[Neurofeedback for children with ADHD: a comparison of SCP- and theta/beta-protocols].
Research groups have consistently reported on behavioral and cognitive improvements of children with ADHD after neurofeedback. However, neurofeedback has not been commonly accepted as a treatment for ADHD. This is due, in part, to several methodological limitations. The neurofeedback literature is further complicated by having several different training protocols. Differences between the clinical efficacy of such protocols have not been examined. This study addresses previous methodological shortcomings while comparing the training of theta-beta-frequencies (theta-beta-group) with the training of slow cortical potentials (SCP-group). Each group comprised of 19 children with ADHD that were blind to group assignment. The training procedure consisted of 30 sessions and a six months follow-up training. Pre-/post measures at pretest, the end of the training and the follow-up included tests of attention, intelligence and behavioral variables. After having already reported intermediate data (Strehl et al. 2004), this paper gives account on final results: Both groups are able to voluntarily regulate cortical activity, with the extent of learned self-regulation depending on task and condition. Both groups improve in attention and IQ. Parents and teachers report significant behavioral and cognitive improvements. Clinical effects for both groups remain stable six months after training. Groups do not differ in behavioral or cognitive outcome variables.


Terpenoid trans-caryophyllene inhibits weed germination and induces plant water status alteration and oxidative damage in adult Arabidopsis.
trans-Caryophyllene (TC) is a sesquiterpene commonly found as volatile component in many different aromatic plants. Although the phytotoxic effects of trans-caryophyllene on seedling growth are relatively explored, not many information is available regarding the phytotoxicity of this sesquiterpenes on weed germination and on adult plants. The phytotoxic potential of TC was assayed in vitro on weed germination and seedling growth to validate its phytotoxic potential on weed species. Moreover, it was assayed on the metabolism of Arabidopsis thaliana adult plants, through two different application ways, spraying and watering, in order to establish the primary affected organ and to deal with the unknown mobility of the compound. The results clearly indicated that TC inhibited both seed germination and root growth, as demonstrated by comparison of the ED50 values. Moreover, although trans-caryophyllene-sprayed adult Arabidopsis plants did not show any effect, trans-caryophyllene-watered plants became strongly affected. The results suggested that root uptake was a key step for the effectiveness of this natural compound and its phytotoxicity on adult plants was mainly due to the alteration of plant water status accompanied by oxidative damage.


Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson's disease.
Parkinson's disease is characterized by the loss of midbrain dopamine neurons that innervate the caudate and the putamen. Studies in animals suggest that fetal dopaminergic neurons can survive transplantation and restore neurologic function. This report compares the clinical results in four case patients with severe Parkinson's disease who underwent stereotaxic implantation of human fetal ventral mesencephalic tissue in one caudate nucleus with the results in a control group of similar subjects assigned at random to a one-year delay in surgery. Each case patient received cryopreserved tissue from one fetal cadaver (gestational age, 7 to 11 weeks). Before implantation, adjacent midbrain tissue underwent microbiologic, biochemical, and viability testing. Cyclosporine was administered for six months postoperatively. The procedure was well tolerated. Three case patients showed bilateral improvement on motor tasks, as assessed on videotape, and were more functional in the activities of daily living, as assessed by themselves and neurologists, during both optimal drug therapy and "drug holiday" periods. One case patient, who died after four months from continued disease progression, had striatonigral degeneration at autopsy. In the patients who received transplants, optimal control was achieved with a lower dose of antiparkinsonian medications, whereas the controls required more medication. Positron-emission tomography with [18F]fluorodopa before and after surgery in one patient revealed a bilateral restoration of caudate dopamine synthesis to the range of normal controls, but continued bilateral deficits in the putamen. Although the case patients continued to be disabled by their disease, unilateral intracaudate grafts of fetal tissue containing dopamine diminished the symptoms and signs of parkinsonism during 18 months of evaluation.


Dietary Isomers of Sialyllactose Increase Ganglioside Sialic Acid Concentrations in the Corpus Callosum and Cerebellum and Modulate the Colonic Microbiota of Formula-Fed Piglets.
Sialyllactose is a key human milk oligosaccharide and consists of sialic acid (SA) bound to a lactose molecule. Breastfed infants have increased accumulation of ganglioside-bound SA compared with formula-fed infants. This study aimed to determine whether different isomers of sialyllactose enrich brain SA and modulate the microbiome of developing neonatal piglets. Day-old pigs were randomly allocated to 6 diets (control, 2 or 4 g 3'-sialyllactose/L, 2 or 4 g 6'-sialyllactose/L, or 2 g polydextrose/L + 2 g galacto-oligosaccharides/L; n = 9) and fed 3 times/d for 21 d. Pigs were killed, and the left hemisphere of the brain was dissected into cerebrum, cerebellum, corpus callosum, and hippocampus regions. SA was determined by using a modified periodic acid-resorcinol reaction. Microbial composition of the intestinal digesta was analyzed with the use of 16S ribosomal DNA Illumina sequencing. Dietary sialyllactose did not affect feed intake, growth, or fecal consistency. Ganglioside-bound SA in the corpus callosum of pigs fed 2 g 3'-sialyllactose or 6'-sialyllactose/L increased by 15% in comparison with control pigs. Similarly, ganglioside-bound SA in the cerebellum of pigs fed 4 g 3'-sialyllactose/L increased by 10% in comparison with control pigs. Significant (P < 0.05, Adonis Test) microbiome differences were observed in the proximal and distal colons of piglets fed control compared with 4-g 6'-sialyllactose/L formulas. Differences were attributed to an increase in bacterial taxa belonging to species Collinsella aerofaciens (phylum Actinobacteria), genera Ruminococcus and Faecalibacterium (phylum Firmicutes), and genus Prevotella (phylum Bacteroidetes) (Wald test, P < 0.05, DeSeq2) compared with piglets fed the control diet. Taxa belonging to families Enterobacteriaceae and Enterococcaceae (phylum Proteobacteria), as well as taxa belonging to family Lachnospiraceae and order Lactobacillales (phylum Firmicutes), were 2.3- and 4-fold lower, respectively, in 6'-sialyllactose-fed piglets than in controls. Supplementation of formula with 3'- or 6'-sialyllactose can enrich ganglioside SA in the brain and modulate gut-associated microbiota in neonatal pigs. We propose 2 potential routes by which sialyllactose may positively affect the neonate: serving as a source of SA for neurologic development and promoting beneficial microbiota.


Timing jitter reduction of passively mode-locked semiconductor lasers by self- and external-injection: numerical description and experiments.
In this paper the influence of different feedback (FB) and synchronization schemes on the timing phase noise (TPN) power spectral density (PSD) of a quantum-dot based passively mode-locked laser (MLL) is studied numerically and by experiments. The range of investigated schemes cover hybrid mode-locking, an opto-electrical feedback configuration, an all-optical feedback configuration and optical pulse train injection configuration by means of a master MLL. The mechanism responsible for TPN PSD reduction in the case of FB is identified for the first time for monolithic passively MLL and relies on the effective interaction of the timing of the intra-cavity pulse and the time-delayed FB pulse or FB modulation together with an statistical averaging of the independent timing deviations of both. This mechanism is quantified by means of simulation results obtained by introducing an universal and versatile simple time-domain model.


Epidemic risk from friendship network data: an equivalence with a non-uniform sampling of contact networks.
Contacts between individuals play an important role in determining how infectious diseases spread. Various methods to gather data on such contacts co-exist, from surveys to wearable sensors. Comparisons of data obtained by different methods in the same context are however scarce, in particular with respect to their use in data-driven models of spreading processes. Here, we use a combined data set describing contacts registered by sensors and friendship relations in the same population to address this issue in a case study. We investigate if the use of the friendship network is equivalent to a sampling procedure performed on the sensor contact network with respect to the outcome of simulations of spreading processes: such an equivalence might indeed give hints on ways to compensate for the incompleteness of contact data deduced from surveys. We show that this is indeed the case for these data, for a specifically designed sampling procedure, in which respondents report their neighbors with a probability depending on their contact time. We study the impact of this specific sampling procedure on several data sets, discuss limitations of our approach and its possible applications in the use of data sets of various origins in data-driven simulations of epidemic processes.


Assessing occupational exposure to chemicals in an international epidemiological study of brain tumours.
The INTEROCC project is a multi-centre case-control study investigating the risk of developing brain cancer due to occupational chemical and electromagnetic field exposures. To estimate chemical exposures, the Finnish Job Exposure Matrix (FINJEM) was modified to improve its performance in the INTEROCC study and to address some of its limitations, resulting in the development of the INTEROCC JEM. An international team of occupational hygienists developed a crosswalk between the Finnish occupational codes used in FINJEM and the International Standard Classification of Occupations 1968 (ISCO68). For ISCO68 codes linked to multiple Finnish codes, weighted means of the exposure estimates were calculated. Similarly, multiple ISCO68 codes linked to a single Finnish code with evidence of heterogeneous exposure were refined. One of the key time periods in FINJEM (1960-1984) was split into two periods (1960-1974 and 1975-1984). Benzene exposure estimates in early periods were modified upwards. The internal consistency of hydrocarbon exposures and exposures to engine exhaust fumes was improved. Finally, exposure to polycyclic aromatic hydrocarbon and benzo(a)pyrene was modified to include the contribution from second-hand smoke. The crosswalk ensured that the FINJEM exposure estimates could be applied to the INTEROCC study subjects. The modifications generally resulted in an increased prevalence of exposure to chemical agents. This increased prevalence of exposure was not restricted to the lowest categories of cumulative exposure, but was seen across all levels for some agents. Although this work has produced a JEM with important improvements compared to FINJEM, further improvements are possible with the expansion of agents and additional external data.


Competitive Coadsorption Dynamics of Viruses and Dissolved Organic Matter to Positively Charged Sorbent Surfaces.
Adsorption onto solid-water interfaces is a key process governing the fate and transport of waterborne viruses. Although negatively charged viruses are known to extensively adsorb onto positively charged adsorbent surfaces, virus adsorption in such systems in the presence of negatively charged dissolved organic matter (DOM) as coadsorbate remains poorly studied and understood. This work provides a systematic assessment of the adsorption dynamics of negatively charged viruses (i.e., bacteriophages MS2, fr, GA, and Qβ) and polystyrene nanospheres onto a positively charged model sorbent surface in the presence of varying DOM concentrations. In all systems studied, DOM competitively suppressed the adsorption of the viruses and nanospheres onto the model surface. Electrostatic repulsion of the highly negatively charged MS2, fr, and the nanospheres impaired their adsorption onto DOM adlayers that formed during the coadsorption process. In contrast, the effect of competition on overall adsorption was attenuated for less-negatively charged GA and Qβ because these viruses also adsorbed onto DOM adlayer surfaces. Competition in MS2-DOM coadsorbate systems were accurately described by a random sequential adsorption model that explicitly accounts for the unfolding of adsorbed DOM. Consistent findings for viruses and nanospheres suggest that the coadsorbate effects described herein generally apply to systems containing negatively charged nanoparticles and DOM.


