Bupropion sustained release. A therapeutic review of Zyban.
Originally developed as an antidepressant, bupropion hydrochloride is a selective re-uptake inhibitor of dopamine and noradrenalin which was found to reduce nicotine withdrawal symptoms and the urge to smoke. Bupropion came onto the Australian market in November 2000 as a 150 mg sustained release preparation to be used as an aid to smoking cessation in combination with counselling. Following the PBS listing in February 2001, there was a dramatic increase in prescribing, and considerable public and professional attention focused on this drug. This review summarises the evidence on how bupropion sustained release (SR) works, its contraindications and risks, adverse effects, studies on efficacy and place in smoking cessation pharmacotherapy. Bupropion SR is a useful oral and non-nicotine form of pharmacotherapy for smoking cessation. Efficacy has been demonstrated in two key published trials. In one of these trials efficacy was superior to nicotine patch. There is also evidence of efficacy in patients with mild to moderate chronic obstructive pulmonary disease. Bupropion SR is contraindicated in a number of conditions where there is an increased risk of seizures. This includes patients with a current seizure disorder or any history of seizures. It must not be used concurrently with monoamine oxidase inhibitors and interacts with medications which can lower the seizure threshold. Minor adverse effects such as insomnia, headache, dry mouth and nausea are common. Serious adverse effects are rare but include seizures (risk of 1/1000) and hypersensitivity reactions. The latter can manifest as skin rash and a serum sickness-like reaction.


Fine mapping and replication of QTL in outbred chicken advanced intercross lines.
Linkage mapping is used to identify genomic regions affecting the expression of complex traits. However, when experimental crosses such as F(2) populations or backcrosses are used to map regions containing a Quantitative Trait Locus (QTL), the size of the regions identified remains quite large, i.e. 10 or more Mb. Thus, other experimental strategies are needed to refine the QTL locations. Advanced Intercross Lines (AIL) are produced by repeated intercrossing of F(2) animals and successive generations, which decrease linkage disequilibrium in a controlled manner. Although this approach is seen as promising, both to replicate QTL analyses and fine-map QTL, only a few AIL datasets, all originating from inbred founders, have been reported in the literature. We have produced a nine-generation AIL pedigree (n = 1529) from two outbred chicken lines divergently selected for body weight at eight weeks of age. All animals were weighed at eight weeks of age and genotyped for SNP located in nine genomic regions where significant or suggestive QTL had previously been detected in the F(2) population. In parallel, we have developed a novel strategy to analyse the data that uses both genotype and pedigree information of all AIL individuals to replicate the detection of and fine-map QTL affecting juvenile body weight. Five of the nine QTL detected with the original F(2) population were confirmed and fine-mapped with the AIL, while for the remaining four, only suggestive evidence of their existence was obtained. All original QTL were confirmed as a single locus, except for one, which split into two linked QTL. Our results indicate that many of the QTL, which are genome-wide significant or suggestive in the analyses of large intercross populations, are true effects that can be replicated and fine-mapped using AIL. Key factors for success are the use of large populations and powerful statistical tools. Moreover, we believe that the statistical methods we have developed to efficiently study outbred AIL populations will increase the number of organisms for which in-depth complex traits can be analyzed.


Chikungunya virus: emerging targets and new opportunities for medicinal chemistry.
Chikungunya virus is an emerging arbovirus that is widespread in tropical regions and is spreading quickly to temperate climates with recent epidemics in Africa and Asia and documented outbreaks in Europe and the Americas. It is having an increasingly major impact on humankind, with potentially life-threatening and debilitating arthritis. There is no treatment available, and only in the past 24 months have lead compounds for development as potential therapeutics been reported. This Perspective discusses the chikungunya virus as a significant, new emerging topic for medicinal chemistry, highlighting the key viral target proteins and their molecular functions that can be used in drug design, as well as the most important ongoing developments for anti-chikungunya virus research. It represents a complete picture of the current medicinal chemistry of chikungunya, supporting the development of chemotherapeutics through drug discovery and design targeting this virus.


Dynamical simulation priors for human motion tracking.
We propose a simulation-based dynamical motion prior for tracking human motion from video in presence of physical ground-person interactions. Most tracking approaches to date have focused on efficient inference algorithms and/or learning of prior kinematic motion models; however, few can explicitly account for the physical plausibility of recovered motion. Here, we aim to recover physically plausible motion of a single articulated human subject. Toward this end, we propose a full-body 3D physical simulation-based prior that explicitly incorporates a model of human dynamics into the Bayesian filtering framework. We consider the motion of the subject to be generated by a feedback "control loop" in which Newtonian physics approximates the rigid-body motion dynamics of the human and the environment through the application and integration of interaction forces, motor forces, and gravity. Interaction forces prevent physically impossible hypotheses, enable more appropriate reactions to the environment (e.g., ground contacts), and are produced from detected human-environment collisions. Motor forces actuate the body, ensure that proposed pose transitions are physically feasible, and are generated using a motion controller. For efficient inference in the resulting high-dimensional state space, we utilize an exemplar-based control strategy that reduces the effective search space of motor forces. As a result, we are able to recover physically plausible motion of human subjects from monocular and multiview video. We show, both quantitatively and qualitatively, that our approach performs favorably with respect to Bayesian filtering methods with standard motion priors.


A randomised, controlled trial evaluating a low cost, 3D-printed bronchoscopy simulator.
Low-fidelity, simulation-based psychomotor skills training is a valuable first step in the educational approach to mastering complex procedural skills. We developed a cost-effective bronchial tree simulator based on a human thorax computed tomography scan using rapid-prototyping (3D-print) technology. This randomised, single-blind study evaluated how realistic our 3D-printed simulator would mimic human anatomy compared with commercially available bronchial tree simulators (Laerdal® Airway Management Trainer with Bronchial Tree and AirSim Advance Bronchi, Stavanger, Norway). Thirty experienced anaesthetists and respiratory physicians used a fibreoptic bronchoscope to rate each simulator on a visual analogue scale (VAS) (0 mm = completely unrealistic anatomy, 100 mm = indistinguishable from real patient) for: localisation of the right upper lobe bronchial lumen; placement of a bronchial blocker in the left main bronchus; aspiration of fluid from the right lower lobe; and overall realism. The 3D-printed simulator was rated most realistic for the localisation of the right upper lobe bronchial lumen (p = 0.002), but no differences were found in placement of a bronchial blocker or for aspiration of fluid (p = 0.792 and p = 0.057) compared with using the commercially available simulators. Overall, the 3D-printed simulator was rated most realistic (p = 0.021). Given the substantially lower costs for the 3D-printed simulator (£85 (€100/US$110) compared with > ~ £2000 (€2350/US$2590) for the commercially available simulators), our 3D-printed simulator provides an inexpensive alternative for learning bronchoscopy skills, and offers the possibility of practising procedures on patient-specific models before attempting them in clinical practice.


Youth Depression Screening with Parent and Self-Reports: Assessing Current and Prospective Depression Risk.
Few studies have examined the incremental validity of multi-informant depression screening approaches. In response, we examined how recommendations for using a multi-informant approach may vary for identifying concurrent or prospective depressive episodes. Participants included 663 youth (AgeM = 11.83; AgeSD = 2.40) and their caregiver who independently completed youth depression questionnaires, and clinical diagnostic interviews, every 6 months for 3 years. Receiver operating characteristic (ROC) analyses showed that youth-report best predicted concurrent episodes, and that both youth and parent-report were necessary to adequately forecast prospective episodes. More specifically, youth-reported negative mood symptoms and parent-reported anhedonic symptoms incrementally predicted future depressive episodes. Findings were invariant to youth's sex and age, and results from person and variable-centered analyses suggested that discrepancies between informants were not clinically meaningful. Implications for future research and evidence-based decision making for depression screening initiatives are discussed.


Discrimination of liver malignancies with 1064 nm dispersive Raman spectroscopy.
Raman spectroscopy has been widely demonstrated for tissue characterization and disease discrimination, however current implementations with either 785 or 830 nm near-infrared (NIR) excitation have been ineffectual in tissues with intense autofluorescence such as the liver. Here we report the use of a dispersive 1064 nm Raman system using a low-noise Indium-Gallium-Arsenide (InGaAs) array to discriminate highly autofluorescent bulk tissue ex vivo specimens from healthy liver, adenocarcinoma, and hepatocellular carcinoma (N = 5 per group). The resulting spectra have been combined with a multivariate discrimination algorithm, sparse multinomial logistic regression (SMLR), to predict class membership of healthy and diseased tissues, and spectral bands selected for robust classification have been extracted. A quantitative metric called feature importance is defined based on classification outputs and is used to guide the association of spectral features with biological indicators of healthy and diseased liver tissue. Spectral bands with high feature importance for healthy and liver tumor specimens include retinol, heme, biliverdin, or quinones (1595 cm(-1)); lactic acid (838 cm(-1)); collagen (873 cm(-1)); and nucleic acids (1485 cm(-1)). Classification performance in both binary (normal versus tumor, 100% sensitivity and 89% specificity) and three-group cases (classification accuracy: normal 89%, adenocarcinoma 74%, hepatocellular carcinoma 64%) indicates the potential for accurately separating healthy and cancerous tissues and suggests implications for utilizing Raman techniques during surgical guidance in liver resection.


