the evaluated studies. OTSC Proctology is part of the novel armamentarium for the treatment for anorectal fistulas, which is based on high-technology devices. They can be repeatedly used and even combined without causing irreversible sphincter damage.


DNA-binding properties of T4 UvsY recombination mediator protein: polynucleotide wrapping promotes high-affinity binding to single-stranded DNA.
To carry out homologous recombination events in the cell, recombination proteins must be able to recognize and form presynaptic filaments on single-stranded DNA (ssDNA) in the presence of a vast excess of double-stranded DNA (dsDNA). Therefore recombination machineries stringently discriminate between ssDNA and dsDNA lattices. Recent single-molecule studies of bacteriophage T4 recombination proteins revealed that, surprisingly, the UvsY recombination mediator protein binds stronger to stretched dsDNA molecules than to stretched ssDNA. Here, we show that for relaxed DNA lattices, the opposite is true: UvsY exhibits a 1000-fold intrinsic affinity preference for ssDNA over dsDNA at moderate salt concentrations. This finding suggests that UvsY preferentially loads UvsX recombinase onto ssDNA under physiological conditions. The biochemical basis for high-affinity UvsY-ssDNA binding was investigated by hydrodynamic and cross-linking methods. Results show that UvsY forms ring-like hexamers in solution, and that ssDNA binds to multiple subunits within each hexamer, consistent with ssDNA wrapping. The data support a model in which ssDNA wrapping by UvsY protein is important for the selective nucleation of presynaptic filaments on ssDNA versus dsDNA, and for the coordinated transfer of ssDNA from Gp32 (SSB) to UvsY (RMP) to UvsX (recombinase) during filament assembly.


Essential role of p53 in silica-induced apoptosis.
Occupational exposure to mineral dusts, such as silica, has been associated with progressive pulmonary inflammation, lung cancer, and fibrosis. However, the mechanisms involved in this process are poorly understood. Because p53 is a key transcription factor regulating many important apoptosis-related genes, we hypothesized that p53 may play a key role in silica-induced apoptosis and that abnormal regulation of p53 by silica may contribute to development of lung cancer as well as silicosis. We used both in vitro and in vivo studies to test this hypothesis. Treatment of JB6 cells carrying a p53-luciferase reporter plasmid with silica caused dose-dependent p53 transactivation. Western blot indicates that silica not only stimulated p53 protein expression but also caused p53 phosphorylation at Ser392. TUNEL and DNA fragmentation analysis show that silica caused apoptosis in both JB6 cells and wild-type p53 (p53+/+) fibroblasts but not in p53-deficient (p53-/-) fibroblasts. Similar results were obtained by in vivo studies. Intratracheal instillation of mice with silica induced apoptosis in the lung of p53+/+ mice, whereas this induction was significantly inhibited in p53-/- mice. Confocal image analysis indicates that most apoptotic cells induced by silica were alveolar macrophages. These results demonstrate for the first time that silica induces p53 transactivation via induction of p53 protein expression and phosphorylation of p53 protein and that p53 plays a crucial role in the signal transduction pathways of silica-induced apoptosis. This finding may provide an important link in understanding the molecular mechanisms of silica-induced carcinogenesis and pathogenesis in the lung.


A recombinant topoisomerase I used for autoantibody detection in sera from patients with systemic sclerosis.
We report the expression of a cDNA clone encoding 695 carboxyl-terminal amino acids of human DNA topoisomerase I (topoI) in Escherichia coli. More than 96% of the anti-HeLa topoI-positive sera from patients with a connective tissue disease displayed also an immunoreactivity with this recombinant protein (the HTopoA protein). Sera from patients with a definite diagnosis systemic sclerosis and reacting with HeLa topoI, all reacted with the HTopoA protein as well. Sera from patients with systemic sclerosis that did not contain anti-topoI antibodies (about 30% of the systemic sclerosis sera), as concluded from HeLa immunoblot, displayed also no immunoreactivity with our recombinant antigen. By expressing different fragments of HTopoA, we were able to assign at least three different autoimmune epitope regions on the HTopoA protein and we show that over a period of 5 years the amount of anti-topoI antibodies against these regions may fluctuate.