Electrophysiological correlates of remembering emotional pictures.
Extensive evidence shows that emotional events tend to be remembered in greater detail and with an enhanced sense of vividness compared to neutral events. The current study investigated the neural correlates of this phenomenon during retrieval using the event-related potentials technique (ERP). Participants were asked to perform a memory recognition test of previously studied ("Old") and unstudied ("New") emotional and neutral pictures encoded a week before the test session. Next, they were asked to perform a Remember-Know task (Gardiner and Java, 1993) for each "old" decision. ERPs were created for retrieval activity corresponding to six conditions: Remember-Emotional, Remember-Neutral, Know-Emotional, Know-Neutral, New-Emotional and New-Neutral. Results showed that negative emotion enhanced three distinct subtypes of the electrophysiological old-new effect specifically for old items associated with a "Remember" judgment. This effect was observed for ERP old-new effects conforming to an early frontal P2 old-new effect peaking at ~180 ms, a midfrontal old-new effect starting at ~300 ms (the "FN400") and a late positive complex (LPC) with parietal maxima observed at 500-700 ms. In addition, a breakdown of our data in different levels of emotional arousal revealed that the relationship between ERP correlates of retrieval and arousal conformed to a nonlinear, inverted U-shaped function for posterior late effects (500-700) and to a linear function for early effects (P2 and FN400). Taken together, these results suggest that multiple retrieval subprocesses contribute to the emotional enhancement of recollective experience.


Capillary electrophoresis with on-chip four-electrode capacitively coupled conductivity detection for application in bioanalysis.
Microchip capillary electrophoresis (CE) with integrated four-electrode capacitively coupled conductivity detection is presented. Conductivity detection is a universal detection technique that is relatively independent on the detection pathlength and, especially important for chip-based analysis, is compatible with miniaturization and on-chip integration. The glass microchip structure consists of a 6 cm etched channel (20 microm x 70 microm cross section) with silicon nitride covered walls. In the channel, a 30 nm thick silicon carbide layer covers the electrodes to enable capacitive coupling with the liquid inside the channel as well as to prevent interference of the applied separation field. The detector response was found to be linear over the concentration range from 20 microM up to 2 mM. Detection limits were at the low microM level. Separation of two short peptides with a pI of respectively 5.38 and 4.87 at the 1 mM level demonstrates the applicability for biochemical analysis. At a relatively low separation field strength (50 V/cm) plate numbers in the order of 3500 were achieved. Results obtained with the microdevice compared well with those obtained in a bench scale CE instrument using UV detection under similar conditions.


Chewing variation in lepidosaurs and primates.
Mammals chew more rhythmically than lepidosaurs. The research presented here evaluated possible reasons for this difference in relation to differences between lepidosaurs and mammals in sensorimotor systems. Variance in the absolute and relative durations of the phases of the gape cycle was calculated from kinematic data from four species of primates and eight species of lepidosaurs. The primates exhibit less variance in the duration of the gape cycle than in the durations of the four phases making up the gape cycle. This suggests that increases in the durations of some gape cycle phases are accompanied by decreases in others. Similar effects are much less pronounced in the lepidosaurs. In addition, the primates show isometric changes in gape cycle phase durations, i.e. the relative durations of the phases of the gape cycle change little with increasing cycle time. In contrast, in the lepidosaurs variance in total gape cycle duration is associated with increases in the proportion of the cycle made up by the slow open phase. We hypothesize that in mammals the central nervous system includes a representation of the optimal chew cycle duration maintained using afferent feedback about the ongoing state of the chew cycle. The differences between lepidosaurs and primates do not lie in the nature of the sensory information collected and its feedback to the feeding system, but rather the processing of that information by the CNS and its use feed-forward for modulating jaw movements and gape cycle phase durations during chewing.


Kinetic modeling and exploratory numerical simulation of chloroplastic starch degradation.
Higher plants and algae are able to fix atmospheric carbon dioxide through photosynthesis and store this fixed carbon in large quantities as starch, which can be hydrolyzed into sugars serving as feedstock for fermentation to biofuels and precursors. Rational engineering of carbon flow in plant cells requires a greater understanding of how starch breakdown fluxes respond to variations in enzyme concentrations, kinetic parameters, and metabolite concentrations. We have therefore developed and simulated a detailed kinetic ordinary differential equation model of the degradation pathways for starch synthesized in plants and green algae, which to our knowledge is the most complete such model reported to date. Simulation with 9 internal metabolites and 8 external metabolites, the concentrations of the latter fixed at reasonable biochemical values, leads to a single reference solution showing β-amylase activity to be the rate-limiting step in carbon flow from starch degradation. Additionally, the response coefficients for stromal glucose to the glucose transporter k(cat) and KM are substantial, whereas those for cytosolic glucose are not, consistent with a kinetic bottleneck due to transport. Response coefficient norms show stromal maltopentaose and cytosolic glucosylated arabinogalactan to be the most and least globally sensitive metabolites, respectively, and β-amylase k(cat) and KM for starch to be the kinetic parameters with the largest aggregate effect on metabolite concentrations as a whole. The latter kinetic parameters, together with those for glucose transport, have the greatest effect on stromal glucose, which is a precursor for biofuel synthetic pathways. Exploration of the steady-state solution space with respect to concentrations of 6 external metabolites and 8 dynamic metabolite concentrations show that stromal metabolism is strongly coupled to starch levels, and that transport between compartments serves to lower coupling between metabolic subsystems in different compartments. We find that in the reference steady state, starch cleavage is the most significant determinant of carbon flux, with turnover of oligosaccharides playing a secondary role. Independence of stationary point with respect to initial dynamic variable values confirms a unique stationary point in the phase space of dynamically varying concentrations of the model network. Stromal maltooligosaccharide metabolism was highly coupled to the available starch concentration. From the most highly converged trajectories, distances between unique fixed points of phase spaces show that cytosolic maltose levels depend on the total concentrations of arabinogalactan and glucose present in the cytosol. In addition, cellular compartmentalization serves to dampen much, but not all, of the effects of one subnetwork on another, such that kinetic modeling of single compartments would likely capture most dynamics that are fast on the timescale of the transport reactions.


Keratin-dependent regulation of Aire and gene expression in skin tumor keratinocytes.
Expression of the intermediate filament protein keratin 17 (K17) is robustly upregulated in inflammatory skin diseases and in many tumors originating in stratified and pseudostratified epithelia. We report that autoimmune regulator (Aire), a transcriptional regulator, is inducibly expressed in human and mouse tumor keratinocytes in a K17-dependent manner and is required for timely onset of Gli2-induced skin tumorigenesis in mice. The induction of Aire mRNA in keratinocytes depends on a functional interaction between K17 and the heterogeneous nuclear ribonucleoprotein hnRNP K. Further, K17 colocalizes with Aire protein in the nucleus of tumor-prone keratinocytes, and each factor is bound to a specific promoter region featuring an NF-κB consensus sequence in a relevant subset of K17- and Aire-dependent proinflammatory genes. These findings provide radically new insight into keratin intermediate filament and Aire function, along with a molecular basis for the K17-dependent amplification of inflammatory and immune responses in diseased epithelia.


Simvastatin Sensitizes Radioresistant Prostate Cancer Cells by Compromising DNA Double-Strand Break Repair.
Prostate cancer (PCa) is one of the most prevalent male cancers in western world. Radiation therapy (RT) is commonly used to treat PCa patients. However, a certain proportion of patients develop radioresistant PCa cells, which results in metastatic disease. Statins, which inhibit 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, are commonly used to treat hypercholesterolemia, exhibiting beneficial effects on cardiovascular diseases and on several types of cancers, including PCa. However, the mechanistic details and crosstalk between statins and RT in PCa cells remain unknown. In this study, radioresistant DOC-2/DAB2 interactive protein (DAB2IP)-deficient PCa cells were used to evaluate whether simvastatin could enhance the effect of ionizing radiation (IR). The crucial molecules that associated with simvastatin elevated radiosensitivity in PCa cells were explored. Our results demonstrated that a combination treatment with simvastatin and IR synergistically induced apoptosis of radioresistant PCa cells. In addition, simvastatin appeared to compromise DNA double-strand breaks repair by activating the expressions of histone 2A family member X (γ-H2AX) and phospho-checkpoint kinase 1 (p-CHK1), suggesting an underlying mechanism for this radiosensitization of PCa cells. These findings reveal that simvastatin may be a potent therapeutic agent for co-treatment with radiation to overcome radioresistance in PCa cells.


Synthetic antibodies against BRIL as universal fiducial marks for single-particle cryoEM structure determination of membrane proteins.
We propose the concept of universal fiducials based on a set of pre-made semi-synthetic antibodies (sABs) generated by customized phage display selections against the fusion protein BRIL, an engineered variant of apocytochrome b562a. These sABs can bind to BRIL fused either into the loops or termini of different GPCRs, ion channels, receptors and transporters without disrupting their structure. A crystal structure of BRIL in complex with an affinity-matured sAB (BAG2) that bound to all systems tested delineates the footprint of interaction. Negative stain and cryoEM data of several examples of BRIL-membrane protein chimera highlight the effectiveness of the sABs as universal fiducial marks. Taken together with a cryoEM structure of sAB bound human nicotinic acetylcholine receptor, this work demonstrates that these anti-BRIL sABs can greatly enhance the particle properties leading to improved cryoEM outcomes, especially for challenging membrane proteins.