Psychosocial interventions following self-harm in adults: a systematic review and meta-analysis.
Self-harm (intentional acts of non-fatal self-poisoning or self-injury) is common, particularly in young adults aged 15-35 years, often repeated, and strongly associated with suicide. Effective aftercare of individuals who self-harm is therefore important. We have undertaken a Cochrane systematic review and meta-analysis of the effectiveness of psychosocial interventions for self-harm in adults. We searched five electronic databases (CCDANCTR-Studies and References, CENTRAL, MEDLINE, Embase, and PsycINFO) between Jan 1, 1998, and April 29, 2015, for randomised controlled trials of psychosocial interventions for adults after a recent (within 6 months) episode of self-harm. Most interventions were assessed in single trials. We report results for interventions for which at least three randomised controlled trials comparing interventions with treatment as usual have been published and hence might contribute to clinical guidance. The primary outcome was repetition of self-harm at the conclusion of treatment and at 6, 12, and 24 months' follow-up analysed, when available, with the intention-to-treat method; if this was not possible, we analysed with all available case data. We identified 29 non-overlapping randomised controlled trials with three independent trials of the same intervention. Cognitive-behavioural-based psychotherapy (CBT; comprising cognitive-behavioural and problem-solving therapy) was associated with fewer participants repeating self-harm at 6 months' (odds ratio 0·54, 95% CI 0·34-0·85; 12 trials; n=1317) and at 12 months' follow-up (0·80, 0·65-0·98; ten trials; n=2232). There were also significant improvements in the secondary outcomes of depression, hopelessness, suicidal ideation, and problem solving. Patients receiving dialectical behaviour therapy (in three trials) were not less likely to repeat self-harm compared with those provided with treatment as usual at 6 months (odds ratio [OR] 0·59, 95% CI 0·16-2·15; n=267, three trials) or at 12 months (0·36, 0·05-2·47; n=172, two trials). However, the secondary endpoint of frequency of self-harm was associated with a significant reduction with use of dialectical behaviour therapy (mean difference -18·82, 95% CI -36·68 to -0·95). Four trials each of case management (OR 0·78, 95% CI 0·47-1·30; n=1608) and sending regular postcards (OR 0·87, 95% CI 0·62-1·23; n=3277) did not reduce repetition of self-harm. CBT seems to be effective in patients after self-harm. Dialectical behaviour therapy did not reduce the proportion of patients repeating self-harm but did reduce the frequency of self-harm. However, aside from CBT, there were few trials of other promising interventions, precluding firm conclusions as to their effectiveness. National Institute for Health Research.


"Breaking through the 40% adoption ceiling: Mind the seed system gaps." A perspective on seed systems research for development in One CGIAR.
Seed systems research is central to achieving the United Nations Sustainable Development Goals. Improved varieties with promise for ending hunger, improving nutrition, and increasing livelihood security may be released, but how do they reach and benefit different types of farmers? Without widespread adoption the genetic gains achieved with improved crop varieties can never be actualized. Progress has been made toward demand responsive breeding, however the draft CGIAR 2030 Research and Innovation Strategy fails to recognize the complexity of seed systems and thus presents a narrow vision for the future of seed systems research. This points to the lack of evidence-based dialogue between seed systems researchers and breeders. This perspective paper presents findings from an interdisciplinary group of more than 50 CGIAR scientists who used a suite of seed systems tools to identify four knowledge gaps and associated insights from work on the seed systems for vegetatively propagated crops (VPCs), focusing on bananas (especially cooking bananas and plantains), cassava, potato, sweetpotato, and yam. We discuss the implications for thinking about and intervening in seed systems using a combined biophysical and socioeconomic perspective and how this can contribute to increased varietal adoption and benefits to farmers. The tools merit wider use, not only for the seed systems of VPCs, but for the seed of crops facing similar adoption challenges. We argue for deeper collaboration between seed systems researchers, breeders and national seed system stakeholders to address these and other knowledge gaps and generate the evidence and innovations needed to break through the 40% adoption ceiling for modern varieties, and ensure good quality seed once the new varieties have been adopted. Without this, the achievements of breeders may remain stuck in the seed delivery pipeline.


Effect of a brief progressive resistance training program in hospital porters on pain, work ability, and physical function.
Hospital porters are possibly exposed to the greatest mechanical loads within the hospital environment. However, the evidence about preventive strategies in this population is scarce. To investigate the effect of a workplace-based progressive resistance-training program on musculoskeletal pain among hospital porters. A total of 37 hospital porters (27 women, 10 men) participated. Participants allocated to the intervention group performed five brief resistance training sessions/week, for 9 weeks during working hours at the hospital. Intensity was progressively increased. Participants allocated to the control group maintained their usual physical activity. The primary outcome was pain assessed with the patient global impression of pain change scale. Secondary outcome measures were average pain intensity, work ability, use of analgesics, and physical function. Additionally, perceived general changes were evaluated at follow-up: wellness, satisfaction at work, desire to exercise, motivation to eat healthy, energy to be with family and friends, and socialization with colleagues. For the primary outcome, the intervention group showed lower general pain (p < 0.0001) and greater wellbeing (p < 0.0001), work satisfaction (p = 0.0048), desire for practicing exercise (p = 0.0007), and energy (p = 0.0474) compared with the control group. Significant between-group interactions were found for work impairment due to diseases (d = -1.2), hips/thighs pain (d = 0.7), ankles/feet pain (d = 0.4), the Biering-Sorensen test (d = -0.6) and the push-ups test (d = -2.3) favoring the intervention group. All between-group differences were clinically important. A progressive resistance training program performed at the workplace is feasible and effective in reducing musculoskeletal pain and improving work ability and physical function among hospital porters.


Mucin glycosylation changes in cystic fibrosis lung disease are not manifest in submucosal gland secretions.
SMG (submucosal gland) secretions are a major component of the airway surface liquid, are associated with innate immunity in the lung, and have been reported to be altered in lung disease. Changes in lung mucosal glycosylation have been reported in CF (cystic fibrosis), which may be responsible for differential bacterial binding to glycosylated components in the lung mucosa and hence increased pre-disposition to pulmonary infection. Glycoproteomic analysis was performed on SMG secretions collected from explanted bronchial tissue of subjects with severe lung disease, with and without CF, and controls without lung disease. Mucins MUC5B and MUC5AC were shown to be the dominant high-molecular-mass glycoprotein components, with a minor non-mucin glycoprotein component, gp-340, also present. Oligosaccharides containing blood-group determinants corresponding to subjects' blood type were abundant on MUC5B/MUC5AC, as were Lewis-type epitopes and their sialylated analogues, which are ligands for pathogens and leucocytes. No significant differences were found in the glycosylation of MUC5B/MUC5AC or gp-340 between CF and non-CF subjects with severe lung disease, implying that CF does not influence SMG secretion mucin glycosylation in end-stage lung disease. There were also no significant differences found in the glycosylation of these components in severe lung disease compared with non-diseased lungs. This suggests that previously reported changes in the glycosylation of respiratory glycoconjugates in CF, and other pulmonary conditions, are not due to the glycosylation of components in SMG secretions, but may involve other secretions, responses or extracellular factors.


Evidence for no sexual isolation between Drosophila albomicans and D. nasuta.
Sexual isolation, the reduced tendency to mate, is one of the reproductive barriers that prevent gene flow between different species. Various species-specific signals during courtship contribute to sexual isolation between species. Drosophila albomicans and D. nasuta are closely related species of the nasuta subgroup within the Drosophila immigrans group and are distributed in allopatry. We analyzed mating behavior and courtship as well as cuticular hydrocarbon profiles within and between species. Here, we report that these two species randomly mated with each other. We did not observe any sexual isolation between species or between strains within species by multiple-choice tests. Significant difference in the courtship index was detected between these two species, but males and females of both species showed no discrimination against heterospecific partners. Significant quantitative variations in cuticular hydrocarbons between these two species were also found, but the cuticular hydrocarbons appear to play a negligible role in both courtship and sexual isolation between these two species. In contrast to the evident postzygotic isolation, the lack of sexual isolation between these two species suggests that the evolution of premating isolation may lag behind that of the intergenomic incompatibility, which might be driven by intragenomic conflicts.


Novel platelet substitutes: disk-shaped biodegradable nanosheets and their enhanced effects on platelet aggregation.
We have studied biocompatible spherical carriers carrying a dodecapeptide, HHLGGAKQAGDV (H12), on their surface as platelet substitutes. This peptide is a fibrinogen γ-chain carboxy-terminal sequence (γ400-411) and specifically recognizes the active form of glycoprotein IIb/IIIa on activated platelets. Our purpose is to assess the possibility of making a novel platelet substitute consisting of disk-shaped nanosheets having a large contact area for the targeting site, rather than conventional small contact area spherical carriers. The H12 peptide was conjugated to the surface of the free-standing nanosheets made of biodegradable poly(d,l-lactide-co-glycolide) (PLGA). These H12-PLGA nanosheets were fabricated onto 3 μm disk-shaped patterned hydrophobic octadecyl regions on a SiO(2) substrate. By way of comparison, spherical H12-PLGA microparticles with the same surface area and conjugation number of H12 were also prepared. The resulting H12-PLGA nanosheets specifically interacted with the activated platelets adhered on the collagen surface at twice the rate of the H12-PLGA microparticles under flow conditions, and showed platelet thrombus formation in a two-dimensional spreading manner. Thus, H12-PLGA nanosheets might be a suitable candidate novel platelet alternative substitute for infused human platelet concentrates for the treatment of bleeding in patients with severe thrombocytopenia.


Genetic basis of nonresponse to hepatitis B vaccine in hemodialyzed patients.
Genetic factors are implicated in the response of normal subjects to hepatitis B vaccine. The aim of our study was to investigate if HLA Class I and II proteins could participate in a nonresponse to this vaccine in immunocompromised, namely hemodialyzed, patients. One hundred and seven hemodialyzed patients (68 men and 39 women, mean age 35 years) were vaccinated with Pasteur Hevac B vaccine, with a mean delay of 2 months following the onset of chronic hemodialysis. Patients were considered nonresponders when their serum antiHBs remained less than 10 mUI/ml on at least two occasions within the 12 months following the vaccination. HLA-A, B and DR antigens were determined by complement-dependent microlymphotoxicity. Ninety patients (84%) were responders and 17 (16%) nonresponders. The HLA-A1, B8 and DR3 frequency was higher in nonresponders (35, 35 and 44%, respectively) than in responders (18, 4 and 14%, respectively). The extended haplotype HLA-A1, B8, DR3 was more frequent in the former (19%) than in the latter (2%) (p less than 0.03). There was only one female within the nonresponders (6%) as compared to 37 (41%) in the responders (p less than 0.05). We conclude that genetic determinants (sex and HLA markers) play a critical role in the induction of an antiHBs immune response in both immunoincompetent hemodialyzed patients and normal immunocompetent hosts.