Atypical MAP kinases - new insights and directions from amoeba.
Mitogen-activated protein kinases (MAPKs) have been the focus of many studies over the past several decades, but the understanding of one subgroup of MAPKs, orthologs of MAPK15, known as atypical MAPKs, has lagged behind others. In most organisms, specific activating signals or downstream responses of atypical MAPK signaling pathways have not yet been identified even though these MAPKs are associated with many eukaryotic processes, including cancer and embryonic development. In this Review, we discuss recent studies that are shedding new light on both the regulation and function of atypical MAPKs in different organisms. In particular, the analysis of the atypical MAPK in the amoeba Dictyostelium discoideum has revealed important roles in chemotactic responses and gene regulation. The rapid and transient phosphorylation of the atypical MAPK in these responses suggest a highly regulated activation mechanism in vivo despite the ability of atypical MAPKs to autophosphorylate in vitro. Atypical MAPK function can also impact the activation of other MAPKs in amoeba. These advances are providing new perspectives on possible MAPK roles in animals that have not been previously considered, and this might lead to the identification of potential targets for regulating cell movement in the treatment of diseases.


Morphine and HIV-Tat increase microglial-free radical production and oxidative stress: possible role in cytokine regulation.
Opiate abuse alters the progression of human immunodeficiency virus and may increase the risk of neuroAIDS. As neuroAIDS is associated with altered microglial reactivity, the combined effects of human immunodeficiency virus-Tat and morphine were determined in cultured microglia. Specifically, experiments determined the effects of Tat and morphine on microglial-free radical production and oxidative stress, and on cytokine release. Data show that combined Tat and morphine cause early and synergistic increases in reactive oxygen species, with concomitant increases in protein oxidation. Furthermore, combined Tat and morphine, but not Tat or morphine alone, cause reversible decreases in proteasome activity. The effects of morphine on free radical production and oxidative stress are prevented by pre-treatment with naloxone, illustrating the important role of opioid receptor activation in these phenomena. While Tat is well known to induce cytokine release from cultured microglia, morphine decreases Tat-induced release of the cytokines tumor necrosis factor-alpha and interleukin-6, as well as the chemokine monocyte chemoattractant protein-1 (MCP-1). Finally, experiments using the reversible proteasome inhibitor MG115 show that temporary, non-cytotoxic decreases in proteasome activity increase protein oxidation and decrease tumor necrosis factor-alpha, interleukin-6, and MCP-1 release from microglia. Taken together, these data suggest that oxidative stress and proteasome inhibition may be involved in the immunomodulatory properties of opioid receptor activation in microglia.


Genome-Wide Identification of the PP2C Gene Family and Analyses with Their Expression Profiling in Response to Cold Stress in Wild Sugarcane.
Type 2C protein phosphatases (PP2Cs) represent a major group of protein phosphatases in plants, some of which have already been confirmed to play important roles in diverse plant processes. In this study, analyses of the phylogenetics, gene structure, protein domain, chromosome localization, and collinearity, as well as an identification of the expression profile, protein-protein interaction, and subcellular location, were carried out on the PP2C family in wild sugarcane (Saccharum spontaneum). The results showed that 145 PP2C proteins were classified into 13 clades. Phylogenetic analysis suggested that SsPP2Cs are evolutionarily closer to those of sorghum, and the number of SsPP2Cs is the highest. There were 124 pairs of SsPP2C genes expanding via segmental duplications. Half of the SsPP2C proteins were predicted to be localized in the chloroplast (73), with the next most common predicted localizations being in the cytoplasm (37) and nucleus (17). Analysis of the promoter revealed that SsPP2Cs might be photosensitive, responsive to abiotic stresses, and hormone-stimulated. A total of 27 SsPP2Cs showed cold-stress-induced expressions, and SsPP2C27 (Sspon.01G0007840-2D) and SsPP2C64 (Sspon.03G0002800-3D) were the potential hubs involved in ABA signal transduction. Our study presents a comprehensive analysis of the SsPP2C gene family, which can play a vital role in the further study of phosphatases in wild sugarcane. The results suggest that the PP2C family is evolutionarily conserved, and that it functions in various developmental processes in wild sugarcane.