Delayed alveolar clearance of nanoparticles through control of coating composition and interaction with lung surfactant protein A.
The coating composition of nanomedicines is one of the main features in determining the medicines' fate, clearance, and immunoresponse in the body. To highlight the coatings' impact in pulmonary administration, two micellar superparamagnetic iron oxide nanoparticles (SPION) were compared. These nanoparticles are similar in size and charge but have different coatings: either phosphatidylcholine (PC-SPION) or bovine serum albumin (BSA-SPION). The aim of the study was to increase the understanding of the nano-bio interaction with the cellular and non-cellular components of the lung and underline valuable coatings either for local lung-targeted drug delivery in theranostic application or patient-friendly route systemic administration. PC-SPION and BSA-SPION were deposited in the alveoli by in vivo instillation and, despite the complexity of imaging the lung, SPION were macroscopically visualized by MRI. Impressively, PC-SPION were retained within the lungs for at least a week, while BSA-SPION were cleared more rapidly. The different lung residence times were confirmed by histological analysis and supported by a flow cytometry analysis of the SPION interactions with different myeloid cell populations. To further comprehend the way in which these nanoformulations interact with lung components at the molecular level, we used fluorescence spectroscopy, turbidity measurements, and dynamic light scattering to evaluate the interactions of the two SPION with surfactant protein A (SP-A), a key protein in setting up the nanoparticle behavior in the alveolar fluid. We found that SP-A induced aggregation of PC-SPION, but not BSA-SPION, which likely caused PC-SPION retention in the lung without inducing inflammation. In conclusion, the two SPION show different outcomes from interaction with SP-A leading to distinctive fate in the lung. PC-SPION hold great promise as imaging and theranostic agents when prolonged pulmonary drug delivery is required.


Biochemical and pharmacological characterization of a toxic fraction and its cytotoxin-like component isolated from Russell's viper (Daboia russelii russelii) venom.
The pathophysiological significance of a toxic fraction (GF-VI DEAE-II) isolated from Russell's viper venom (RVV) is characterized. GF-VI DEAE-II represents 1.6% of the total RVV protein and it comprises of a 27.6kDa minor component (RP-I) (0.04%, w/w) and a major 6.6kDa non-enzymatic peptide (1.11%, w/w), named Rusvitoxin. The LC-MS/MS analysis of RP-I showed its identity to snake venom serine proteases, whereas Rusvitoxin demonstrated its close identity with snake venom three finger toxins, cytotoxins and cardiotoxins particularly from Naja sp. GF-VI DEAE-II was found to be non-cytotoxic to the tested mammalian cancer cells and non-hemolytic; nevertheless, it demonstrated α-fibrin(ogen)ase activity and in vivo toxicity in BALB/c mice with an LD50 (i.p.) of 2.3mg/kg. GF-VI DEAE-II induced lethargy and hind-leg paralysis in mice within 10min of i.p. injection. GF-VI DEAE-II induced hyperfibrinogenomia, and significantly altered (p<0.05) the plasma levels of factor X, pro- and anti-inflammatory cytokines viz. TNF-α, IL-6 and IL-10 in treated mice. Histological observations of tissues and biochemical properties of serum from GF-VI DEAE-II-treated mice suggested multiple organ dysfunctions. Conversely, Rusvitoxin at a dose of 5mg/kg did not induce toxicity in BALB/c mice. At 1:15 (antigen: antivenom, w/w) ratio, commercially polyvalent and monovalent antivenoms neutralized more than 80% of the fibrinolytic and anticoagulant activities of GF-VI DEAE-II. The present study suggests the significant role of GF-VI DEAE-II in RVV-induced pathogenesis in victim/prey.


Integration of depth modules: stereopsis and texture.
Global shape judgements were employed to examine the combination of stereopsis and shape-from-texture in the determination of three-dimensional shape. Adding textural variations to stereograms increased perceived depth. Thus, texture was not simply vetoed by the strong stereo cue. In experiments where the depth specified by texture was incongruent with that specified by stereo, the data were well described by a weighted linear combination rule. Although only a small weight was assigned to texture, this weight was somewhat greater at a farther viewing distance. This could be a consequence of the decreased reliability of stereopsis at far viewing distances.


Real-life interactions and the eight sources of information framework (8-SIF): a reply to Champagne-Lavau and Moreau (2013).
In this response to the comment by Champagne-Lavau and Moreau (2013), we acknowledge the importance of ecological mentalizing assessments that allow direct interactions between the agent and the person to whom mental states are attributed. Furthermore, we clarify that our model, the 8 sources of information framework (8-SIF; Achim, Guitton, Jackson, Boutin, & Monetta, 2013), aims to document the sources of information on which mentalizing processes can act, rather than specifying the numerous affective and cognitive processes involved in mentalizing. We argue that the sources of information that can contribute to mentalizing judgments during real or realistic interactions are included in the 8-SIF. The interaction may have an impact on the amount of information from each source that is available to the agent, but gaining additional information from a given source does not change the type of information or its classification to a specific source in the 8-SIF. The point raised by Champagne-Lavau and Moreau calls for a new comprehensive model of social cognition that focuses on the mentalizing processes, which would nicely complement our model of the sources of information on which these processes can act, the 8-SIF.


Rectal 5-aminosalicylic acid for maintenance of remission in ulcerative colitis.
5-Aminosalicylic acid (5-ASA) is a first-line therapy for inducing and maintaining remission of mild and moderately active ulcerative colitis (UC). When the proximal margin of inflammation is distal to the splenic flexure, 5-ASA therapy can be delivered as a rectal suppository, foam or liquid enema. The primary objective was to assess the efficacy and safety of rectal 5-ASA for maintaining remission of distal UC. We searched MEDLINE (1966 to August 2012), the Cochrane Library (August 2012), abstracts from major gastroenterology meetings (1997-2011) and bibliographies of relevant publications to identify relevant studies. Eligible studies were randomized controlled trials comparing rectal 5-ASA to placebo or another active treatment for a minimum duration of six months. Symptom scores needed to be assessed in at least one study outcome. Patients had to be at least 12 years of age with disease extent less than 60 cm from the anal verge or distal to the splenic flexure, as determined by barium enema, colonoscopy or sigmoidoscopy. Patients were expected to be in remission prior to the treatment trial. Study eligibility was independently assessed by three authors. Data were extracted using standardized forms by two independent reviewers, with inter-rater agreement assessed using Cohen's Kappa and disagreements resolved by consensus. In cases where clarification of study results or methodology was needed, corresponding authors were contacted. The methodological quality of each trial was assessed by the Cochrane risk of bias tool and by a 30-point scale developed and used previously by the authors. Pooled risk ratios (RR) and corresponding 95% confidence intervals (CI) for continued clinical, endoscopic and histologic remission were estimated for comparisons between rectal 5-ASA and placebo or oral 5-ASA, and for comparisons among 5-ASA doses. Heterogeneity was assessed using the Chi(2) test and visual inspection of forest plots. If no significant heterogeneity was identified (P > 0.10 for Chi(2)) a fixed-effect model (Mantel-Haenstzel) was used. If heterogeneity was significant, a random-effects model was used. Nine studies (484 patients) met the pre-specified inclusion criteria (Kappa 1.00). Six studies were rated as low risk of bias. Three studies were rated as high risk of bias due to blinding (two open label and one single-blind). The total daily dose of rectal 5-ASA ranged from 0.5 g to 4 g, and dose frequency ranged from once to three times daily. 5-ASA was delivered as liquid enema in five studies or as a suppository in four studies. Follow-up ranged from 6 to 24 months. Rectal 5-ASA was significantly superior to placebo for maintenance of symptomatic remission over a period of 12 months.Sixty-two per cent of patients in the rectal 5-ASA group maintained symptomatic remission compared to 30% of patients in the placebo group (4 studies; 301 patients; RR 2.22, 95% CI 1.26 to 3.90; I(2) = 67%; P < 0.01). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome was low due to imprecision (i.e. sparse data 144 events) and inconsistency (i.e. unexplained heterogeneity). Rectal 5-ASA was significantly superior to placebo for maintenance of endoscopic remission over a 12 month period. Seventy-five per cent of patients in the rectal 5-ASA group maintained endoscopic remission compared to 15% of patients in the placebo group (1 study; 25 patients; RR 4.88, 95% CI 1.31 to 18.18; P < 0.05). There was no statistically significant difference in the proportion of patients who experienced at least one adverse event. Sixteen per cent of patients in the rectal 5-ASA group experienced at least one adverse compared to 12% of placebo patients (2 studies; 160 patients; RR 1.35, 95% CI 0.63 to 2.89; I(2) = 0%; P = 0.44). The most commonly reported adverse events were anal irritation and abdominal pain. No statistically significant differences between rectal and oral 5-ASA were identified for either symptomatic or endoscopic remission over a period of six months. Eighty per cent of patients in the rectal 5-ASA group maintained symptomatic remission compared to 65% of patients in the oral 5-ASA group (2 studies; 69 patients; RR 1.24, 95% CI 0.92 to 1.66; I(2) = 0%; P = 0.15). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome was low due to imprecision (i.e. sparse data 50 events) and high risk of bias (i.e. both studies in the pooled analysis were open label). Eighty per cent of patients in the rectal 5-ASA group maintained endoscopic remission compared to 70% of patients in the oral 5-ASA group (2 studies; 91 patients; RR 1.14, 95% CI 0.90 to 1.45; I(2) = 0%; P = 0.26). In two small trials, one comparing 2 g/day 5-ASA enemas to 4 g/day 5-ASA enemas and the other comparing 0.5 g/day 5-ASA suppositories to 1 g/day 5-ASA suppositories no dose response relationship was observed. The limited data available suggest that rectal 5-ASA is effective and safe for maintenance of remission of mild to moderately active distal UC. Well designed randomized trials are needed to establish the optimal dosing regimen for rectal 5-ASA, to compare rectal 5-ASA with rectal corticosteroids and to identify subgroups of patients who are more or less responsive to specific rectal 5-ASA regimens. The combination of oral and rectal 5-ASA appears to be more effective than either oral or rectal monotherapy for induction of remission. The efficacy of combination therapy for maintenance of remission has not been assessed and could be evaluated in future trials.


Optimization of Pumpkin Oil Recovery by Using Aqueous Enzymatic Extraction and Comparison of the Quality of the Obtained Oil with the Quality of Cold-Pressed Oil.
The study was carried out to optimize pumpkin oil recovery in the process of aqueous extraction preceded by enzymatic maceration of seeds, as well as to compare the quality of the obtained oil to the quality of cold-pressed pumpkin seed oil. Hydrated pulp of hulless pumpkin seeds was macerated using a 2% (by mass) cocktail of commercial pectinolytic, cellulolytic and proteolytic preparations (Rohapect® UF, Rohament® CL and Colorase® 7089). The optimization procedure utilized response surface methodology based on Box- -Behnken plan of experiment. The optimized variables of enzymatic pretreatment were pH, temperature and maceration time. The results showed that the pH value, temperature and maceration time of 4.7, 54 °C and 15.4 h, respectively, were conducive to maximize the oil yield up to 72.64%. Among these variables, the impact of pH was crucial (above 73% of determined variation) for oil recovery results. The oil obtained by aqueous enzymatic extraction was richer in sterols, squalene and tocopherols, and only slightly less abundant in carotenoids than the cold-pressed one. However, it had a lower oxidative stability, with induction period shortened by approx. 30% in relation to the cold-pressed oil.