African-American women who use crack cocaine: a comparison of mothers who live with and have been separated from their children.
This study examined factors that influenced caregiver status for African-American mothers who use crack cocaine but are not receiving drug treatment and participated in an HIV prevention study in North Carolina. Caregiver mothers who were living with at least one of their children at intake (n = 257) were compared with non-Caregivers who were separated from all of their children (n = 378). Bivariate analyses and logistic regression were used to compare these mothers at intake on current drug use, risky sex practices, psychological symptoms, victimization, and aggression. Compared with Caregiver mothers, non-Caregivers reported higher frequencies of drug use, risky sex practices, psychological distress, and victimization experiences. Caregiver mothers were more likely than non-Caregiver mothers to have health insurance, but were less likely to have received drug treatment. Logistic regression found that non-Caregiver mothers were significantly more likely than Caregiver mothers to be older, to have been physically abused as children, to trade sex more frequently, to be homeless, and to have no health insurance. Recent crack use, psychological symptoms, and victimization were not significantly related to caregiver status. Findings that socio-environmental factors were more strongly associated with caregiver status than crack use underscore the importance of contextual issues such as housing, victimization history, and resources in serving maternal crack users. Community outreach and interventions that engage mothers who use drugs and live with their children may be more effective strategies than formal office-based services to link mothers who use crack and their children to needed drug treatment and family and child services.


Inactivation of allergens and toxins.
Plants are replete with thousands of proteins and small molecules, many of which are species-specific, poisonous or dangerous. Over time humans have learned to avoid dangerous plants or inactivate many toxic components in food plants, but there is still room for ameliorating food crops (and plants in general) in terms of their allergens and toxins content, especially in their edible parts. Inactivation at the genetic rather than physical or chemical level has many advantages and classical genetic approaches have resulted in significant reduction of toxin content. The capacity, offered by genetic engineering, of turning off (inactivating) specific genes has opened up the possibility of altering the plant content in a far more precise manner than previously available. Different levels of intervention (genes coding for toxins/allergens or for enzymes, transporters or regulators involved in their metabolism) are possible and there are several tools for inactivating genes, both direct (using chemical and physical mutagens, insertion of transposons and other genetic elements) and indirect (antisense RNA, RNA interference, microRNA, eventually leading to gene silencing). Each level/strategy has specific advantages and disadvantages (speed, costs, selectivity, stability, reversibility, frequency of desired genotype and regulatory regime). Paradigmatic examples from classical and transgenic approaches are discussed to emphasize the need to revise the present regulatory process. Reducing the content of natural toxins is a trade-off process: the lesser the content of natural toxins, the higher the susceptibility of a plant to pests and therefore the stronger the need to protect plants. As a consequence, more specific pesticides like Bt are needed to substitute for general pesticides.


Polypropylene Blends with m-EPR Copolymers: Mechanical and Rheological Properties.
The effects of two metallocene ethylene-propylene-based elastomers (m-EPR1 and m-EPR2) differing in molecular mass and viscosity on mechanical, rheological and interfacial properties were compared. The m-EPR elastomers were added to iPP in 2.5, 5, 10, 15, and 20 vol.%. Torque values, elongation at break and impact strength measured of the iPP/m-EPR1 blends were higher than the iPP/m-EPR2 blends due to higher molten viscosity of m-EPR1 than m-EPR2 copolymer. Slight differences in Young moduli as well as in tensile strength at yield and at break might indicate that tensile properties of iPP/m-EPR blends were not significantly affected by difference in viscosity or molecular mass, miscibility and spherulite size. Optimization diagrams indicated the metallocene m-EPR copolymers are efficient impact modifiers for polypropylene and showed good balancing of mechanical properties in iPP/m-EPR blends.


Ventrolateral prefrontal cortex plays an executive regulation role in comprehension of abstract words: convergent neuropsychological and repetitive TMS evidence.
Neuroimaging studies reliably reveal ventrolateral prefrontal cortex (VLPFC) activation for processing of abstract relative to concrete words, but the cause of this effect is unclear. Here, in a convergent neuropsychological and repetitive transcranial magnetic stimulation (rTMS) investigation, we tested the hypothesis that abstract words require VLPFC because they depend heavily on the semantic-executive control processes mediated by this region. Specifically, we hypothesized that accessing the meanings of abstract words require more executive regulation because they have variable, context-dependent meanings. In the neuropsychology component of the study, aphasic patients with multimodal semantic deficits following VLPFC lesions had impaired comprehension of abstract words, but this deficit was ameliorated by providing a sentence cue that placed the word in a specific context. Concrete words were better comprehended and showed more limited benefit from the cues. In the second part of the study, rTMS applied to left VLPFC in healthy subjects slowed reaction times to abstract but not concrete words, but only when words were presented out of context. TMS had no effect when words were preceded by a contextual cue. These converging results indicate that VLPFC plays an executive regulation role in the processing of abstract words. This role is less critical when words are presented with a context that guides the system toward a particular meaning or interpretation. Regulation is less important for concrete words because their meanings are constrained by their physical referents and do not tend to vary with context.


Web-based climate information resources for malaria control in Africa.
Malaria remains a major public health threat to more than 600 million Africans and its control is recognized as critical to achieving the Millennium Development Goals. The greatest burden of malaria in Africa occurs in the endemic regions where the disease pathogen is continuously present in the community. These regions are characterized by an environment that is conducive to interactions between the Anopheles mosquito, malaria parasites and human hosts, as well as housing of generally poor quality, which offers little protection from mosquito-human contact. Epidemic malaria tends to occur along the geographical margins of endemic regions, when the equilibrium between the human, parasite and mosquito vector populations is occasionally disturbed and a sharp but temporary increase in disease incidence results. When malaria control measures are inadequate, as is the case in much of sub-Saharan Africa, the disease distribution is closely linked with seasonal patterns of the climate and local environment. In the absence of good epidemiological data on malaria distribution in Africa, climate information has long been used to develop malaria risk maps that illustrate the boundaries of 'climatic suitability for endemic transmission.' The best known of these are produced by the Pan-African-based MARA Collaboration. This paper describes the development of additional malaria suitability maps which have been produced in an online, interactive format to enable temporal information (i.e., seasonality of climate conditions) to be queried and displayed along with spatial information. These maps and the seasonal information that they contain should be useful to the malaria control and health service communities for their planning and operational activities.


Evolutionary relationships among G protein-coupled receptors using a clustered database approach.
Guanine nucleotide-binding protein-coupled receptors (GPCRs) comprise large and diverse gene families in fungi, plants, and the animal kingdom. GPCRs appear to share a common structure with 7 transmembrane segments, but sequence similarity is minimal among the most distant GPCRs. To reevaluate the question of evolutionary relationships among the disparate GPCR families, this study takes advantage of the dramatically increased number of cloned GPCRs. Sequences were selected from the National Center for Biotechnology Information (NCBI) nonredundant peptide database using iterative BLAST (Basic Local Alignment Search Tool) searches to yield a database of approximately 1700 GPCRs and unrelated membrane proteins as controls, divided into 34 distinct clusters. For each cluster, separate position-specific matrices were established to optimize sequence comparisons among GPCRs. This approach resulted in significant alignments between distant GPCR families, including receptors for the biogenic amine/peptide, VIP/secretin, cAMP, STE3/MAP3 fungal pheromones, latrophilin, developmental receptors frizzled and smoothened, as well as the more distant metabotrobic glutamate receptors, the STE2/MAM2 fungal pheromone receptors, and GPR1, a fungal glucose receptor. On the other hand, alignment scores between these recognized GPCR clades with p40 (putative GPCR) and pm1 (putative GPCR), as well as bacteriorhodopsins, failed to support a finding of homology. This study provides a refined view of GPCR ancestry and serves as a reference database with hyperlinks to other sources. Moreover, it may facilitate database annotation and the assignment of orphan receptors to GPCR families.


Isolation and identification of a growth inhibitory substance from Heliotropium indicum L.
Heliotropium indicum L. belongs to the family Boraginaceae. The plant has been used as a folk medicine because it contains substances of various biological activities. It is also identified as a common weed which grows wildly in crop fields in tropical and subtropical regions of the world. However, there is little information on the allelopathic effect in this plant. Therefore, this study was undertaken to investigate the growth inhibitory effect and to identify the growth inhibitory substances in H. indicum. An aqueous methanol extract of H. indicum inhibited shoot and root growth of barnyard grass, foxtail fescue, timothy, cress, lettuce and rapeseed at concentrations higher than 10 mg dry weight equivalent extract/mL. The concentrations required for 50% growth inhibition (I50) of those test plants ranged from 3-282 mg dry weight equivalent extract/mL. The extract was then separated using a sequence of chromatographic fractionations and a growth inhibitory substance was isolated and identified by spectral analysis as methyl caffeate. Methyl caffeate inhibited the growth of lettuce and foxtail fescue at concentrations higher than 1.0 mM. The results suggest that methyl caffeate may contribute to the growth inhibitory effect of H. indicum and may play an important role in the allelopathic effect of H. indicum.


The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes.
The present study attempted to identify an alpha-2 agonist that could improve working memory in aged nonhuman primates without the marked hypotensive and sedative side effects produced by clonidine. Toward this end, the hypotensive, sedative, and memory-altering properties of the alpha-2 adrenergic agonists, B-HT920 and guanfacine, were compared with clonidine's effects in 9 aged rhesus monkeys. Memory capacity was assessed by a variable delay, spatial delayed response paradigm that requires the animal to remember information over short temporal intervals and to update this information on every trial. B-HT920 was found to produce a dose-response profile qualitatively similar to, but weaker than, clonidine: low doses impaired memory and began to lower blood pressure and produce sedation, while high doses improved memory. In contrast, guanfacine produced a dose-response profile opposite to that seen with clonidine: low doses improved memory without inducing hypotension or sedation, while the memory-impairing, hypotensive, and sedating properties of the drug were observed at higher doses. The potency of the 3 agonists to lower blood pressure was clonidine = B-HT920 greater than guanfacine; sedation was affected in the order clonidine greater than B-HT920 greater than guanfacine; for memory impairment, as measured by performance on the delayed response task, the rank order potency was clonidine greater than B-HT920 greater than guanfacine, while for memory improvement it was guanfacine greater than clonidine greater than B-HT920. These differences in rank order potency are consistent with the recent proposal of alpha-2 receptor subtypes, a rauwolscine-sensitive site (Rs) that binds clonidine greater than B-HT920 greater than guanfacine and a rauwolscine-insensitive site (Ri) that binds guanfacine greater than clonidine greater than B-HT920 (Boyajian and Leslie, 1987). The data suggest that the hypotensive, sedating, and memory-impairing effects of alpha-2 agonists may be due to actions at one subtype of receptor (Rs), while the memory-enhancing effects of these drugs may result from actions at another alpha-2 receptor subtype, the Ri site. The ability of low doses of guanfacine to improve memory without inducing hypotension or sedation indicates that this agonist may be an excellent candidate for treating memory disorders in man.