Ferric carboxymaltose: a review of its use in iron deficiency.
Ferric carboxymaltose (Ferinject(®), Injectafer(®)) is an intravenous iron preparation approved in numerous countries for the treatment of iron deficiency. A single high dose of ferric carboxymaltose (up to 750 mg of iron in the US and 1,000 mg of iron in the EU) can be infused in a short time frame (15 min). Consequently, fewer doses of ferric carboxymaltose may be needed to replenish iron stores compared with some other intravenous iron preparations (e.g. iron sucrose). Ferric carboxymaltose improved self-reported patient global assessment, New York Heart Association functional class and exercise capacity in patients with chronic heart failure and iron deficiency in two randomized, placebo-controlled trials (FAIR-HF and CONFIRM-HF). In other randomized controlled trials, ferric carboxymaltose replenished iron stores and corrected anaemia in various populations with iron-deficiency anaemia, including patients with chronic kidney disease, inflammatory bowel disease or heavy uterine bleeding, postpartum iron-deficiency anaemia and perioperative anaemia. Intravenous ferric carboxymaltose was generally well tolerated, with a low risk of hypersensitivity reactions. It was generally better tolerated than oral ferrous sulfate, mainly reflecting a lower incidence of gastrointestinal adverse effects. The most common laboratory abnormality seen in ferric carboxymaltose recipients was transient, asymptomatic hypophosphataemia. The higher acquisition cost of ferric carboxymaltose appeared to be offset by lower costs for other items, with the potential for cost savings. In conclusion, ferric carboxymaltose is an important option for the treatment of iron deficiency.


Controlling the Interfacial Environment in the Electrosynthesis of MnOx Nanostructures for High-Performance Oxygen Reduction/Evolution Electrocatalysis.
High-performance, nonprecious metal bifunctional electrocatalysts for the oxygen reduction and evolution reactions (ORR and OER, respectively) are of great importance for rechargeable metal-air batteries and regenerative fuel cells. A comprehensive study based on statistical design of experiments is presented to investigate and optimize the surfactant-assisted structure and the resultant bifunctional ORR/OER activity of anodically deposited manganese oxide (MnOx) catalysts. Three classes of surfactants are studied: anionic (sodium dodecyl sulfate, SDS), non-ionic (t-octylphenoxypolyethoxyethanol, Triton X-100), and cationic (cetyltrimethylammonium bromide, CTAB). The adsorption of surfactants has two main effects: increased deposition current density due to higher Mn2+ and Mn3+ concentrations at the outer Helmholtz plane (Frumkin effect on the electrodeposition kinetics) and templating of the MnOx nanostructure. CTAB produces MnOx with nanoneedle (1D) morphology, whereas nanospherical- and nanopetal-like morphologies are obtained with SDS and Triton, respectively. The bifunctional performance is assessed based on three criteria: OER/ORR onset potential window (defined at 2 and -2 mA cm-2) and separately the ORR and OER mass activities. The best compromise among these three criteria is obtained either with Triton X-100 deposited catalyst composed of MnOOH and Mn3O4 or SDS deposited catalyst containing a combination of α- and β-MnO2, MnOOH, and Mn3O4.The interaction effects among the deposition variables (surfactant type and concentration, anode potential, Mn2+ concentration, and temperature) reveal the optimal strategy for high-activity bifunctional MnOx catalyst synthesis. Mass activities for OER and ORR up to 49 A g-1 (at 1556 mVRHE) and -1.36 A g-1 (at 656 mVRHE) are obtained, respectively.