Alpha interferon: progress and perspectives in the biotherapy of chronic myelogenous leukemia.
Chronic myelogenous leukemia is a myeloproliferative disorder representing 20%-30% of all leukemias. The disease is characterized by a cytogenetic abnormality called the Philadelphia chromosome. Except in patients who have undergone bone marrow transplantation (BMT), the natural history of chronic myelogenous leukemia has not changed in the last 30 years. Recombinant interferon alpha controls thrombocytosis and leukocytosis, reduces the leukemic infiltrate in the bone marrow, returns the spleen size to normal, and converts some patients to a normal chromosome pattern. This review summarizes the clinical and cytogenetic responses to date. The most significant observation is that, aside from treatment with BMT, interferon is the only agent that induces cytogenetic remissions.


Impact of biocontrol Pseudomonas fluorescens CHA0 and a genetically modified derivative on the diversity of culturable fungi in the cucumber rhizosphere.
Little is known about the effects of Pseudomonas biocontrol inoculants on nontarget rhizosphere fungi. This issue was addressed using the biocontrol agent Pseudomonas fluorescens CHA0-Rif, which produces the antimicrobial polyketides 2,4-diacetylphloroglucinol (Phl) and pyoluteorin (Plt) and protects cucumber from several fungal pathogens, including Pythium spp., as well as the genetically modified derivative CHA0-Rif(pME3424). Strain CHA0-Rif(pME3424) overproduces Phl and Plt and displays improved biocontrol efficacy compared with CHA0-Rif. Cucumber was grown repeatedly in the same soil, which was left uninoculated, was inoculated with CHA0-Rif or CHA0-Rif(pME3424), or was treated with the fungicide metalaxyl (Ridomil). Treatments were applied to soil at the start of each 32-day-long cucumber growth cycle, and their effects on the diversity of the rhizosphere populations of culturable fungi were assessed at the end of the first and fifth cycles. Over 11,000 colonies were studied and assigned to 105 fungal species (plus several sterile morphotypes). The most frequently isolated fungal species (mainly belonging to the genera Paecilomyces, Phialocephala, Fusarium, Gliocladium, Penicillium, Mortierella, Verticillium, Trichoderma, Staphylotrichum, Coniothyrium, Cylindrocarpon, Myrothecium, and Monocillium) were common in the four treatments, and no fungal species was totally suppressed or found exclusively following one particular treatment. However, in each of the two growth cycles studied, significant differences were found between treatments (e.g., between the control and the other treatments and/or between the two inoculation treatments) using discriminant analysis. Despite these differences in the composition and/or relative abundance of species in the fungal community, treatments had no effect on species diversity indices, and species abundance distributions fit the truncated lognormal function in most cases. In addition, the impact of treatments at the 32-day mark of either growth cycle was smaller than the effect of growing cucumber repeatedly in the same soil.


White Book on Physical and Rehabilitation Medicine in Europe. Introductions, Executive Summary, and Methodology.
The White Book (WB) of Physical and Rehabilitation Medicine (PRM) in Europe is produced by the 4 European PRM Bodies (European Academy of Rehabilitation Medicine - EARM, European Society of PRM - ESPRM, European Union of Medical Specialists - PRM Section, European College of PRM-ECPRM served by the European Union of Medical Specialists-PRM Board) and constitutes the reference book for PRM physicians in Europe. It has now reached its third edition; the first was published in 1989 and the second in 2006/2007. The WB has multiple purposes, including providing a unifying framework for European countries, to inform decision-makers on European and national level, to offer educational material for PRM trainees and physicians and information about PRM to the medical community, other rehabilitation professionals and the public. The WB states the importance of PRM, a primary medical specialty that is present all over Europe, with a specific corpus disciplinae, a common background and history throughout Europe. PRM is internationally recognized and a partner of major international bodies, including the World Health Organization (WHO). PRM activities are strongly based on the documents of the United Nations (UN) and WHO, such as the Convention of the Rights of Persons with Disabilities (2006), the World Report on Disability (2011), the WHO Global Disability Action Plan 2014-2021 (2014) and the WHO initiative "Rehabilitation 2030: a call for action" (2017). The WB is organized in 4 sections, 11 chapters and some appendices. The WB starts with basic definitions and concepts of PRM and continues with why rehabilitation is needed by individuals and society. Rehabilitation focuses not only on health conditions but also on functioning. Accordingly, PRM is the medical specialty that strives to improve functioning of people with a health condition or experiencing disability. The fundamentals of PRM, the history of the PRM specialty, and the structure and activities of PRM organizations in Europe are presented, followed by a thorough presentation of the practice of PRM, i.e. knowledge and skills of PRM physicians, the clinical field of competence of PRM, the place of the PRM specialty in the healthcare system and society, education and continuous professional development of PRM physicians, specificities and challenges of science and research in PRM. The WB concludes with the way forward for the specialty: challenges and perspectives for the future of PRM.


Legal considerations for nurses practicing in a telehealth setting.
During the last century the world has become increasingly reliant on a variety of technologies to manage information needs. Escalation in deployment of remote technology to enhance health care, accompanied by expanded public and private reimbursement for distant care, indicates increasing acceptance of these technologies. Yet many legal and regulatory questions regarding the provision of health care using these technologies remain. This article will discuss the foundations of telehealth nursing and address legal and regulatory issues emerging from this new practice modality.


Cinnamaldehyde--a potential antidiabetic agent.
Cinnamonum zeylanicum (cinnamon) is widely used in traditional system of medicine to treat diabetes in India. The present study was carried out to isolate and identify the putative antidiabetic compounds based on bioassay-guided fractionation; the compound identified decreased the plasma glucose levels. The active compound was purified by repeat column and structure of cinnamaldehyde was determined on the basis of chemical and physiochemical evidence. The LD(50) value of cinnamaldehyde was determined as 1850+/-37 mg/kg bw. Cinnamaldehyde was administered at different doses (5, 10 and 20 mg/kg bw) for 45 days to streptozotocin (STZ) (60 mg/kg bw)-induced male diabetic wistar rats. It was found that plasma glucose concentration was significantly (p<0.05) decreased in a dose-dependent manner (63.29%) compared to the control. In addition, oral administration of cinnamaldehyde (20 mg/kg bw) significantly decreased glycosylated hemoglobin (HbA(1C)), serum total cholesterol, triglyceride levels and at the same time markedly increased plasma insulin, hepatic glycogen and high-density lipoprotein-cholesterol levels. Also cinnamaldehyde restored the altered plasma enzyme (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase and acid phosphatase) levels to near normal. Administration of glibenclamide, a reference drug (0.6 mg/kg bw) also produced a significant (p<0.05) reduction in blood glucose concentration in STZ-induced diabetic rats. The results of this experimental study indicate that cinnamaldehyde possesses hypoglycemic and hypolipidemic effects in STZ-induced diabetic rats.


A comparison of Internet and print-based physical activity interventions.
Physical activity interventions tailored to individual characteristics and delivered via print produce greater increases in activity compared with nontailored interventions and controls. Using the Internet to deliver a tailored physical activity intervention offers an alternative to print that might be available to larger populations at a lower cost. Participants (N=249 adults; mean [SD] age, 44.5 [9.3] years; and mean [SD] body mass index [calculated as weight in kilograms divided by height in meters squared], 29.4 [6.1]) were randomized to 1 of 3 physical activity interventions: (1) motivationally tailored Internet (tailored Internet, n=81), (2) motivationally tailored print (tailored print, n=86); and (3) 6 researcher-selected Web sites available to the public (standard Internet, n=82). Participants in the tailored Internet and tailored print arms received the same tailored intervention content. Participants were assessed at baseline and at 6 and 12 months. At 6 months, participants in the tailored print arm reported a median of 112.5 minutes of physical activity per week, those in the tailored Internet arm reported 120.0 minutes, and those in the standard Internet arm reported 90.0 minutes (P=.15). At 12 months, the physical activity minutes per week were 90.0, 90.0, and 80.0 for those in the tailored print, tailored Internet, and standard Internet arms, respectively (P=.74). Results indicated no significant differences between the 3 arms. The use of tailored Internet, tailored print, and standard Internet as part of a behavior change program increased physical activity behavior similarly. Because the use of the Internet was not different from the print-based intervention, this may be an opportunity to reach more sedentary adults in a more cost-effective way. clinicaltrials.gov Identifier: NCT00200317.


ARTS 2.0: feature updates and expansion of the Antibiotic Resistant Target Seeker for comparative genome mining.
Multi-drug resistant pathogens have become a major threat to human health and new antibiotics are urgently needed. Most antibiotics are derived from secondary metabolites produced by bacteria. In order to avoid suicide, these bacteria usually encode resistance genes, in some cases within the biosynthetic gene cluster (BGC) of the respective antibiotic compound. Modern genome mining tools enable researchers to computationally detect and predict BGCs that encode the biosynthesis of secondary metabolites. The major challenge now is the prioritization of the most promising BGCs encoding antibiotics with novel modes of action. A recently developed target-directed genome mining approach allows researchers to predict the mode of action of the encoded compound of an uncharacterized BGC based on the presence of resistant target genes. In 2017, we introduced the 'Antibiotic Resistant Target Seeker' (ARTS). ARTS allows for specific and efficient genome mining for antibiotics with interesting and novel targets by rapidly linking housekeeping and known resistance genes to BGC proximity, duplication and horizontal gene transfer (HGT) events. Here, we present ARTS 2.0 available at http://arts.ziemertlab.com. ARTS 2.0 now includes options for automated target directed genome mining in all bacterial taxa as well as metagenomic data. Furthermore, it enables comparison of similar BGCs from different genomes and their putative resistance genes.