Alphavirus-based vaccines.
Alphavirus vectors have demonstrated high levels of transient heterologous gene expression both in vitro and in vivo and, therefore, possess attractive features for vaccine development. The most commonly used delivery vectors are based on three single-stranded encapsulated alphaviruses, namely Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus. Alphavirus vectors have been applied as replication-deficient recombinant viral particles and, more recently, as replication-proficient particles. Moreover, in vitro transcribed RNA, as well as layered DNA vectors have been applied for immunization. A large number of highly immunogenic viral structural proteins expressed from alphavirus vectors have elicited strong neutralizing antibody responses in multispecies animal models. Furthermore, immunization studies have demonstrated robust protection against challenges with lethal doses of virus in rodents and primates. Similarly, vaccination with alphavirus vectors expressing tumor antigens resulted in prophylactic protection against challenges with tumor-inducing cancerous cells. As certain alphaviruses, such as Chikungunya virus, have been associated with epidemics in animals and humans, attention has also been paid to the development of vaccines against alphaviruses themselves. Recent progress in alphavirus vector development and vaccine technology has allowed conducting clinical trials in humans.


Nephronectin plays critical roles in Sox2 expression and proliferation in dental epithelial stem cells via EGF-like repeat domains.
Tooth development is initiated by epithelial-mesenchymal interactions via basement membrane (BM) and growth factors. In the present study, we found that nephronectin (Npnt), a component of the BM, is highly expressed in the developing tooth. Npnt localizes in the BM on the buccal side of the tooth germ and shows an expression pattern opposite that of the dental epithelial stem cell marker Sox2. To identify the roles of Npnt during tooth development, we performed knockdown and overexpression experiments using ex vivo organ and dental epithelial cell cultures. Our findings showed that loss of Npnt induced ectopic Sox2-positive cells and reduced tooth germ size. Over expression of Npnt showed increased proliferation, whereas the number of Sox2-positive cells was decreased in dental epithelial cells. Npnt contains 5 EGF-like repeat domains, as well as an RGD sequence and MAM domain. We found that the EGF-like repeats are critical for Sox2 expression and cell proliferation. Furthermore, Npnt activated the EGF receptor (EGFR) via the EGF-like repeat domains and induced the PI3K-Akt signaling pathway. Our results indicate that Npnt plays a critical scaffold role in dental epithelial stem cell differentiation and proliferation, and regulates Sox2 expression during tooth development.


Concentration Accuracy of Compounded Mitomycin C for Ophthalmic Surgery.
Ophthalmologists rely on accurate concentrations of mitomycin C (MMC) to prevent scarring with trabeculectomy surgery. To our knowledge, the concentration accuracy and variability of compounded MMC are unknown. To determine whether the measured concentration differs from the expected concentration of 0.4 mg/mL of MMC used in ophthalmic surgery. Laboratory experimental investigation conducted in July 2013. We acquired 60 samples of 0.4 mg/mL of MMC from a spectrum of common compounding and storage techniques (refrigeration, freezing, and immediately compounded dry powder) and a variety of pharmacies (an academic hospital, a community hospital, and an independent Pharmacy Compounding Accreditation Board-accredited pharmacy). We used C18 reversed-phase high-performance liquid chromatography to measure the MMC concentration of all samples. We used pure MMC (Medisca Inc) to generate calibration curves and sulfanilamide as an internal standard. We calculated MMC concentration using a calibration curve (range, 0.3-0.5 mg/mL) generated by dividing MMC peak area by internal standard peak area and plotting the area ratio against the calibrant concentrations. We compared the measured concentration against the expected 0.4 mg/mL concentration for all samples. Measurement of MMC using the high-performance liquid chromatography method demonstrated acceptable accuracy (92%-100%), precision (2%-6% coefficient of variation), and linearity (mean correlation coefficient of r2 = 0.99). The measured MMC concentration determined using the high-performance liquid chromatography method for all samples was 12.5% lower than the expected 0.4 mg/mL value (mean [SD], 0.35 [0.04] mg/mL; 95% CI, 0.34-0.36; P < .001) with a wide concentration range between 0.26 and 0.46 mg/mL. Common compounding and storage techniques for MMC resulted in a lower accuracy and wider range of concentration than expected. These differences in concentration may result from compounding techniques and/or MMC degradation. Variability in MMC concentration could cause inconsistency in glaucoma surgical results, but the clinical relevance of such findings on glaucoma surgery outcomes remains unknown.


Symptom Trajectories After an Emergency Department Visit for Potential Acute Coronary Syndrome.
Many patients evaluated for acute coronary syndrome (ACS) in emergency departments (EDs) continue to experience troubling symptoms after discharge-regardless of their ultimate medical diagnosis. However, comprehensive understanding of common post-ED symptom trajectories is lacking. The aim of this study was to identify common trajectories of symptom severity in the 6 months after an ED visit for potential ACS. This was a secondary analysis of data from a larger observational, prospective study conducted in five U.S. EDs. Patients (N = 1005) who had electrocardiogram and biomarker testing ordered, and were identified by the triage nurse as potentially having ACS, were enrolled. Symptom severity was assessed in the hospital after initial stabilization and by telephone at 30 days and 6 months using the validated 13-item ACS Symptom Checklist. Growth mixture modeling was used for the secondary analysis. The eight most commonly reported symptoms (chest discomfort, chest pain, chest pressure, light-headedness, shortness of breath, shoulder pain, unusual fatigue, and upper back pain) were modeled across the three study time points. Models with increasing numbers of classes were compared, and final model selection was based on a combination of interpretability, theoretical justification, and statistical fit indices. The sample was 62.6% male with a mean age of 60.2 years (SD = 14.17 years), and 57.1% ruled out for ACS. Between two and four distinct trajectory classes were identified for each symptom. The seven different types of trajectories identified across the eight symptoms were labeled "tapering off," "mild/persistent," "moderate/persistent," "moderate/worsening," "moderate/improving," "late onset, "and "severe/improving." Trajectories differed on age, gender, and diagnosis. Research on the individual nature of symptom trajectories can contribute to patient-centered, rather than disease-centered, care. Further research is needed to verify the existence of multiple symptoms trajectories in diverse populations and to assess the antecedents and consequences of individual symptom trajectories.


Abstraction and perceptual individuation in primed word identification are modulated by distortion and repetition: a dissociation.
One experiment investigated the effects of distortion and multiple prime repetition (super-repetition) on repetition priming using divided-visual-field word identification at test and mixed-case words (e.g., goAT). The experiment measured form-specificity (the effect of matching lettercase at study and test) for two non-conceptual study tasks. For an ideal typeface, super-repetition increased form-independent priming leaving form-specificity constant. The opposite pattern was found for a distorted typeface; super-repetition increased form-specificity, leaving form-independent priming constant. These priming effects did not depend on the study task or test hemifield for either typeface. An additional finding was that only the ideal typeface showed the usual advantage of right hemifield presentation. These results demonstrate that super-repetition produced abstraction for the ideal typeface and perceptual individuation for the distorted typeface; abstraction and perceptual individuation dissociated. We suggest that there is a fundamental duality between perceptual individuation and abstraction consistent with Tulving's (1984) distinction between episodic and semantic memory. This could reflect a duality of system or process.


Secondary Organic Aerosol Formation from Urban Roadside Air in Hong Kong.
Motor vehicle emissions are an important but poorly constrained source of secondary organic aerosol (SOA). Here, we investigated in situ SOA formation from urban roadside air in Hong Kong during winter time using an oxidation flow reactor (OFR), with equivalent atmospheric oxidation ranging from several hours to several days. The campaign-average mass enhancement of OA, nitrate, sulfate, and ammonium upon OFR aging was 7.0, 7.2, 0.8, and 2.6 μg m-3, respectively. To investigate the sources of SOA formation potential, we performed multilinear regression analysis between measured peak SOA concentrations from OFR and the concentrations of toluene that represent motor vehicle emissions and cooking OA from positive matrix factorization (PMF) analysis of ambient OA. Traffic-related SOA precursors contributed 92.3%, 92.4%, and 83.1% to the total SOA formation potential during morning rush hours, noon and early afternoon, and evening meal time, respectively. The SOA production factor (PF) was approximately 5.2 times of primary OA (POA) emission factor (EF) and the secondary particulate matter (PM) PF was approximately 2.6 times of primary particles EF. This study highlights the potential benefit of reducing secondary PM production from motor vehicle emissions in mitigating PM pollutions.


Genetic Diversity of Landraces and Improved Varieties of Rice (Oryza sativa L.) in Taiwan.
Rice, the most important crop in Asia, has been cultivated in Taiwan for more than 5000 years. The landraces preserved by indigenous peoples and brought by immigrants from China hundreds of years ago exhibit large variation in morphology, implying that they comprise rich genetic resources. Breeding goals according to the preferences of farmers, consumers and government policies also alter gene pools and genetic diversity of improved varieties. To unveil how genetic diversity is affected by natural, farmers', and breeders' selections is crucial for germplasm conservation and crop improvement. A diversity panel of 148 rice accessions, including 47 cultivars and 59 landraces from Taiwan and 42 accessions from other countries, were genotyped by using 75 molecular markers that revealed an average of 12.7 alleles per locus with mean polymorphism information content of 0.72. These accessions could be grouped into five subpopulations corresponding to wild rice, japonica landraces, indica landraces, indica cultivars, and japonica cultivars. The genetic diversity within subpopulations was: wild rices > landraces > cultivars; and indica rice > japonica rice. Despite having less variation among cultivars, japonica landraces had greater genetic variation than indica landraces because the majority of Taiwanese japonica landraces preserved by indigenous peoples were classified as tropical japonica. Two major clusters of indica landraces were formed by phylogenetic analysis, in accordance with immigration from two origins. Genetic erosion had occurred in later japonica varieties due to a narrow selection of germplasm being incorporated into breeding programs for premium grain quality. Genetic differentiation between early and late cultivars was significant in japonica (FST = 0.3751) but not in indica (FST = 0.0045), indicating effects of different breeding goals on modern germplasm. Indigenous landraces with unique intermediate and admixed genetic backgrounds were untapped, representing valuable resources for rice breeding. The genetic diversity of improved rice varieties has been substantially shaped by breeding goals, leading to differentiation between indica and japonica cultivars. Taiwanese landraces with different origins possess various and unique genetic backgrounds. Taiwanese rice germplasm provides diverse genetic variation for association mapping to unveil useful genes and is a precious genetic reservoir for rice improvement.