Effect of O6-benzylguanine on the sensitivity of human colon tumor xenografts to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU).
A number of trials were conducted to determine the effect of O6-benzylguanine pretreatment on the sensitivity of human colon tumor xenografts to the antitumor effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). O6-Benzylguanine has been shown to inactivate the DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT), which is primarily responsible for resistance to alkylnitrosoureas including BCNU. Colon tumor xenografts carried in nude mice were analyzed for their AGT content, and tumors with low, intermediate and high levels were chosen for further study. The AGT activity of HC-1, GC-3, VRC-5 and CX-1 human colon tumor xenografts was 16, 113, 180 and 367 fmol/mg protein, respectively. Treatment of mice consisted of vehicle alone, 6.25 to 50 mg/kg BCNU administered alone or BCNU (6.25 to 25 mg/kg) 1 hr after 120 mg/kg O6-benzylguanine on days 7 and 14 post-inoculation. Toxicity studies revealed that pretreatment with O6-benzylguanine increased the toxicity of BCNU, requiring administration of about 4-fold less drug. The growth of the VRC-5 tumor at day 42 post-inoculation was inhibited by 39% following treatment with 12.5 mg/kg BCNU alone and 92% when BCNU was combined with O6-benzylguanine pretreatment. The combination of O6-benzylguanine and BCNU (12.5 mg/kg) at day 42 resulted in an inhibition of HC-1 and CX-1 tumor growth by 84 and 72%, whereas BCNU alone inhibited growth by 54 and 14%, respectively. Therefore, the degree to which the antitumor effect of BCNU was increased by O6-benzylguanine pretreatment was dependent on the AGT activity, with a greater effect in tumors of intermediate or high activity. These data suggest that there is a role for O6-benzylguanine combined with BCNU in the treatment of human colon tumors.


Toxicity evaluation of pesticide chlorpyrifos in male Japanese quails (Coturnix japonica).
In the current study, chlorpyrifos was used as a test chemical to evaluate its possible toxicological effect on birds. A total of 45 adult male Japanese quails were divided into five groups (A to E). Each group, containing 9 birds was further divided into 3 sub-groups (containing 3 birds each). Group A served as control, while all other groups and sub-groups were exposed to selected pesticide for different trial periods. Chlorpyrifos sub-lethal doses were orally administered daily at the rate of 3, 6, 9, and 12 mg/kg body weight per day to group B, C, D, and E, respectively. Birds were kept under observation for behavioral changes throughout the trial periods. Clinical signs, histological alterations, genotoxicity, and blood biochemical alterations were recorded after each 15-day trial. Mild to moderate clinical signs like staggering gait, tremors, diarrhea, dullness, less frequency of crowing, and decrease foam production were observed in group D and E throughout the study. The changes in the body weight gain and blood biochemical parameters among different groups at a given trial period were insignificant. The appearance of micronuclei in group E birds was more significant, indicating that nucleus damage was dose-dependent while to lesser extent duration-dependent. The comet assay showed significant dose- and duration-dependent DNA damage among various groups. In comparison with control group, extensive histological degenerative alterations in the liver, testes, and kidneys were observed in birds of group D and E, where mild to severe alteration like congestion, vacuolation, necrosis, apoptosis, karyopyknosis, extensive degeneration, and alteration in many cellular structures were noticeable.


Halogen-bonded adduct of 1,2-dibromo-1,1,2,2-tetrafluoroethane and 1,4-diazabicyclo[2.2.2]octane.
Halogen bonding is an intermolecular interaction capable of being used to direct extended structures. Typical halogen-bonding systems involve a noncovalent interaction between a Lewis base, such as an amine, as an acceptor and a halogen atom of a halofluorocarbon as a donor. Vapour-phase diffusion of 1,4-diazabicyclo[2.2.2]octane (DABCO) with 1,2-dibromotetrafluoroethane results in crystals of the 1:1 adduct, C2Br2F4·C6H12N2, which crystallizes as an infinite one-dimensional polymeric structure linked by intermolecular N...Br halogen bonds [2.829 (3) Å], which are 0.57 Å shorter than the sum of the van der Waals radii.