Clinical impact of Endoscopic Surgical Skill Qualification System (ESSQS) by Japan Society for Endoscopic Surgery (JSES) for laparoscopic distal gastrectomy and low anterior resection based on the National Clinical Database (NCD) registry.
This study aimed to evaluate the association between surgeons certified via the Endoscopic Surgical Skill Qualification System (ESSQS) of the Japan Society for Endoscopic Surgery (JSES) and surgical outcomes of laparoscopic distal gastrectomy (LDG) and laparoscopic low anterior resection (LLAR). Japanese National Clinical Database data on the patients undergoing LDG and LLAR between 2014-2016 were analyzed retrospectively. The proportion of cases performed by ESSQS-certified surgeons was calculated for each procedure, and clinicopathological factors with or without participation of ESSQS-certified surgeons as an operator were assessed. Then, effects of operations performed by ESSQS-certified surgeons on short-term patient outcomes were analyzed using generalized estimating equations logistic regression analysis. There were 110 610 and 65 717 patients who underwent LDG and LLAR, respectively. The operations performed by ESSQS-certified surgeons in each procedure totaled 28 467 (35.3%) and 12 866 (31.2%), respectively. A multivariable logistic regression model showed that odds ratios of mortality for LDG and LLAR performed by ESSQS-certified surgeons were 0.774 (95% CI, 0.566-1.060, P = 0.108) and 0.977 (0.591-1.301, P = 0.514), respectively. Odds ratios for secondary endpoints of anastomotic leakage in LDG and LLAR performed by ESSQS-certified surgeons were 0.835 (95% CI, 0.723-0.964, P = 0.014) and 0.929 (0.860-1.003, P = 0.059), respectively, whereas that of ileus/bowel obstruction for LLAR performed by ESSQS-certified surgeons was 1.265 (1.132-1.415, P < 0.001). There were no significant associations between the two operations performed by ESSQS-certified surgeons and other factors such as mortality and overall complications. ESSQS certification did not affect postoperative mortality following LDG and LLAR, but annual experience of laparoscopic surgery was associated with it. ESSQS certification may contribute to favorable outcomes regarding anastomotic leakage following LDG and LLAR.


Impact of feed restriction and housing hygiene conditions on specific and inflammatory immune response, the cecal bacterial community and the survival of young rabbits.
Limiting the post-weaning intake of the young rabbit is known to improve its resistance to digestive disorders, whereas a degradation of its housing hygiene is assumed to have a negative impact on its health. This study aims at providing insights into the mechanism of digestive health preservation regarding both host (growth and immune response) and its symbiotic digestive microbiota. A 2×2 factorial design from weaning (day 28) to day 64 was set up: ad libitum intake or restricted intake at 70% of ad libitum, and high v. low hygiene of housing (n=105 per group). At day 36 and day 45, 15 animals/group were subcutaneously immunized with ovalbumin (OVA) to assess their specific immune response. Blood was sampled at 36, 45, 57 and 64 days of age to determine total and anti-OVA immunoglobulin type G (IgG) and haptoglobin levels. The cecal bacterial community was explored (18 per group) by 454 pyrosequencing of genes coding for the 16S ribosomal RNA, whereas cecal pH, NH3 and volatile fatty acid (VFA) concentrations were measured to characterize fermentative activity. A 30% reduction in feed intake reduced the growth by only 17% (P<0.001), and improved the feed conversion ratio by 15% (P<0.001), whereas the degradation of hygiene conditions slightly decreased the feed intake in ad libitum fed rabbits (-3.5%, P<0.02). As poor hygiene conditions did not affect weight gain, feed conversion was improved from day 42 (P<0.05). Restricted feeding led to a lower mortality between day 28 and day 40 (P=0.047), whereas degraded hygiene conditions decreased overall morbidity (7.8% v. 16.6%; P<0.01). Both a reduced intake and low hygiene conditions of housing affected microbiota composition and especially dominant genera belonging to the Ruminococcaceae family (P<0.01). Moreover, low hygiene was associated with a higher Ruminococcaceae/Lachnospiraceae ratio (3.7 v. 2.4; P<0.05). Cecal total VFA and pH were increased (+19%; P<0.001) and decreased (-0.1 pH unit; P<0.05), respectively, in feed-restricted rabbits. Neither specific anti-OVA IgG nor haptoglobin was affected by treatments. Total IgG concentrations were the highest in animals raised in poor hygiene conditions after 8 days of restriction, but decreased after 19 days of restriction in high hygiene conditions (-2.15%; P<0.05). In conclusion, the degradation of hygiene conditions failed to induce a systematic specific and inflammatory response in rabbit, but reduced morbidity instead. Our results suggest that the microbiota composition would be a helpful source of biomarkers of digestive health.


Assessing the consumption of berries and associated factors in the United States using the National Health and Nutrition Examination Survey (NHANES), 2007-2012.
Intake of berries was assessed relative to other fruit and fruit juices and total fruit intake in the U.S. population age 2 years and older using the National Health and Nutrition Examination Survey, 2007-2012. Average daily intake of total fruit was about 1 cup, and berries comprised approximately 10% of total fruit consumption. Only 18% of the population met the recommendation of at least 2 cups of fruit per day. Children ages 2 to 5 years consumed the most total fruit of which about half was juice and 4% of which was berries. Among adults, the highest berry consumption was by those who were 65 years and older, non-Hispanic White, and had the highest education and income levels. Use of the Nutrition Facts panel and ingredient labeling was associated with greater total fruit and berry intake. Those who were aware of an amount of fruit that is associated with good health and of dietary guidance in general and those who had fruit available in the home consumed about twice as much berries as others. Fruit intake remains below recommendations in the U.S.; berry intake is particularly low. Behavioral indicators provided insight on how fruit and berry consumption might be increased.


Screening for recombinant human erythropoietin using [Hb], reticulocytes, the OFF(hr score), OFF(z score) and Hb(z score): status of the Blood Passport.
Haemoglobin concentration ([Hb]), reticulocyte percentage (retic%) and OFF(hr score) are well-implemented screening tools to determine potential recombinant human erythropoietin (rHuEpo) abuse in athletes. Recently, the International Cycling Union implemented the OFF(z score) and the Hb(z score) in their anti-doping testing programme. The aim of this study is to evaluate the sensitivity of these indirect screening methods. Twenty-four human subjects divided into three groups with eight subjects each (G1; G2 and G3) were injected with rHuEpo. G1 and G2 received rHuEpo for a 4-week period with 2 weeks of "boosting" followed by 2 weeks of "maintenance" and a wash-out period of 3 weeks. G3 received rHuEpo for a 10-week period (boost = 3 weeks; maintenance = 7 weeks; wash out = 1 week). Three, seven and eight of the 24 volunteers exceeded the cut-off limits for OFF(hr score), [Hb] and retic%, respectively. One subject from G1, nobody from G2, and seven subjects from G3 exceeded the cut-off limit for Hb(z score.) In total, ten subjects exceeded the cut-off limit for the OFF(z score); two subjects from G1, two subjects from G2 and six subjects from G3. In total, indirect screening methods were able to indicate rHuEpo injections in 58% of subjects. However, 42% of our rHuEpo-injected subjects were not detected. It should be emphasised that the test frequency in real world anti-doping is far less than the present study, and hence the detection rate will be lower.


Revision of the genus Seminemacheilus, with the description of three new species (Teleostei: Nemacheilidae).
The nemacheilid genus Seminemacheilus is revised. Six species are recognised, three of them described herein as new. All species are endemic to Central Anatolia. Seminemacheilus lendlii from the Sakarya River drainage and the endorheic Lake Aksehir and Eber basins, S. ispartensis from Lake Eğirdir basin and S. ahmeti from Sultan Sazlığı are valid species. Although Seminemacheilus lendlii and S. ispartensis have almost identical COI sequences, they are distinguished by the shape of the caudal peduncle and the presence of scales on the caudal peduncle in S. ispartensis (vs. absent in S. lendlii). Seminemacheilus attalicus, new species, from Kırkgöz drainage, is distinguished by having a slightly emarginated caudal fin, a central pore in the supratemporal canal and a marbled flank pattern. Seminemacheilus ekmekciae, new species, from Lake Tuz basin is distinguished by having a roundish caudal fin, a short post-dorsal length and large brown blotches fused into stripes on the flank. Seminemacheilus tubae, new species, from Lake Beyşehir basin, is distinguished by having a truncate caudal fin and 2-5 (6) supraorbital head pores. Seminemacheilus dursunavsari from the Göksu River drainage is not a valid name and this population is identified as S. tubae.


Disproportionate exposure to early-life adversity and sexual orientation disparities in psychiatric morbidity.
Lesbian, gay, and bisexual (LGB) populations exhibit elevated rates of psychiatric disorders compared to heterosexuals, and these disparities emerge early in the life course. We examined the role of exposure to early-life victimization and adversity-including physical and sexual abuse, homelessness, and intimate partner violence-in explaining sexual orientation disparities in mental health among adolescents and young adults. Data were drawn from the National Longitudinal Study of Adolescent Health, Wave 3 (2001-2002), a nationally representative survey of adolescents. Participants included gay/lesbian (n=227), bisexual (n=245), and heterosexual (n=13,490) youths, ages 18-27. We examined differences in the prevalence of exposure to child physical or sexual abuse, homelessness or expulsion from one's home by caregivers, and physical and sexual intimate partner violence according to sexual orientation. Next we examined the associations of these exposures with symptoms of psychopathology including suicidal ideation and attempts, depression, binge drinking, illicit drug use, tobacco use, alcohol abuse, and drug abuse. Finally, we determined whether exposure to victimization and adversity explained the association between sexual orientation and psychopathology. Gay/lesbian and bisexual respondents had higher levels of psychopathology than heterosexuals across all outcomes. Gay/lesbian respondents had higher odds of exposure to child abuse and housing adversity, and bisexual respondents had higher odds of exposure to child abuse, housing adversity, and intimate partner violence, than heterosexuals. Greater exposure to these adversities explained between 10 and 20% of the relative excess of suicidality, depression, tobacco use, and symptoms of alcohol and drug abuse among LGB youths compared to heterosexuals. Exposure to victimization and adversity experiences in childhood and adolescence significantly mediated the association of both gay/lesbian and bisexual orientation with suicidality, depressive symptoms, tobacco use, and alcohol abuse. Exposure to victimization in early-life family and romantic relationships explains, in part, sexual orientation disparities in a wide range of mental health and substance use outcomes, highlighting novel targets for preventive interventions aimed at reducing these disparities.