Proteases as regulators of pathogenesis: examples from the Apicomplexa.
The diverse functional roles that proteases play in basic biological processes make them essential for virtually all organisms. Not surprisingly, proteolysis is also a critical process required for many aspects of pathogenesis. In particular, obligate intracellular parasites must precisely coordinate proteolytic events during their highly regulated life cycle inside multiple host cell environments. Advances in chemical, proteomic and genetic tools that can be applied to parasite biology have led to an increased understanding of the complex events centrally regulated by proteases. In this review, we outline recent advances in our knowledge of specific proteolytic enzymes in two medically relevant apicomplexan parasites: Plasmodium falciparum and Toxoplasma gondii. Efforts over the last decade have begun to provide a map of key proteotolyic events that are essential for both parasite survival and propagation inside host cells. These advances in our molecular understanding of proteolytic events involved in parasite pathogenesis provide a foundation for the validation of new networks and enzyme targets that could be exploited for therapeutic purposes. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.


Lactobacillus silagincola sp. nov. and Lactobacillus pentosiphilus sp. nov., isolated from silage.
Three Gram-stain positive, non-motile, non-spore-forming, catalase-negative and rod-shaped bacterial strains (IWT5T, IWT25T and IWT140), isolated from silage, were investigated by using a polyphasic taxonomic approach. Strains IWT5T and IWT25T grew at 10-37 °C and 30-37 °C, and at pH 4.0-7.5 and 4.0-7.0, respectively. The G+C contents of genomic DNA of strains IWT5T and IWT25T were 43.2 and 44.4 mol%, respectively. Strains IWT5T and IWT25T contained C16 : 0, C18 : 1 ω9c and summed feature 7 (unknown 18.846/C19 : 1 ω6c/C19 : 0cyclo ω10c) as the major fatty acids. Strain IWT5T was most closely related to the type strains of Lactobacillus mixtipabuli (99.9 % 16S rRNA gene sequence similarity) and Lactobacillus silagei (99.5 %). For IWT25T, the 16S rRNA gene sequence similarities with the closely related neighbour type strains L. mixtipabuli and L. silagei were 99.5 and 99.5 %, respectively. The 16S rRNA gene sequence similarities among the three novel isolates were 99.5-99.9 %. The average nucleotide identities of strains IWT5T and IWT25T to other neighbours of the genus Lactobacillus were less than 82 % and the genomes of IWT25T and IWT140 shared 97.3 % average nucleotide identity, demonstrating that the three strains were allocated to two different novel species of the genus Lactobacillus. Together with multilocus sequence analysis, phenotypic and chemotaxonomic characteristics, strains IWT5T (=JCM 31144T=DSM 102973T) and IWT25T (=JCM 31145T=DSM 102974T) are proposed as the type strains of novel species of the genus Lactobacillus, with the names Lactobacillus silagincola sp. nov. and Lactobacillus pentosiphilus sp. nov., respectively.


Teacher-student neural coupling during teaching and learning.
Human communication is remarkably versatile, enabling teachers to share highly abstracted and novel information with their students. What neural processes enable such transfer of information across brains during naturalistic teaching and learning? Here, a teacher was scanned in functional magnetic resonance imaging while giving an oral lecture with slides on a scientific topic followed by a review lecture. Students were then scanned while watching either the intact Lecture and Review (N = 20) or a temporally scrambled version of the lecture (N = 20). Using intersubject correlation, we observed widespread Teacher-Student neural coupling spanning sensory cortex and language regions along the superior temporal sulcus as well as higher-level regions including posterior medial cortex (PMC), superior parietal lobule, and dorsolateral and dorsomedial prefrontal cortex. Teacher-student alignment in higher-level areas was not observed when learning was disrupted by temporally scrambling the lecture. Moreover, teacher-student coupling in PMC was significantly correlated with learning: the more closely the student's brain mirrored the teacher's brain, the more the student improved their learning score. Together, these results suggest that the alignment of neural responses between teacher and students may reflect effective communication of complex information across brains in classroom settings.


SNAREs Interact with Retinal Degeneration Slow and Rod Outer Segment Membrane Protein-1 during Conventional and Unconventional Outer Segment Targeting.
Mutations in the photoreceptor protein peripherin-2 (also known as RDS) cause severe retinal degeneration. RDS and its homolog ROM-1 (rod outer segment protein 1) are synthesized in the inner segment and then trafficked into the outer segment where they function in tetramers and covalently linked larger complexes. Our goal is to identify binding partners of RDS and ROM-1 that may be involved in their biosynthetic pathway or in their function in the photoreceptor outer segment (OS). Here we utilize several methods including mass spectrometry after affinity purification, in vitro co-expression followed by pull-down, in vivo pull-down from mouse retinas, and proximity ligation assay to identify and confirm the SNARE proteins Syntaxin 3B and SNAP-25 as novel binding partners of RDS and ROM-1. We show that both covalently linked and non-covalently linked RDS complexes interact with Syntaxin 3B. RDS in the mouse is trafficked from the inner segment to the outer segment by both conventional (i.e., Golgi dependent) and unconventional secretory pathways, and RDS from both pathways interacts with Syntaxin3B. Syntaxin 3B and SNAP-25 are enriched in the inner segment (compared to the outer segment) suggesting that the interaction with RDS/ROM-1 occurs in the inner segment. Syntaxin 3B and SNAP-25 are involved in mediating fusion of vesicles carrying other outer segment proteins during outer segment targeting, so could be involved in the trafficking of RDS/ROM-1.


Effect of swallowed bolus variables on oral and pharyngeal phases of swallowing.
In this investigation, we studied the effects of bolus volume and viscosity on the quantitative features of the oral and pharyngeal phases of swallowing. Concurrent videofluoroscopic and manometric studies were done in 10 healthy volunteers who were imaged in lateral projection. Videofluorography was done at 30 frames/s while concurrent manometry was done with 5 intraluminal transducers that straddled the pharynx and upper esophageal sphincter (UES). Submental electromyography was recorded also. Swallows of 2-20 ml were recorded for low-viscosity liquid barium and high-viscosity paste barium. Analysis indicated that the major effect of increases in bolus volume was an earlier onset of anterior tongue base movement, superior palatal movement, anterior laryngeal movement, and UES opening. These events provide receptive adaptation for receiving a swallowed bolus. Earlier UES opening was associated with an increase in the duration of sphincter opening and sphincter diameter. The major effects of high bolus viscosity, unrelated to bolus volume, were to delay oral and pharyngeal bolus transit, increase the duration of pharyngeal peristaltic waves, and prolong and increase UES opening. Thus the specific effect of bolus viscosity per se differs substantially from that of bolus volume. We conclude that 1) specific variables of swallowing are affected significantly by the variables of the swallowed bolus, such as volume and viscosity; 2) overall, bolus volume and viscosity affect swallowing in a different manner; and 3) the study findings have implications about the neural control mechanisms that govern swallowing as well as about the diagnosis and treatment of patients with abnormal oral-pharyngeal swallowing.


Recombination between polioviruses and co-circulating Coxsackie A viruses: role in the emergence of pathogenic vaccine-derived polioviruses.
Ten outbreaks of poliomyelitis caused by pathogenic circulating vaccine-derived polioviruses (cVDPVs) have recently been reported in different regions of the world. Two of these outbreaks occurred in Madagascar. Most cVDPVs were recombinants of mutated poliovaccine strains and other unidentified enteroviruses of species C. We previously reported that a type 2 cVDPV isolated during an outbreak in Madagascar was co-circulating with coxsackieviruses A17 (CA17) and that sequences in the 3' half of the cVDPV and CA17 genomes were related. The goal of this study was to investigate whether these CA17 isolates can act as recombination partners of poliovirus and subsequently to evaluate the major effects of recombination events on the phenotype of the recombinants. We first cloned the infectious cDNA of a Madagascar CA17 isolate. We then generated recombinant constructs combining the genetic material of this CA17 isolate with that of the type 2 vaccine strain and that of the type 2 cVDPV. Our results showed that poliovirus/CA17 recombinants are viable. The recombinant in which the 3' half of the vaccine strain genome had been replaced by that of the CA17 genome yielded larger plaques and was less temperature sensitive than its parental strains. The virus in which the 3' portion of the cVDPV genome was replaced by the 3' half of the CA17 genome was almost as neurovirulent as the cVDPV in transgenic mice expressing the poliovirus cellular receptor gene. The co-circulation in children and genetic recombination of viruses, differing in their pathogenicity for humans and in certain other biological properties such as receptor usage, can lead to the generation of pathogenic recombinants, thus constituting an interesting model of viral evolution and emergence.


Predicting mucositis risk associated with cytotoxic cancer treatment regimens: rationale, complexity, and challenges.
The goals of this review are to describe the complexity of factors influencing the risk of cancer regimen-related mucosal injury (CRRMI), to evaluate the contribution of the innate immune response to CRRMI risk, to compare the concordance of genome analytics in describing mechanism and risk, and to determine if common biological pathways are noted when CRRMI is compared to a disease with a similar phenotype. The pathogenesis of and risk for CRRMI are complex and influenced by multiple intrinsic and extrinsic factors. It is incumbent on analyses to recognize the likelihood that the interplay and cross-talk of synergistically expressed factors is critical and that the contributing weights of these factors is not uniform from patient to patient. Genomically derived analyses imply final common pathways are implicit in phenotype expression. The identification of specific factors (both genomic and otherwise) which contribute to CRRMI risk represents an important opportunity to apply principles of precision medicine to the management of regimen-related toxicities.


Gadopentetate dimeglumine-enhanced MR in the diagnosis of the Tolosa-Hunt syndrome.
A 54-year-old man first was admitted with a right oculomotor nerve palsy that ameliorated spontaneously. Two months later, he was readmitted with right proptosis, ophthalmoplegia, and optic nerve involvement. MR showed an enlarged right cavernous sinus. There was dramatic improvement after high doses of steroids. MR findings 10 months later were normal. Thus, the diagnosis of the Tolosa-Hunt syndrome was established.