Immune therapy for nonalcoholic steatohepatitis: are we there yet?
Metabolic syndrome, obesity, and nonalcoholic steatohepatitis are associated with a state of chronic inflammation. The immune system and the inflammatory cascade can be involved in the development of any of the above common conditions. This association raises the question of whether immune therapy can be used for the treatment of nonalcoholic steatohepatitis. Although immune therapy is not yet feasible for clinical use, here, we review some of the recent data on the potential role of the various arms of the immune system in the development of nonalcoholic steatohepatitis and several potential therapeutic targets.


Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa.
Mutations in pre-mRNA processing factors (PRPFs) cause autosomal-dominant retinitis pigmentosa (RP), but it is unclear why mutations in ubiquitously expressed genes cause non-syndromic retinal disease. Here, we generate transcriptome profiles from RP11 (PRPF31-mutated) patient-derived retinal organoids and retinal pigment epithelium (RPE), as well as Prpf31+/- mouse tissues, which revealed that disrupted alternative splicing occurred for specific splicing programmes. Mis-splicing of genes encoding pre-mRNA splicing proteins was limited to patient-specific retinal cells and Prpf31+/- mouse retinae and RPE. Mis-splicing of genes implicated in ciliogenesis and cellular adhesion was associated with severe RPE defects that include disrupted apical - basal polarity, reduced trans-epithelial resistance and phagocytic capacity, and decreased cilia length and incidence. Disrupted cilia morphology also occurred in patient-derived photoreceptors, associated with progressive degeneration and cellular stress. In situ gene editing of a pathogenic mutation rescued protein expression and key cellular phenotypes in RPE and photoreceptors, providing proof of concept for future therapeutic strategies.


Mercury in eggs of aquatic birds, Lake St. Clair--1973.
Eggs from four species of aquatic birds inhabiting waterways of the Lake St. Clair region were collected in 1973 and analyzed for mercury. Species analyzed were mallard ducks (Anas platyrhynchos), common terns (Sterna hirundo), black-crowned night herons (Nycticorax nycticorax), and great egrets (Casmerodius albus). Mallard eggs contained relatively low residue levels, less than 0.05-0.26 ppm, and common tern eggs contained the highest residues, ranging up to 1.31 ppm. Mercury levels in the eggs were appreciably lower than those in the same species in 1970. The declines are attributed to the 1970 restrictions placed on industrial discharges of mercury into the St. Clair and Detroit Rivers.


Berberine Improves Vascular Dysfunction by Inhibiting Trimethylamine-N-oxide via Regulating the Gut Microbiota in Angiotensin II-Induced Hypertensive Mice.
Berberine (BBR) has been demonstrated to exert cardiovascular protective effects by regulating gut microbiota. However, few studies examine the effect of BBR on the gut microbiota in hypertension. This study aims to investigate the role of BBR in regulating microbial alterations and vascular function in hypertension. C57BL/6 J mice were infused with Ang II (0.8 mg/kg/day) via osmotic minipumps and treated with BBR (150 mg/kg/day) or choline (1%) for 4 weeks. Blood pressure was detected by tail-cuff measurement once a week. Abdominal aorta pulse wave velocity (PWV) and endothelium dependent vasodilatation were measured to evaluate vascular function. Vascular remodeling was assessed by histological staining of aortic tissue. The fecal microbiota was profiled using 16S ribosomal DNA (rDNA) sequencing. Plasma trimethylamine (TMA)/trimethylamine-N-oxide (TMAO) and hepatic FMO3 expression were measured. We found that BBR treatment significantly alleviated the elevated blood pressure, vascular dysfunction, and pathological remodeling in Ang II-induced hypertensive mice, while choline treatment aggravated hypertension-related vascular dysfunction. 16S rDNA gene sequencing results showed that BBR treatment altered gut microbiota composition (reduced the Firmicutes/Bacteroidetes (F/B) ratio and increased the abundances of Lactobacillus). Moreover, BBR inhibited FMO3 expression and plasma TMA/TMAO production in hypertensive mice. TMAO treatment increased the apoptosis and oxidative stress of human aortic endothelial cells (HAECs) and aggravated Ang II-induced HAECs dysfunction in vitro. These results indicate that the protective effect of BBR in hypertension might be attributed (at least partially) to the inhibition of TMAO production via regulating the gut microbiota.