Guidelines for vitamin K prophylaxis in newborns.
Newborns are at risk for vitamin K deficiency bleeding (VKDB) caused by inadequate prenatal storage and deficiency of vitamin K in breast milk. Systematic review of evidence to date suggests that a single intramuscular (IM) injection of vitamin K at birth effectively prevents VKDB. Current scientific data suggest that single or repeated doses of oral (PO) vitamin K are less effective than IM vitamin K in preventing VKDB. The Canadian Paediatric Society and the College of Family Physicians of Canada recommend routine IM administration of a single dose vitamin K at 0.5 mg to 1.0 mg to all newborns. Administering PO vitamin K (2.0 mg at birth, repeated at 2 to 4 and 6 to 8 weeks of age), should be confined to newborns whose parents decline IM vitamin K. Health care providers should clarify with parents that newborns are at increased risk of VKDB if such a regimen is chosen. Current evidence is insufficient to recommend routine intravenous vitamin K administration to preterm infants undergoing intensive care.


Complete Anopheles funestus mitogenomes reveal an ancient history of mitochondrial lineages and their distribution in southern and central Africa.
Anopheles funestus s.s. is a primary vector of malaria in sub-Saharan Africa. Despite its important role in human Plasmodium transmission, evolutionary history, genetic diversity, and population structure of An. funestus in southern and central Africa remains understudied. We deep sequenced, assembled, and annotated the complete mitochondrial genome of An. funestus s.s. for the first time, providing a foundation for further genetic research of this important malaria vector species. We further analyzed the complete mitochondrial genomes of 43 An. funestus s.s. from three sites in Zambia, Democratic Republic of the Congo, and Tanzania. From these 43 mitogenomes we identified 41 unique haplotypes that comprised 567 polymorphic sites. Bayesian phylogenetic reconstruction confirmed the co-existence of two highly divergent An. funestus maternal lineages, herein defined as lineages I and II, in Zambia and Tanzania. The estimated coalescence time of these two mitochondrial lineages is ~500,000 years ago (95% HPD 426,000-594,000 years ago) with subsequent independent diversification. Haplotype network and phylogenetic analysis revealed two major clusters within lineage I, and genetic relatedness of samples with deep branching in lineage II. At this time, data suggest that the lineages are partially sympatric. This study illustrates that accurate retrieval of full mitogenomes of Anopheles vectors enables fine-resolution studies of intraspecies genetic relationships, population differentiation, and demographic history. Further investigations on whether An. funestus mitochondrial lineages represent biologically meaningful populations and their potential implications for malaria vector control are warranted.


Direct deflection method for determining refractive-index profiles of polymer optical fiber preforms.
We present a method for determining the refractive-index profile of polymer optical fiber preforms through a direct-deflection measurement. The method is simple to use, compact, and has good resolution. The profile is obtained from the deflection data by numerically integrating the differential-ray equation for a radial refractive-index gradient. Corrections for topographical deviations are also discussed. Results for both graded-index and step-index fibers are presented.


Coenrollment in a randomized trial of high-frequency oscillation: prevalence, patterns, predictors, and outcomes*.
Enrollment of individual patients into more than one study has been poorly evaluated. The objective of this study was to describe the characteristics of patients, researchers and centers involved in coenrollment, studies precluding coenrollment, and the prevalence, patterns, predictors, and outcomes of coenrollment in a randomized clinical trial. We conducted an observational study nested within the OSCILLation for Acute Respiratory Distress Syndrome Treated Early Trial, which compared high-frequency oscillatory ventilation to conventional ventilation. We collected patient, center, and study data on coenrollment in randomized patients. Multilevel regression examined factors independently associated with coenrollment, considering clustering within centers. We examined the effect of coenrollment on safety and the trial outcome. None. Overall, 127 of 548 randomized patients (23.2%) were coenrolled in 25 unique studies. Coenrollment was reported in 17 of 39 centers (43.6%). Patients were most commonly coenrolled in one additional randomized clinical trial (76; 59.8%). Coenrollment was less likely in older patients (odds ratio, 0.87; 95% CI, 0.76-0.997), and in ICUs with greater than 26 beds (odds ratio, 0.56; 95% CI, 0.34-0.94), and more likely by investigators with more than 11 years of experience (odds ratio, 1.73; 95% CI, 1.06-2.82), by research coordinators with more than 8 years of experience (odds ratio, 1.87; 95% CI, 1.11-3.18) and in Canada (odds ratio, 4.66; 95% CI, 1.43-15.15). Serious adverse events were similar between coenrolled high-frequency oscillatory ventilation and control patients. Coenrollment did not modify the treatment effect of high-frequency oscillatory ventilation on hospital mortality. Coenrollment occurred in 23% of patients, commonly in younger patients, in smaller centers with more research infrastructure, and in Canada. Coenrollment did not influence patient safety or trial results.


Antidepressant use in the absence of common mental disorders in the general population.
To examine the prevalence of antidepressant use in the absence of lifetime mental disorders and to examine sociodemographic correlates, indicators of need (hospitalization, suicidal behavior, perceived need, subthreshold disorders, disability, traumatic events), and antidepressant characteristics of such use. Data came from the Collaborative Psychiatric Epidemiologic Surveys (N = 20,013), a nationally representative cross-sectional sample of community-dwelling adults in the United States. Sociodemographic correlates and indicators of need were examined as predictors of past-year use of antidepressants in the absence of a lifetime DSM-IV diagnosis as assessed by the World Mental Health Composite Diagnostic Interview. The surveys were conducted between 2001 and 2003. Among individuals who took an antidepressant in the past year (n = 1,441), 396 (26.3%) did not meet criteria for any lifetime diagnosis assessed. Respondents taking antidepressants in the absence of a lifetime diagnosis tended to be older, white, and female. All indicators of need except past-year suicidal behavior were significant predictors (adjusted odds ratios ranging from 2.12 to 14.22, P < .001), with 89% of individuals taking antidepressants in the absence of a lifetime diagnosis endorsing at least 1 indicator of need. Individuals taking antidepressants in the absence of a DSM-IV disorder were more likely to have been prescribed these medications by family physicians or other doctors compared to psychiatrists. These results suggest that antidepressant use among individuals without psychiatric diagnoses is common in the United States and is typically motivated by other indicators of need. These findings have important implications for the delivery of medical and psychiatric care and psychiatric nosology.


The novel nitric oxide donor PDNO attenuates ovine ischemia-reperfusion induced renal failure.
Renal ischemia-reperfusion injury is a common cause of acute kidney injury in intensive care and surgery. Recently, novel organic mononitrites of 1,2-propanediol (PDNO) were synthesized and shown to rapidly and controllably deploy nitric oxide in the circulation when administered intravenously. We hypothesized that intravenous infusion of PDNO during renal ischemia reperfusion would improve post-ischemic renal function and microcirculation. Sixteen sheep were anesthetized, mechanically ventilated, and surgically instrumented. The left renal artery was clamped for 90 min, and the effects of ischemia were studied for a total of 8 h. Fifteen minutes prior to the release of the clamp, intravenous infusions of PDNO (n = 8) or vehicle (1,2 propanediol + inorganic nitrite, n = 8) were initiated (180 nmol/kg/min for 30 min, thereafter 60 nmol/kg/min for the remainder of the experiment). Renal artery blood flow, cortical and medullary perfusion, and diuresis and creatinine clearance decreased in the left kidney post ischemia. However, in the sheep treated with PDNO, diuresis and creatinine clearance in the left kidney were significantly higher post ischemia compared to vehicle-treated animals (1.7 ± 0.5 vs 0.7 ± 0.3 ml/kg/h, p = 0.04 and 7.5 ± 2.1 vs 1.7 ± 0.6 ml/min, p = 0.02, respectively). Left renal medullary perfusion and oxygen uptake were higher in the PDNO group (73 ± 9 vs 37 ± 5% of baseline, p = 0.004 and 2.6 ± 0.4 vs 1.6 ± 0.3 ml/min, p = 0.02, respectively). PDNO significantly increased renal oxygen consumption and reduced the oxygen utilization for sodium reabsorption (p = 0.03 for both). Mean arterial blood pressure was significantly reduced by PDNO (83 ± 3 vs 94 ± 3 mmHg, p = 0.02) but was still within normal limits. Total renal blood flow was not affected, and there were no signs of increased blood methemoglobin concentrations or tachyphylaxis. The novel nitric oxide donor PDNO improved renal function after ischemia. PDNO also prevented the persistent reduction in medullary perfusion during reperfusion and improved renal oxygen utilization without severe side effects.


Sex-specific gene-environment interactions underlying ASD-like behaviors.
The male bias in the incidence of autism spectrum disorders (ASDs) is one of the most notable characteristics of this group of neurodevelopmental disorders. The etiology of this sex bias is far from known, but pivotal for understanding the etiology of ASDs in general. Here we investigate whether a "three-hit" (genetic load × environmental factor × sex) theory of autism may help explain the male predominance. We found that LPS-induced maternal immune activation caused male-specific deficits in certain social responses in the contactin-associated protein-like 2 (Cntnap2) mouse model for ASD. The three "hits" had cumulative effects on ultrasonic vocalizations at postnatal day 3. Hits synergistically affected social recognition in adulthood: only mice exposed to all three hits showed deficits in this aspect of social behavior. In brains of the same mice we found a significant three-way interaction on corticotropin-releasing hormone receptor-1 (Crhr1) gene expression, in the left hippocampus specifically, which co-occurred with epigenetic alterations in histone H3 N-terminal lysine 4 trimethylation (H3K4me3) over the Crhr1 promoter. Although it is highly likely that multiple (synergistic) interactions may be at work, change in the expression of genes in the hypothalamic-pituitary-adrenal/stress system (e.g., Crhr1) is one of them. The data provide proof-of-principle that genetic and environmental factors interact to cause sex-specific effects that may help explain the male bias in ASD incidence.