Shock, acute disseminated intravascular coagulation, and microvascular thrombosis: is 'shock liver' the unrecognized provocateur of ischemic limb necrosis?
For unknown reasons, a small minority of critically ill patients with septic or cardiogenic shock, multiorgan failure, and disseminated intravascular coagulation develop symmetrical acral (distal extremity) limb loss due to microvascular thrombosis ('limb gangrene with pulses'). Case reports have described preceding 'shock liver' in some critically ill patients who developed such a picture of ischemic limb necrosis. This suggests that profoundly disturbed procoagulant-anticoagulant balance featuring uncontrolled generation of thrombin-resulting from failure of the protein C and antithrombin natural anticoagulant systems due to insufficient hepatic synthesis of these crucial proteins-could explain the microvascular thrombosis and associated limb loss. We hypothesize that shock liver is the key predisposing risk factor underlying ischemic limb necrosis in the majority of patients who develop this complication in the setting of acute disseminated intravascular coagulation complicating septic or cardiogenic shock. As shock liver precedes onset of limb ischemia by several days, therapeutic intervention may be possible.


An Evaluation of the Acceptability, Appropriateness, and Utility of a Bibliotherapy for Children of Parents With a Mental Illness.
Children of parents with a mental illness are at higher risk for various psychiatric problems and adaptive difficulties compared to those of parents without mental health problems. Certain preventive psychoeducational interventions target these children to promote their well-being and resilience and prevent the emergence of adaptive difficulties. However, few such interventions have been developed and evaluated specifically for elementary school-aged children of parents with a mental illness. This study aims to evaluate an interpersonal psychotherapy-based book targeting children living with a parent with a mental illness. The study examines children, parents and psychosocial workers' perception of the acceptability, appropriateness and utility of the book. In total, 22 participants answered online open-ended questions after reading the book. The book was highly appreciated and positively perceived by the families and psychosocial workers. Results suggest that children, parents and psychosocial workers viewed it as an appropriate and useful tool for supporting children with a parent with a mental illness. The present study reveals that the bibliotherapy appears well adapted to the developmental level of school-age children. This study presents a book that shows promise for supporting the resilience of elementary school-aged children having a parent with a mental illness. Results highlight the importance of tailoring the content and modalities of interventions to the developmental level, needs and preferences of elementary school-aged children. The relevance of a collaborative method is also discussed, thus providing knowledge regarding this type of approach for the development of interventions targeting children.


Genetic variation of DKK3 may modify renal disease severity in ADPKD.
Significant variation in the course of autosomal dominant polycystic kidney disease ( ADPKD) within families suggests the presence of effect modifiers. Recent studies of the variation within families harboring PKD1 mutations indicate that genetic background may account for 32 to 42% of the variance in estimated GFR (eGFR) before ESRD and 43 to 78% of the variance in age at ESRD onset, but the genetic modifiers are unknown. Here, we conducted a high-throughput single-nucleotide polymorphism (SNP) genotyping association study of 173 biological candidate genes in 794 white patients from 227 families with PKD1. We analyzed two primary outcomes: (1) eGFR and (2) time to ESRD (renal survival). For both outcomes, we used multidimensional scaling to correct for population structure and generalized estimating equations to account for the relatedness among individuals within the same family. We found suggestive associations between each of 12 SNPs and at least one of the renal outcomes. We genotyped these SNPs in a second set of 472 white patients from 229 families with PKD1 and performed a joint analysis on both cohorts. Three SNPs continued to show suggestive/significant association with eGFR at the Dickkopf 3 (DKK3) gene locus; no SNPs significantly associated with renal survival. DKK3 antagonizes Wnt/beta-catenin signaling, which may modulate renal cyst growth. Pending replication, our study suggests that genetic variation of DKK3 may modify severity of ADPKD resulting from PKD1 mutations.


Virgin coconut oil supplementation ameliorates cyclophosphamide-induced systemic toxicity in mice.
Virgin coconut oil (VCO) is an unrefined kernal oil, prepared from Cocos nucifera L., having substantial nutritional and medicinal value. Experimental studies have suggested its antioxidant, anti-inflammatory, immunostimulatory and hypolipidemic effects. The present study assesses its effect on formalin-induced chronic inflammation and cyclophosphamide (CTX)-induced systemic toxicity in murine models. Oral administration of VCO effectively reduced formalin-induced paw oedema in mice with more or less similar efficacy as that of diclofenac. The CTX-induced hike in blood urea, creatinine, thiobarbituric acid reactive substances (TBARS) and liver marker enzymes in mice was marginally decreased by VCO (8 g/kg body weight) ingestion orally. The liver and kidney catalase, superoxide dismutase and glutathione peroxidase activities, together with cellular glutathione and TBARS levels, were found to be improved in these animals. Overall the study reveals the protective efficacy of VCO against secondary toxicity induced by CTX possibly through its antioxidant and anti-inflammatory properties.


No genetic erosion after five generations for Impatiens glandulifera populations across the invaded range in Europe.
The observation that many alien species become invasive despite low genetic diversity has long been considered the 'genetic paradox' in invasion biology. This paradox is often resolved through the temporal buildup genetic diversity through multiple introduction events. These temporal dynamics in genetic diversity are especially important for annual invasive plants that lack a persistent seed bank, for which population persistence is strongly dependent on consecutive seed 're-establishment' in each growing season. Theory predicts that the number of seeds during re-establishment, and the levels of among-population gene flow can strongly affect recolonization dynamics, resulting in either an erosion or build-up of population genetic diversity through time. This study focuses on temporal changes in the population genetic structure of the annual invasive plant Impatiens glandulifera across Europe. We resampled 13 populations in 6 regions along a 1600 km long latitudinal gradient from northern France to central Norway after 5 years, and assessed population genetic diversity with 9 microsatellite markers. Our study suggests sufficiently high numbers of genetically diverse founders during population re-establishment, which prevent the erosion of local genetic diversity. We furthermore observe that I. glandulifera experiences significant among-population gene flow, gradually resulting in higher genetic diversity and lower overall genetic differentiation through time. Nonetheless, moderate founder effects concerning population genetic composition (allele frequencies) were evident, especially for smaller populations. Despite the initially low genetic diversity, this species seems to be successful at persisting across its invaded range, and will likely continue to build up higher genetic diversity at the local scale.


Effectiveness of financial incentives to improve adherence to maintenance treatment with antipsychotics: cluster randomised controlled trial.
To test whether offering financial incentives to patients with psychotic disorders is effective in improving adherence to maintenance treatment with antipsychotics. Cluster randomised controlled trial. Community mental health teams in secondary psychiatric care in the United Kingdom. Patients with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder, who were prescribed long acting antipsychotic (depot) injections but had received 75% or less of the prescribed injections. We randomly allocated 73 teams with a total of 141 patients. Primary outcome data were available for 35 intervention teams with 75 patients (96% of randomised) and for 31 control teams with 56 patients (89% of randomised). Participants in the intervention group were offered £15 (€17; $22) for each depot injection over a 12 month period. Participants in the control condition received treatment as usual. The primary outcome was the percentage of prescribed depot injections given during the 12 month intervention period. 73 teams with 141 consenting patients were randomised, and outcomes were assessed for 131 patients (93%). Average baseline adherence was 69% in the intervention group and 67% in the control group. During the 12 month trial period adherence was 85% in the intervention group and 71% in the control group. The adjusted effect estimate was 11.5% (95% confidence interval 3.9% to 19.0%, P=0.003). A secondary outcome was an adherence of ≥ 95%, which was achieved in 28% of the intervention group and 5% of the control group (adjusted odds ratio 8.21, 95% confidence interval 2.00 to 33.67, P=0.003). Although differences in clinician rated clinical improvement between the groups failed to reach statistical significance, patients in the intervention group had more favourable subjective quality of life ratings (β=0.71, 95% confidence interval 0.26 to 1.15, P=0.002). The number of admissions to hospital and adverse events were low in both groups and did not show substantial differences. Offering modest financial incentives to patients with psychotic disorders is an effective method for improving adherence to maintenance treatment with antipsychotics. Current Controlled Trials ISRCTN77769281.


Dose response to vitamin D supplementation in postmenopausal women: a randomized trial.
Serum 25-hydroxyvitamin D (25-[OH]D) is considered the best biomarker of clinical vitamin D status. To determine the effect of increasing oral doses of vitamin D(3) on serum 25-(OH)D and serum parathyroid hormone (PTH) levels in postmenopausal white women with vitamin D insufficiency (defined as a 25-[OH]D level ≤50 nmol/L) in the presence of adequate calcium intake. These results can be used as a guide to estimate the Recommended Dietary Allowance (RDA) (defined as meeting the needs of 97.5% of the population) for vitamin D(3). Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00472823) Creighton University Medical Center, Omaha, Nebraska. 163 healthy postmenopausal white women with vitamin D insufficiency enrolled in the winter or spring of 2007 to 2008 and followed for 1 year. Participants were randomly assigned to receive placebo or vitamin D(3), 400, 800, 1600, 2400, 3200, 4000, or 4800 IU once daily. Daily calcium supplements were provided to increase the total daily calcium intake to 1200 to 1400 mg. The primary outcomes were 25-(OH)D and PTH levels at 6 and 12 months. The mean baseline 25-(OH)D level was 39 nmol/L. The dose response was curvilinear and tended to plateau at approximately 112 nmol/L in patients receiving more than 3200 IU/d of vitamin D(3). The RDA of vitamin D(3) to achieve a 25-(OH)D level greater than 50 nmol/L was 800 IU/d. A mixed-effects model predicted that 600 IU of vitamin D(3) daily could also meet this goal. Compared with participants with a normal body mass index (<25 kg/m(2)), obese women (≥30 kg/m(2)) had a 25-(OH)D level that was 17.8 nmol/L lower. Parathyroid hormone levels at 12 months decreased with an increasing dose of vitamin D(3) (P = 0.012). Depending on the criteria used, hypercalcemia occurred in 2.8% to 9.0% and hypercalciuria in 12.0% to 33.0% of participants; events were unrelated to dose. Findings may not be generalizable to other age groups or persons with substantial comorbid conditions. A vitamin D(3) dosage of 800 IU/d increased serum 25-(OH)D levels to greater than 50 nmol/L in 97.5% of women; however, a model predicted the same response with a vitamin D(3) dosage of 600 IU/d. These results can be used as a guide for the RDA of vitamin D(3), but prospective trials are needed to confirm the clinical significance of these results. National Institute on Aging.