Epigenetic modifiers enhance the synergistic cytotoxicity of combined nucleoside analog-DNA alkylating agents in lymphoma cell lines.
Hematopoietic stem cell transplantation is used for treatment of lymphoma. In an attempt to design an efficacious and safe prehematopoietic stem cell transplantation conditioning regimen, we investigated the cytotoxicity of the combination of busulfan (B), melphalan (M), and gemcitabine (G) in lymphoma cell lines in the absence or presence of drugs that induce epigenetic changes. Cells were exposed to drugs individually or in combination and analyzed by the MTT proliferation assay, flow cytometry, and Western blotting. We used ~IC(10) drug concentrations (57 μM B, 1 μM M and 0.02 μM G), which individually did not have major effects on cell proliferation. Their combination resulted in 50% inhibition of proliferation. Reduction to almost half concentration (20 μM B, 0.7 μM M and 0.01 μM G) did not have significant effects, but addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (0.6 μM) to this combination resulted in a marked (~65%) growth inhibition. The cytotoxicity of these combinations correlates with the activation of the ataxia telangiectasia mutated-CHK2 pathway, phosphorylation of KRAB-associated protein-1, epigenetic changes such as methylation and acetylation of histone 3, and activation of apoptosis. The relevance of epigenetic changes is further shown by the induction of DNA methyltransferases in tumor cells with low constitutive levels of DNMT3A and DNMT3B. The addition of 5-aza-2'-deoxycytidine to (BMG+suberoylanilide hydroxamic acid) further enhances cell killing. Overall, BMG combinations are synergistically cytotoxic to lymphoma cells. Epigenetic changes induced by suberoylanilide hydroxamic acid and 5-aza-2'-deoxycytidine further enhance the cytotoxicity. This study provides a rationale for an ongoing clinical trial in our institution using (BMG+suberoylanilide hydroxamic acid) as pre-hematopoietic stem cell transplantation conditioning for lymphoma.


The lizard celestial compass detects linearly polarized light in the blue.
The present study first examined whether ruin lizards, Podarcis sicula, are able to orientate using plane-polarized light produced by an LCD screen. Ruin lizards were trained and tested indoors, inside a hexagonal Morris water maze positioned under an LCD screen producing white polarized light with a single E-vector, which provided an axial cue. White polarized light did not include wavelengths in the UV. Lizards orientated correctly either when tested with E-vector parallel to the training axis or after 90 deg rotation of the E-vector direction, thus validating the apparatus. Further experiments examined whether there is a preferential region of the light spectrum to perceive the E-vector direction of polarized light. For this purpose, lizards reaching learning criteria under white polarized light were subdivided into four experimental groups. Each group was tested for orientation under a different spectrum of plane-polarized light (red, green, cyan and blue) with equalized photon flux density. Lizards tested under blue polarized light orientated correctly, whereas lizards tested under red polarized light were completely disoriented. Green polarized light was barely discernible by lizards, and thus insufficient for a correct functioning of their compass. When exposed to cyan polarized light, lizard orientation performances were optimal, indistinguishable from lizards detecting blue polarized light. Overall, the present results demonstrate that perception of linear polarization in the blue is necessary - and sufficient - for a proper functioning of the sky polarization compass of ruin lizards. This may be adaptively important, as detection of polarized light in the blue improves functioning of the polarization compass under cloudy skies, i.e. when the alternative celestial compass based on detection of the sun disk is rendered useless because the sun is obscured by clouds.