A Protocol for a Cluster Randomized Trial on the Effect of a "feeding buddy" Program on adherence to the Prevention of Mother-To-Child-Transmission Guidelines in a Rural Area of KwaZulu-Natal, South Africa.
The uptake of prevention of mother-to-child-transmission (PMTCT) services has improved in South Africa but challenges remain, including adherence to the World Health Organization's (WHO) PMTCT recommendations of exclusive breastfeeding (EBF), taking antiretroviral medication (ARV); testing for early infant diagnosis; and reducing stigma. Women who practice EBF for the first 6 months are less likely to transmit HIV to their infants, yet only 7% of women EBF for 6 months in South Africa. Adherence to these recommendations remains challenging because of difficulties relating to disclosure and stigma. To address this challenge, the feeding buddy concept was developed based on studies where ARV buddies have proved effective in providing support for women living with HIV. Buddies have demonstrated a positive effect on providing emotional and social support to adhere to PMTCT guidelines. A cluster randomized controlled trial was conducted in 16 selected randomly assigned clinics in uMhlathuze and uMlalazi districts of KwaZulu Natal, South Africa. HIV-positive pregnant women (n = 625) who intended to breastfeed were enrolled at 8 control clinics and 8 intervention clinics. The clinics were stratified on the basis of urban/rural/periurban locale and then randomly allocated to either intervention or control. In the intervention clinics, the mother chose a feeding buddy to be enrolled alongside her. Quantitative interviews with mothers and their chosen buddies took place at enrollment during pregnancy and at routine postdelivery visits at day 3 and weeks 6, 14 and 22. Women in the control clinics were followed using the same evaluation schedule. The trial evaluated the effect of a voluntary PMTCT feeding buddy program on HIV-infected women's adherence to PMTCT recommendations and stigma reduction. The proportion of women exclusively feeding at 5.5 months postpartum was the primary end-point of the trial. In-depth interviews were conducted among a convenience sample of PMTCT counselors, community caregivers, mothers, and buddies from intervention clinics and control clinics to document their overall experiences. The information collected in this study could be used to guide recommendations on how to build upon the current South Africa. PMTCT "buddy" strategy and to improve safe infant feeding. The information would be applicable to many other similar resource poor settings with poor social support structures.


C-Reactive Protein in Atherothrombosis and Angiogenesis.
C-reactive protein (CRP) is a short pentraxin mainly found as a pentamer in the circulation, or as non-soluble monomers CRP (mCRP) in tissues, exerting different functions. This review is focused on discussing the role of CRP in cardiovascular disease, including recent advances on the implication of CRP and its forms specifically on the pathogenesis of atherothrombosis and angiogenesis. Besides its role in the humoral innate immune response, CRP contributes to cardiovascular disease progression by recognizing and binding multiple intrinsic ligands. mCRP is not present in the healthy vessel wall but it becomes detectable in the early stages of atherogenesis and accumulates during the progression of atherosclerosis. CRP inhibits endothelial nitric oxide production and contributes to plaque instability by increasing endothelial cell adhesion molecules expression, by promoting monocyte recruitment into the atheromatous plaque and by enzymatically binding to modified low-density lipoprotein. CRP also contributes to thrombosis, but depending on its form it elicits different actions. Pentameric CRP has no involvement in thrombogenesis, whereas mCRP induces platelet activation and thrombus growth. In addition, mCRP has apparently contradictory pro-angiogenic and anti-angiogenic effects determining tissue remodeling in the atherosclerotic plaque and in infarcted tissues. Overall, CRP contributes to cardiovascular disease by several mechanisms that deserve an in-depth analysis.


A randomized controlled trial of risperidone in the treatment of aggression in hospitalized adolescents with subaverage cognitive abilities.
Risperidone is an atypical antipsychotic drug that blocks dopamine as well as serotonin receptor systems. The present study was designed to examine the efficacy and safety of risperidone in a 6-week double-blind, randomized, parallel-group design in the treatment of aggression in adolescents with a primary diagnosis of DSM-IV disruptive behavior disorders and with subaverage intelligence. We randomly assigned 38 adolescents (33 boys; 10 subjects with slightly subaverage IQ, 14 with borderline IQ, and 14 with mild mental retardation), who were hospitalized for treatment of psychiatric disorders associated with severe aggression, to receive risperidone or placebo. The main efficacy measures were the Clinical Global Impressions-Severity of Illness scale (CGI-S), the modified Overt Aggression Scale (OAS-M), and the Aberrant Behavior Checklist (ABC). Side effects were measured using the Extrapyramidal Symptom Rating Scale (ESRS). The mean daily dose of risperidone at the end of treatment was 2.9 mg (range, 1.5-4 mg). Risperidone, compared with placebo, was associated with significant improvements on the CGI-S (p < .001) and the at-school ABC overall and hyperactivity scales (p < .05). During a 2-week washout following the 6-week trial, a statistically significant worsening was found in the risperidone group on the CGI-S scale, the OAS-M. and the ABC. Extrapyramidal symptoms were absent or very mild during risperidone treatment. Transient tiredness was present in 11 (58%) of 19 drug-treated subjects. Other untoward effects included sialorrhea, nausea, and slight weight gain (mean = 3.5% of body weight in the risperidone group). No clinically relevant changes were found in laboratory parameters, electrocardiogram, heart rate, or blood pressure. These results suggest that risperidone may be effective for severe aggression in adolescents with disruptive behavior disorders and subaverage intelligence, and these results are consistent with reports suggesting its effectiveness for treating severe aggression in adolescents in general.


Divergence of function and regulation of class B floral organ identity genes.
Regulatory mechanisms controlling basic aspects of floral morphogenesis seem to be highly conserved among plant species. The class B organ identity genes, which are required to establish the identity of organs in the second (petals) and third (stamens) floral whorls, are a good example of such conservation. This work compares the function of two similar class B genes in the same genetic background. The DEFICIENS (DEF) gene from Antirrhinum, including its promoter, was transformed into Arabidopsis and compared in function and expression with the Arabidopsis class B genes APETALA3 (AP3) and PISTILLATA (PI). The DEF gene was expressed in the second, third, and fourth whorls, as was PI. Functionally, DEF could replace AP3 in making petals and stamens. The DEF gene's AP3-like function and PI-like expression caused transformation of fourth-whorl carpels to stamens. Like AP3, all aspects of DEF function in Arabidopsis required a functional PI protein. Surprisingly, DEF could not replace the AP3 protein in properly maintaining AP3 transcripts (autoregulation). Our data allow us to revise the current model for class B autoregulation and propose a hypothesis for the evolution of class B gene expression in dicotyledonous plants.


Nucleosome occupancy reveals regulatory elements of the CFTR promoter.
Access to regulatory elements of the genome can be inhibited by nucleosome core particles arranged along the DNA strand. Hence, sites that are accessible by transcription factors may be located by using nuclease digestion to identify the relative nucleosome occupancy of a genomic region. In order to define novel cis regulatory elements in the ∼2.7-kb promoter region of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, we define its nucleosome occupancy. This profile reveals the precise positions of nucleosome-free regions (NFRs), both cell-type specific and others apparently unrelated to CFTR-expression level and offer the first high-resolution map of the chromatin structure of the entire CFTR promoter in relevant cell types. Several of these NFRs are strongly bound by nuclear factors in a sequence-specific manner, and directly influence CFTR promoter activity. Sequences within the NFR1 and NFR4 elements are highly conserved in many human gene promoters. Moreover, NFR1 contributes to promoter activity of another gene, angiopoietin-like 3 (ANGPTL3), while NFR4 is constitutively nucleosome-free in promoters genome wide. Conserved motifs within NFRs of the CFTR promoter also show a high level of protection from DNase I digestion genome-wide, and likely have important roles in the positioning of nucleosome core particles more generally.


Hyperthermic-related challenges in aquatics, athletics, football, tennis and triathlon.
Although many elite sporting events occur in climate-controlled venues, some athletes train and compete in environments that can potentially pose a risk to the athlete's health. In particular, athletes in aquatics, track and field, tennis, football and triathlon can be exposed to extreme heat during competition or while training. The International Federations responsible for these sports are aware of these health risks and have implemented measures to help protect the health of their athletes. This review paper outlines the sport-specific environmental health risks and the safety standards implemented to safeguard athlete health.


Maternal regulation of embryonic growth: the role of vasoactive intestinal peptide.
Vasoactive intestinal peptide (VIP) is an important growth regulator of the embryonic day (E)9-E11 mouse. In comparably aged rat embryos, VIP messenger RNA (mRNA) is not detectable; however, peak concentrations of VIP in maternal rat serum indicate a nonembryonic source. In the current study, mouse maternal and embryonic tissues were examined from E6-E12. Although RT-PCR revealed VIP mRNA in E6-E7 conceptuses, by E8 (when extraembryonic tissues could be separated from the embryo), VIP mRNA was detected only in the decidua/trophoblast. Decidual/trophoblastic VIP mRNA decreased until E10, after which it was not detectable. VIP mRNA was not apparent in the embryo until E11-E12. At E9, VIP immunoreactivity was localized to abundant, diffuse cells in the decidua basalis, which were also immunoreactive for T cell markers. VIP binding sites were dense in the decidua/trophoblast at E6, but gradually decreased until E10, after which they were not apparent. VIP binding sites were detected in embryonic neuroepithelium by E9. The transient presence of VIP binding sites and mRNA in the decidua/trophoblast correlate with the critical period of VIP growth regulation, when VIP mRNA is absent in the embryo. These findings suggest that maternal lymphocytes are the source of VIP's regulating early postimplantation embryonic growth.


Molecular imaging identifies regions with microthromboemboli during primary angioplasty in acute coronary thrombosis.
Microthromboemboli (MTE) may contribute to the no-reflow phenomenon in acute myocardial infarction (AMI) either spontaneously or after primary percutaneous transluminal coronary angioplasty (PTCA). We hypothesized that myocardial MTE in acute coronary syndromes can be identified on imaging by in vivo (99m)Tc labeling of the coronary thrombus with a compound that binds to the glycoprotein IIb/IIIa present on activated platelets (DMP-444). Fifteen dogs underwent left anterior descending coronary artery (LAD) injury in to produce thrombus, whereas 5 control dogs had LAD ligation. Before recanalization, the risk area (RA) and myocardial blood flow (MBF) were measured, and in vivo thrombus labeling was performed using (99m)Tc-labeled DMP-444. Nine of the 15 LAD injury dogs had occlusive thrombus on angiography and underwent PTCA. MBF measurements were repeated 30 and 60 min after recanalization, and (99m)Tc autoradiography (hot spot imaging) was performed ex vivo to determine the extent and magnitude of MTE. The ratio of hot spot size to RA size was higher in the 9 LAD injury dogs with thrombus compared with the 6 dogs with no thrombus (90% +/- 22% vs. 42% +/- 16%; P = 0.005). In control dogs, this ratio was significantly lower (29% +/- 11%; P = 0.05). (99m)Tc activity within the RA was higher in 8 of the 15 coronary injury dogs with AMI compared with those without AMI (1.8 +/- 0.48 vs. 1.24 +/- 0.22; P = 0.02). MTE can be detected and quantified after primary PTCA. The infarct size is proportional to the magnitude and extent of MTE, indicating that MTE may contribute to the AMI. Thus, in vivo thrombus labeling during reperfusion may provide important information in patients with AMI that may lead to better adjuvant therapy during PTCA.