Cytotoxicity and effect on wound re-epithelialization after topical administration of tranexamic acid.
Topical administration of tranexamic acid (TXA) reduces bleeding from surgical wounds similarly to intravenous use, but with negligible risk of adverse systemic events. Topical use is expanding, but is off-label. Surgeons lack guidelines regarding safe topical dosages and modes of administration. The effects of topical TXA on skin cells and wound healing are unknown. This study investigated whether topical TXA might be cytotoxic or affect wound re-epithelialization. Human keratinocytes and fibroblast cell cultures and an ex vivo human skin wound model were subjected to both short (limited) and long (chronic) exposure to various clinically relevant concentrations of TXA to mimic different modalities of topical administration. Cytotoxicity and effects on wound re-epithelialization were evaluated. In cell culture, toxicity from chronic exposure was associated with increasing concentration and exposure time. Limited exposure to TXA did not cause significant cytotoxicity even at high concentrations. Re-epithelialization was completely absent in wounds chronically exposed to TXA concentrations of 25 mg/ml or above, and 50-100 mg/ml induced epidermolysis of normal epithelium, possibly by a non-toxic mechanism. Wound re-epithelialization was slightly delayed, but not impaired, by limited exposure to 100 mg/ml or chronic exposure to 6·25 mg/ml. Although short exposure to even high concentrations of topical TXA seems well tolerated in vitro, prolonged exposure can be cytotoxic and may affect wound re-epithelialization. Surgeons should adjust the TXA concentration to the planned mode of topical administration in clinical practice.


Synthetic peptides derived from E7 region of human papillomavirus type 16 used as antigens in ELISA.
Nine overlapping peptides (20 amino acid) covering the entire sequence of early antigen E7 of human papillomavirus type 16 (HPV-16) were synthesized and tested as antigens with human sera in ELISA. Five of these peptides (no. 1 to 5 counting from the N terminus of the E7 protein) reacted with a pool of sera from HPV-16-infected individuals (as determined by molecular hybridization with their biopsy specimens); one (no. 5) was also reactive with pools of HPV-18- and HPV-6- or 11-infected individuals. Sera from 24 patients with cervical intraepithelial neoplasia (CIN) and from 29 invasive cervical carcinoma (INCA) patients were tested for the presence of antibodies reactive with peptides, no. 1 to 4 covering amino acids 1 to 50 and with peptide no. 5 covering amino acids 41 to 60. Only one of the sera from CIN patients was reactive with peptides no. 1 (amino acids 1 to 20) and no. 4 (amino acids 31 to 50). However, the majority of these sera reacted with peptide no. 5. The occurrence of this antibody was only slightly less frequent in sera from healthy subjects compared to CIN patients. On the other hand, sera from the INCA patients were reactive with the peptides no. 1 to 3 more frequently than the sera from matched control subjects. Positive reactions of sera from INCA patients were most frequently seen with no. 2; 24% of these sera but only 7% of the controls were reactive with no. 2 peptide. The present data suggest that no. 1 to 3 are HPV-16-specific, whereas no. 5 is broadly cross-reactive.


No association between interferon-gamma receptor-1 gene polymorphism and pulmonary tuberculosis in a Gambian population sample.
Tuberculosis (TB) is a major global cause of mortality and morbidity, and host genetic factors influence disease susceptibility. Interferon-gamma mediates immunity to mycobacteria and rare mutations in the interferon-gamma receptor-1 gene (IFNGR1) result in increased susceptibility to mycobacterial infection, including TB, in affected families. The role of genetic variation in IFNGR1 in susceptibility to common mycobacterial diseases such as pulmonary TB in outbred populations has not previously been investigated. The association between IFNGR1 and susceptibility to pulmonary TB was investigated in a Gambian adult population sample using a case-control study design. The coding and promoter regions of IFNGR1 were sequenced in 32 patients with pulmonary TB, and the frequencies of six common IFNGR1 polymorphisms were determined using PCR based methods in 320 smear positive TB cases and 320 matched controls. Haplotypes were estimated from the genotype data using the expectation-maximisation algorithm. There was no association between the IFNGR1 variants studied and TB in this Gambian population sample. Three common haplotypes were identified within the study population, none of which was associated with TB. These data represent an important negative finding and suggest that, while IFNGR1 is implicated in rare Mendelian susceptibility to mycobacterial disease, the common variants studied here do not have a major influence on susceptibility to pulmonary TB in The Gambian population.


Mortality risk over time after early fluid resuscitation in African children.
African children hospitalised with severe febrile illness have a high risk of mortality. The Fluid Expansion As Supportive Therapy (FEAST) trial (ISCRTN 69856593) demonstrated increased mortality risk associated with fluid boluses, but the temporal relationship to bolus therapy and underlying mechanism remains unclear. In a post hoc retrospective analysis, flexible parametric models were used to compare change in mortality risk post-randomisation in children allocated to bolus therapy with 20-40 ml/kg 5% albumin or 0.9% saline over 1-2 h or no bolus (control, 4 ml/kg/hour maintenance), overall and for different terminal clinical events (cardiogenic, neurological, respiratory, or unknown/other). Two thousand ninety-seven and 1041 children were randomised to bolus vs no bolus, of whom 254 (12%) and 91 (9%) respectively died within 28 days. Median (IQR) bolus fluid in the bolus groups received by 4 h was 20 (20, 40) ml/kg and was the same at 8 h; total fluids received in bolus groups at 4 h and 8 h were 38 (28, 43) ml/kg and 40 (30, 50) ml/kg, respectively. Total fluid volumes received in the control group by 4 h and 8 h were median (IQR) 10 (6, 15) ml/kg and 10 (10, 26) ml/kg, respectively. Mortality risk was greatest 30 min post-randomisation in both groups, declining sharply to 4 h and then more slowly to 28 days. Maximum mortality risk was similar in bolus and no bolus groups; however, the risk declined more slowly in the bolus group, with significantly higher mortality risk compared to the no bolus group from 1.6 to 101 h (4 days) post-randomisation. The delay in decline in mortality risk in the bolus groups was most pronounced for cardiogenic modes of death. The increased risk from bolus therapy was not due to a mechanism occurring immediately after bolus administration. Excess mortality risk in the bolus group resulted from slower decrease in mortality risk over the ensuing 4 days. Thus, administration of modest bolus volumes appeared to prevent mortality risk declining at the same rate that it would have done without a bolus, rather than harm associated with bolus resulting from a concurrent increased risk of death peri-bolus administration. ISRCTN69856593. Date of registration 15 December 2008.


Gastrointestinal dysfunction in the critically ill: nutritional implications.
Parenteral therapy is frequently indicated for initial repletion in the severely malnourished patient. Attention should be paid to the nutrients required for initial repletion based on the patient's metabolic needs at the time of therapy, as well as allowance for adequate calories for repletion of body and muscle mass. After the initiation of parenteral therapy and the adequate replacement of fluids and electrolytes, slow introduction of oral or enteric feeding is reasonable. This probably is best handled initially by the use of a nasogastric or nasoenteric feeding tube. However, if the patient willingly ingests oral feedings, the oral route is certainly favorable. Close attention should be paid to the adequacy of gastric emptying. Symptoms of abdominal bloating and diarrhea may require modification of the rate at which oral intake is progressing.


Recombinant subviral particles from tick-borne encephalitis virus are fusogenic and provide a model system for studying flavivirus envelope glycoprotein functions.
Recombinant subviral particles (RSPs) obtained by coexpression of the envelope (E) and premembrane (prM) proteins of tick-borne encephalitis virus in COS cells (S. L. Allison, K. Stadler, C. W. Mandl, C. Kunz, and F. X. Heinz, J. Virol. 69:5816-5820, 1995) were extensively characterized and shown to be ordered structures containing envelope glycoproteins with structural and functional properties very similar to those in the virion envelope. The particles were spherical, with a diameter of about 30 nm and a buoyant density of 1.14 g/cm3 in sucrose gradients. They contained mature E proteins with endoglycosidase H-resistant glycans as well as fully cleaved mature M proteins. Cleavage of prM, which requires an acidic pH in exocytic compartments, could be inhibited by treatment of transfected cells with ammonium chloride, implying a common maturation pathway for RSPs and virions. RSPs incorporated [14C]choline but not [3H]uridine, demonstrating that they contain lipid but probably lack nucleic acid. The envelope proteins of RSPs exhibited a native antigenic and oligomeric structure compared with virions, and incubation at an acidic pH (pH <6.5) induced identical conformational changes and structural rearrangements, including an irreversible quantitative conversion of dimers to trimers. The RSPs were also shown to be functionally active, inducing membrane fusion in a low-pH-dependent manner and demonstrating the same specific hemagglutination activity as whole virions. Tick-borne encephalitis virus RSPs thus represent an excellent model system for investigating the structural basis of viral envelope glycoprotein functions.


Dopamine Coupling to Mitochondrial Signaling: Implications for Transplantation.
The persistence of major medical disorders afflicting millions of humans worldwide involves a functional pathophysiological coupling of systemic pro-inflammatory processes and tissue hypoxia. Mechanistically, reciprocal triggering of multiple ischemic/hypoxic and pro-inflammatory events, if not corrected, will promote pathophysiological amplification leading to a deleterious cascade of bio-senescent cellular and molecular signaling pathways that converge to markedly impair mitochondrial energy production. Given the level of energy production and utilization that can vary in and between cells and regionally in the same type of cells found in the body, e.g., dopamine neurons, the metabolic energy regulator, the mitochondrion, assumes a high position in the potential to maintain normal health and develop abnormal activities, resulting in chronic pathologies. The intra-mitochondrial availability of molecular oxygen as the ultimate electron acceptor drives the evolutionarily fashioned chemiosmotic production of ATP as a high-efficiency biological proton pump process. The mechanistic evolutionary bases of diabetes have demonstrated the profound alteration of normative mitochondrial function, notably deregulated respiratory processes. This same phenomenon provides evidence of mitochondrial linkages to neurological disorders, such as Parkinson's disease. To date, and despite considerable research efforts, the practical realization of advanced mitochondrial targeted therapies has not been forthcoming.


a/alpha-control of DNA repair in the yeast Saccharomyces cerevisiae: genetic and physiological aspects.
It has long been known that diploid strains of yeast are more resistant to gamma-rays than haploid cells, and that this is in part due to heterozygosity at the mating type (MAT) locus. It is shown here that the genetic control exerted by the MAT genes on DNA repair involves the a1 and alpha 2 genes, in a RME1-independent way. In rad18 diploids, affected in the error-prone repair, the a/alpha effects are of a very large amplitude, after both UV and gamma-rays, and also depends on a1 and alpha 2. The coexpression of a and alpha in rad18 haploids suppresses the sensitivity of a subpopulation corresponding to the G2 phase cells. Related to this, the coexpression of a and alpha in RAD+ haploids depresses UV-induced mutagenesis in G2 cells. For srs2 null diploids, also affected in the error-prone repair pathway, we show that their G1 UV sensitivity, likely due to lethal recombination events, is partly suppressed by MAT homozygosity. Taken together, these results led to the proposal that a1-alpha 2 promotes a channeling of some DNA structures from the mutagenic into the recombinational repair process.