Impact of minimum winter temperatures on the population dynamics of Dendroctonus frontalis.
Predicting population dynamics is a fundamental problem in applied ecology. Temperature is a potential driver of short-term population dynamics, and temperature data are widely available, but we generally lack validated models to predict dynamics based upon temperatures. A generalized approach involves estimating the temperatures experienced by a population, characterizing the demographic consequences of physiological responses to temperature, and testing for predicted effects on abundance. We employed this approach to test whether minimum winter temperatures are a meaningful driver of pestilence from Dendroctonus frontalis (the southern pine beetle) across the southeastern United States. A distance-weighted interpolation model provided good, spatially explicit, predictions of minimum winter air temperatures (a putative driver of beetle survival). A Newtonian heat transfer model with empirical cooling constants indicated that beetles within host trees are buffered from the lowest air temperatures by approximately 1-4 degrees C (depending on tree diameter and duration of cold bout). The life stage structure of beetles in the most northerly outbreak in recent times (New Jersey) were dominated by prepupae, which were more cold tolerant (by >3 degrees C) than other life stages. Analyses of beetle abundance data from 1987 to 2005 showed that minimum winter air temperature only explained 1.5% of the variance in interannual growth rates of beetle populations, indicating that it is but a weak driver of population dynamics in the southeastern United States as a whole. However, average population growth rate matched theoretical predictions of a process-based model of winter mortality from low temperatures; apparently our knowledge of population effects from winter temperatures is satisfactory, and may help to predict dynamics of northern populations, even while adding little to population predictions in southern forests. Recent episodes of D. frontalis outbreaks in northern forests may have been allowed by a warming trend from 1960 to 2004 of 3.3 degrees C in minimum winter air temperatures in the southeastern United States. Studies that combine climatic analyses, physiological experiments, and spatially replicated time series of population abundance can improve population predictions, contribute to a synthesis of population and physiological ecology, and aid in assessing the ecological consequences of climatic trends.


Policy making on data exclusivity in the European Union: from industrial interests to legal realities.
After lengthening the duration of patents to twenty years in 1984, the pharmaceutical industry has turned to data exclusivity as a major vehicle for extending market protection, even after patents expire. Such protections give companies the power to tax consumers for innovation by charging above-market prices. This article draws upon unique information to describe how key actors lengthened data exclusivity for patented drugs to postpone generic competition in the European Union (EU) just before ten new members joined it. We explore the political route and the interests of different actors to understand the process by which industrial interests are translated into legal realities in the world's largest harmonized market. Several factors influenced the outcome, including the role of the pharmaceutical unit of the Directorate General for Enterprise of the European Commission in promoting the interests of the innovative branch of the industry, the time pressure to find a viable compromise before EU enlargement, and the heterogeneous preferences of the other actors. The case illustrates the inherent tension between the desire of both health care administrators and patients for high-quality, low-cost medicines and the objective of the innovator pharmaceutical industry to find and approve new drugs that are price protected and sell them in a way that maximizes revenues.


Polyanions in syphilis: evidence that glycoproteins and macromolecules resembling glycosaminoglycans are synthesised by host tissues in response to infection with Treponema pallidum.
We investigated by means of radiolabelled precursors the source and nature of the polyanionic macromolecules present in rabbit tissues during active syphilis infection. Previous studies indicated that Treponema pallidum itself does not synthesise glycosaminoglycans, at least in vitro. In replicate experiments on unilaterally infected rabbits, tissue from the orchitic testis incorporated two to three times more 35S-sulphate and 3H-glucosamine (on a wet weight basis) than tissue from the non-orchitic contralateral testis. Incorporation of 35S-sulphate was independent of the number of viable T pallidum organisms present in the infested tissue, which suggested that incorporation represented biosynthesis by the host and not the treponeme. Testes from syphilitic rabbits two days after treatment with high doses (100 mg/kg) of penicillin incorporated less 35S-sulphate than untreated infected testes, but more than normal uninfected rabbit testes. This suggests that active syphilitic infection was necessary for maximum biosynthesis of the macromolecule(s) by host tissue. Hydrodynamic profiles showed incorporation of radiolabelled precursors into two distinct fractions of different sizes, which may represent a proteoglycan and a sulphated glycoprotein. Alcian blue staining of syphilitic testes at or after peak orchitis showed focal deposition of newly synthesised polyanionic components during peak orchitis and a more generalised fibrosis in testes after peak orchitis.


Etoposide in acute nonlymphocytic leukemia. Australian Leukemia Study Group.
Previously untreated patients with acute nonlymphocytic leukemia (ANLL) aged 15 to 70 years were randomized to either cytosine arabinoside 100 mg/m2/d continuous intravenous (IV) infusion days 1 through 7, daunorubicin 50 mg/m2/d IV days 1 through 3 (7-3), or the same drugs intensified with etoposide 75 mg/m2/d IV days 1 through 7 (7-3-7) as induction therapy. Patients achieving complete remission (CR) received two courses of consolidation therapy (5-2 or 5-2-5) followed by maintenance therapy. Of 264 eligible patients, CR occurred in 56% of 7-3 and 59% of 7-3-7 patients; 7-3-7 significantly improved remission duration (P = .01). The median remission duration was 12 months for 7-3 and 18 months for 7-3-7. Survival was similar when the two arms were compared overall. Subset analysis performed to identify patients with the most benefit showed that etoposide significantly prolonged remission duration in younger patients (less than 55 years) with a median of 12 months for 7-3 and 27 months for 7-3-7 (P = .01). Survival appeared to be prolonged with 7-3-7 in patients aged less than 55 years, with a median of 9 months for 7-3 as compared with 17 months for 7-3-7 (P = .03). In older patients (aged greater than or equal to 55 years), 7-3-7 was more toxic, with significantly more severe [World Health Organization (WHO) grade 3 or 4] stomatitis (P = .02) and no additional clinical benefit. Hematologic toxicity for induction courses was similar, with granulocytopenia less than 0.5 x 10(9)/L for a median of 16 days per course for 7-3 and 15 days for 7-3-7. Hematologic toxicity was more severe for 5-2-5 consolidation courses (P = .003). Induction and consolidation therapy intensified with etoposide resulted in significantly improved remission duration but not survival.


Biomimetic Silica Nanoparticles Prepared by a Combination of Solid-Phase Imprinting and Ostwald Ripening.
Herein we describe the preparation of molecularly imprinted silica nanoparticles by Ostwald ripening in the presence of molecular templates immobilised on glass beads (the solid-phase). To achieve this, a seed material (12 nm diameter silica nanoparticles) was incubated in phosphate buffer in the presence of the solid-phase. Phosphate ions act as a catalyst in the ripening process which is driven by differences in surface energy between particles of different size, leading to the preferential growth of larger particles. Material deposited in the vicinity of template molecules results in the formation of sol-gel molecular imprints after around 2 hours. Selective washing and elution allows the higher affinity nanoparticles to be isolated. Unlike other strategies commonly used to prepare imprinted silica nanoparticles this approach is extremely simple in nature and can be performed under physiological conditions, making it suitable for imprinting whole proteins and other biomacromolecules in their native conformations. We have demonstrated the generic nature of this method by preparing imprinted silica nanoparticles against targets of varying molecular mass (melamine, vancomycin and trypsin). Binding to the imprinted particles was demonstrated in an immunoassay (ELISA) format in buffer and complex media (milk or blood plasma) with sub-nM detection ability.


Nano-Engineered Mesenchymal Stem Cells Increase Therapeutic Efficacy of Anticancer Drug Through True Active Tumor Targeting.
Tumor-targeted drug delivery has the potential to improve therapeutic efficacy and mitigate non-specific toxicity of anticancer drugs. However, current drug delivery approaches rely on inefficient passive accumulation of the drug carrier in the tumor. We have developed a unique, truly active tumor-targeting strategy that relies on engineering mesenchymal stem cells (MSC) with drug-loaded nanoparticles. Our studies using the A549 orthotopic lung tumor model show that nano-engineered MSCs carrying the anticancer drug paclitaxel (PTX) home to tumors and create cellular drug depots that release the drug payload over several days. Despite significantly lower doses of PTX, nano-engineered MSCs resulted in significant inhibition of tumor growth and superior survival. Anticancer efficacy of nano-engineered MSCs was confirmed in immunocompetent C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Furthermore, at doses that resulted in equivalent therapeutic efficacy, nano-engineered MSCs had no effect on white blood cell count, whereas PTX solution and PTX nanoparticle treatments caused leukopenia. Biodistribution studies showed that nano-engineered MSCs resulted in greater than 9-fold higher AUClung of PTX (1.5 μg.day/g) than PTX solution and nanoparticles (0.2 and 0.1 μg.day/g tissue, respectively) in the target lung tumors. Furthermore, the lung-to-liver and the lung-to-spleen ratios of PTX were several folds higher for nano-engineered MSCs relative to those for PTX solution and nanoparticle groups, suggesting that nano-engineered MSCs demonstrate significantly less off-target deposition. In summary, our results demonstrate that nano-engineered MSCs can serve as an efficient carrier for tumor-specific drug delivery and significantly improved anti-cancer efficacy of conventional chemotherapeutic drugs. Mol Cancer Ther; 17(6); 1196-206. ©2018 AACR.


CT diagnosis of small bowel obstruction due to phytobezoar.
Small bowel obstruction (SBO) is a commonly encountered abdominal problem in the emergency ward. Phytobezoar is an uncommon cause of SBO which has specific radiographic findings on computed tomography (CT). This study evaluated the CT appearance of small bowel phytobezoar. Eighty two patients with SBO who underwent CT examination and surgical treatment over a 6-year period were included. The presence of fecal ball sign, defined as a clearly distinguishable, ovoid or round intraluminal mass with mottled gas pattern outlined by fluid or oral contrast material in the dilated small bowel at the site of obstruction, and abruptly collapsed lumen beyond the lesion on CT was evaluated in all cases. The CT findings of the patients with SBO and the patients with fecal ball sign on CT were reviewed. The diagnosis was established based on surgical findings. Fecal ball sign was identified in 9 of the 82 patients. Operative findings revealed that SBO was secondary to phytobezoar in 7 of these patients. The specificity and sensitivity of fecal ball sign in the diagnosis of SBO secondary to phytobezoar were 97% and 100%, respectively. Fecal ball sign is accurate in the preoperative diagnosis of phytobezoar as the underlying cause of SBO. Early recognition of fecal ball sign in the CT study is of paramount importance in precise preoperative diagnosis in patients with SBO.