Cyclometalated Ir(iii) complexes based on 2-(2,4-difluorophenyl)-pyridine and 2,2'-(2-phenyl-1H-imidazole-4,5-diyl)dipyridine: acid/base-induced structural transformation and luminescence switching, and photocatalytic activity for hydrogen evolution.
Based on ligands dfppyH and pidpyH, cyclometalated Ir(iii) complexes [Ir(dfppy)2(pidpyH)](PF6) (1·PF6) and [Ir(dfppy)2(pidpy)] (2) have been synthesized. The crystal structures indicate that each {Ir(dfppy)2}+ unit is coordinated by a neutral ligand pidpyH in 1·PF6, while by a pidpy- anion in 2. The packing structure of 1·PF6 only exhibits electrostatic interactions and van der Waals interactions among [Ir(dfppy)2(pidpyH)]+ cations and PF6- ions. In contrast, the neighboring molecules in 2 are linked into a supramolecular chain structure through aromatic stacking interactions between two dfppy- ligands. In solution, 1·PF6 and 2 show acid/base-induced structural transformation due to the protonation/deprotonation of their pyridyl groups and/or imidazole units, which can be confirmed by their 1H NMR spectra. At room temperature, compounds 1·PF6, 2 and pidpyH in CH2Cl2 reveal TFA-induced luminescence switching behaviors, from a non-luminescence state to a luminescence state with an emission at 582 nm for both 1·PF6 and 2, and emission switching from 392 nm to 502 nm for pidpyH. These switching behaviors are associated with the protonation of pyridyl groups and/or imidazole units in 1·PF6, 2 and pidpyH. Moreover, compounds 1·PF6 and 2 were used as photosensitizers (PS) for reduction of water to hydrogen under the same experimental conditions. It was found that the amount of evolved hydrogen and the PS turnover number are 512 μmol and 102 for 1·PF6, and 131 μmol and 26 for 2, respectively. Thus, compound 1·PF6 has better photocatalytic activity than 2. In this paper, we discuss the modulation of luminescence and photocatalytic activities of 1·PF6 and 2 by varying the coordination mode and/or protonation extent of pidpyH/pidpy- ligands.


Analysis of Affordance, Time, and Adaptation in the Assessment of Industrial Control System Cybersecurity Risk.
Industrial control systems increasingly use standard communication protocols and are increasingly connected to public networks-creating substantial cybersecurity risks, especially when used in critical infrastructures such as electricity and water distribution systems. Methods of assessing risk in such systems have recognized for some time the way in which the strategies of potential adversaries and risk managers interact in defining the risk to which such systems are exposed. But it is also important to consider the adaptations of the systems' operators and other legitimate users to risk controls, adaptations that often appear to undermine these controls, or shift the risk from one part of a system to another. Unlike the case with adversarial risk analysis, the adaptations of system users are typically orthogonal to the objective of minimizing or maximizing risk in the system. We argue that this need to analyze potential adaptations to risk controls is true for risk problems more generally, and we develop a framework for incorporating such adaptations into an assessment process. The method is based on the principle of affordances, and we show how this can be incorporated in an iterative procedure based on raising the minimum period of risk materialization above some threshold. We apply the method in a case study of a small European utility provider and discuss the observations arising from this.


Herpes simplex virus ICP27 activation of stress kinases JNK and p38.
We previously reported that herpes simplex virus type 1 (HSV-1) can activate the stress-activated protein kinases (SAPKs) p38 and JNK. In the present study, we undertook a comprehensive and comparative analysis of the requirements for viral protein synthesis in the activation of JNK and p38. Infection with the UL36 mutant tsB7 or with UV-irradiated virus indicated that both JNK and p38 activation required viral gene expression. Cycloheximide reversal or phosphonoacetic acid treatment of wild-type virus-infected cells as well as infection with the ICP4 mutant vi13 indicated that only the immediate-early class of viral proteins were required for SAPK activation. Infection with ICP4, ICP27, or ICP0 mutant viruses indicated that only ICP27 was necessary. Additionally, we determined that in the context of virus infection ICP27 was sufficient for SAPK activation and activation of the p38 targets Mnk1 and MK2 by infecting with mutants deleted for various combinations of immediate-early proteins. Specifically, the d100 (0-/4-) and d103 (4-/22-/47-) mutants activated p38 and JNK, while the d106 (4-/22-/27-/47-) and d107 (4-/27-) mutants did not. Finally, infections with a series of ICP27 mutants demonstrated that the functional domain of ICP27 required for activation was located in the region encompassing amino acids 20 to 65 near the N terminus of the protein and that the C-terminal transactivation activity of ICP27 was not necessary.


Guided Growth of the Distal Posterior Tibial Physis and Short Term Results: A Potential Treatment Option for Children With Calcaneus Deformity.
We present our experience of using tension band plates to achieve guided growth in children for correction of calcaneus deformity around the ankle. Our study included 9 consecutive patients (11 ankles) with calcaneus deformity, over a period of 4 years. Surgical treatment with extra periosteal application of flexible 2 hole plate and screws on posterior aspect of distal tibial physis was carried out.The indications for treatment were residual clubfoot deformity in 9, posttraumatic in 1, and neurologic in 1. The average age of the patients was 10 years (range, 4 to 13 y). There were 7 males and 2 females.Serial preoperative and postoperative radiographs were used to measure deformity correction and anterior distal tibia angle (ADTA), lateral distal tibial angle (LDTA), and Screw Divergence Angle (angle subtended by lines passing through the screws) were measured. A 2-tailed student t test was used to determine statistical significance. The ADTA showed mean correction of 8.41 degrees (range, 3.1 to 16.6 degrees) this was statistically significant with P-value of 0.0003.The change in LDTA was not statistically significant (P-value=0.05) reinforcing the aptness of the procedure and that the procedure did not result in coronal plane deformities. Six ankles required revision of fixation: 4 due to metalwork reaching its maximum limit of divergence at an average of 1 year, 1 ankle had screw pull-out, and another ankle was revised due to technical error in screw selection. In our study there were no cases of infection. We report satisfactory short-term results of correction of calcaneus deformity using flexible tension band plates and screws. In our opinion this is an effective alternative providing gradual correction with easy and minimally invasive surgical technique. It does not violate the physis and is easy to remove and revise. It is safe and well tolerated and can be grouped with other procedures with ease. Level IV—case series.


Advective-diffusive spreading of diffusiophoretic colloids under transient solute gradients.
We analytically calculate the one-dimensional advective-diffusive spreading of a point source of diffusiophoretic (DP) colloids, driven by the simultaneous diffusion of a Gaussian solute patch. The spreading of the DP colloids depends critically on the ratio of the DP mobility, M (which can be positive or negative), to the solute diffusivity, Ds. For instance, we demonstrate, for the first time, that solute-repelling colloids (M < 0) undergo long-time super-diffusive transport for M/Ds < -1. In contrast, the spreading of strongly solute-attracting colloids (M/Ds≫ 1) can be spatially arrested over long periods on the solute diffusion timescale, due to a balance between colloid diffusion and DP under the evolving solute gradient. Further, a patch of the translating solute acts as a "shuttle" that rapidly transports the colloids relative to their diffusive timescale. Finally, we use numerical computations to show that the above behaviors persist for three-dimensional, radially symmetric DP spreading. The results presented here could guide the use of DP colloids for microscale particle sorting, deposition, and delivery.


Self-assembly of the full-length amyloid Aβ42 protein in dimers.
The self-assembly of amyloid (Aβ) proteins into nano-aggregates is a hallmark of Alzheimer's disease (AD) development, yet the mechanism of how disordered monomers assemble into aggregates remains elusive. Here, we applied long-time molecular dynamics simulations to fully characterize the assembly of Aβ42 monomers into dimers. Monomers undergo conformational changes during their interaction, but the resulting dimer structures do not resemble those found in fibril structures. To identify natural conformations of dimers among a set of simulated ones, validation approaches were developed and applied, and a subset of dimer conformations were characterized. These dimers do not contain long β-strands that are usually found in fibrils. The dimers are stabilized primarily by interactions within the central hydrophobic regions and the C-terminal regions, with a contribution from local hydrogen bonding. The dimers are dynamic, as evidenced by the existence of a set of conformations and by the quantitative analyses of the dimer dissociation process.


Genomic Copy Number Variations in the Genomes of Leukocytes Predict Prostate Cancer Clinical Outcomes.
Accurate prediction of prostate cancer clinical courses remains elusive. In this study, we performed whole genome copy number analysis on leukocytes of 273 prostate cancer patients using Affymetrix SNP6.0 chip. Copy number variations (CNV) were found across all chromosomes of the human genome. An average of 152 CNV fragments per genome was identified in the leukocytes from prostate cancer patients. The size distributions of CNV in the genome of leukocytes were highly correlative with prostate cancer aggressiveness. A prostate cancer outcome prediction model was developed based on large size ratio of CNV from the leukocyte genomes. This prediction model generated an average prediction rate of 75.2%, with sensitivity of 77.3% and specificity of 69.0% for prostate cancer recurrence. When combined with Nomogram and the status of fusion transcripts, the average prediction rate was improved to 82.5% with sensitivity of 84.8% and specificity of 78.2%. In addition, the leukocyte prediction model was 62.6% accurate in predicting short prostate specific antigen doubling time. When combined with Gleason's grade, Nomogram and the status of fusion transcripts, the prediction model generated a correct prediction rate of 77.5% with 73.7% sensitivity and 80.1% specificity. To our knowledge, this is the first study showing that CNVs in leukocyte genomes are predictive of clinical outcomes of a human malignancy.