Arabidopsis thaliana isoprenyl diphosphate synthases produce the C25 intermediate geranylfarnesyl diphosphate.
Isoprenyl diphosphate synthases (IDSs) catalyze some of the most basic steps in terpene biosynthesis by producing the prenyl diphosphate precursors of each of the various terpenoid classes. Most plants investigated have distinct enzymes that produce the short-chain all-trans (E) prenyl diphosphates geranyl diphosphate (GDP, C10 ), farnesyl diphosphate (FDP, C15 ) or geranylgeranyl diphosphate (GGDP, C20 ). In the genome of Arabidopsis thaliana, 15 trans-product-forming IDSs are present. Ten of these have recently been shown to produce GGDP by genetic complementation of a carotenoid pathway engineered into Escherichia coli. When verifying the product pattern of IDSs producing GGDP by a new LC-MS/MS procedure, we found that five of these IDSs produce geranylfarnesyl diphosphate (GFDP, C25 ) instead of GGDP as their major product in enzyme assays performed in vitro. Over-expression of one of the GFDP synthases in A. thaliana confirmed the production of GFDP in vivo. Enzyme assays with A. thaliana protein extracts from roots but not other organs showed formation of GFDP. Furthermore, GFDP itself was detected in root extracts. Subcellular localization studies in leaves indicated that four of the GFDP synthases were targeted to the plastoglobules of the chloroplast and one was targeted to the mitochondria. Sequence comparison and mutational studies showed that the size of the R group of the 5th amino acid residue N-terminal to the first aspartate-rich motif is responsible for C25 versus C20 product formation, with smaller R groups (Ala and Ser) resulting in GGDP (C20 ) as a product and a larger R group (Met) resulting in GFDP (C25 ).


Reversibility of apical dendritic retraction in the rat medial prefrontal cortex following repeated stress.
Apical dendritic retraction and axospinous synapse loss in the medial prefrontal cortex (PFC) are structural alterations that result from repeated restraint stress. Such changes in this brain region may be associated with impaired working memory, altered emotionality, and inability to regulate hypothalamic-pituitary adrenal activity, which in turn may underlie stress-related mental illnesses. In the present study, we examined the persistence of these stress-induced dendritic alterations in the medial PFC following the cessation of stress. Animals received either daily restraint stress for a 3-week period and were then allowed to recover for another 3 weeks, restraint stress for 3 or 6 weeks, or no restraint. Following perfusion and fixation, intracellular iontophoretic injections of Lucifer Yellow were performed in layer II/III pyramidal neurons in slices from the medial PFC, and apical and basal dendritic arbors were reconstructed in three dimensions. We observed a significant reduction in apical dendritic length and branch number following 3 or 6 weeks of repeated stress compared to 3-week stress/3-week recovery. These results suggest that stress-induced dendritic plasticity in the medial PFC is reversible and may have implications for the functional recovery of medial PFC function following prolonged psychological stress.


"I help you, and you help me": facilitated telephone peer support among patients with diabetes.
The feasibility and acceptability of using an Interactive Voice Response (IVR)-based platform to facilitate peer support among older adults with diabetes was evaluated. Diabetes patients with poor glycemic control receiving care at a Veterans' Affairs medical center completed a baseline survey, received rudimentary training, and were matched based on their diabetes-related self-management needs. They were asked to contact their partner weekly using the toll-free IVR calling line. At the completion of the 6-week period, participants completed follow-up surveys and brief telephone interviews. Forty of 76 patients screened for eligibility by telephone agreed to participate, and 38 completed the 6-week intervention (50% of eligible patients). More than 80% of the pairs spoke at least once a week for 2 of the 6 weeks of the intervention. A total of 79% of the participants reported that the IVR system was easy to use, and 90% stated that they would be more satisfied with their health care if this type of peer support service were available. Of the participants, 70% found the calls helpful in managing diabetes symptoms, 73% reported that their partner helped them improve their self-care, and 70% stated that they helped their partner do things to stay healthy. There were significant improvements in participants' reported diabetes self-care self-efficacy between baseline and follow-up assessments (P < .01). Qualitative assessments suggested that participants found meaning and positive reinforcement for their own self-care through supporting their partner's efforts to manage diabetes. An IVR peer support intervention is feasible, acceptable to patients, and may have positive effects on patients' diabetes self-management and health outcomes that warrant more rigorous evaluation in a randomized trial.


Comprehensive analysis of alternative splicing in rice and comparative analyses with Arabidopsis.
Recently, genomic sequencing efforts were finished for Oryza sativa (cultivated rice) and Arabidopsis thaliana (Arabidopsis). Additionally, these two plant species have extensive cDNA and expressed sequence tag (EST) libraries. We employed the Program to Assemble Spliced Alignments (PASA) to identify and analyze alternatively spliced isoforms in both species. A comprehensive analysis of alternative splicing was performed in rice that started with >1.1 million publicly available spliced ESTs and over 30,000 full length cDNAs in conjunction with the newly enhanced PASA software. A parallel analysis was performed with Arabidopsis to compare and ascertain potential differences between monocots and dicots. Alternative splicing is a widespread phenomenon (observed in greater than 30% of the loci with transcript support) and we have described nine alternative splicing variations. While alternative splicing has the potential to create many RNA isoforms from a single locus, the majority of loci generate only two or three isoforms and transcript support indicates that these isoforms are generally not rare events. For the alternate donor (AD) and acceptor (AA) classes, the distance between the splice sites for the majority of events was found to be less than 50 basepairs (bp). In both species, the most frequent distance between AA is 3 bp, consistent with reports in mammalian systems. Conversely, the most frequent distance between AD is 4 bp in both plant species, as previously observed in mouse. Most alternative splicing variations are localized to the protein coding sequence and are predicted to significantly alter the coding sequence. Alternative splicing is widespread in both rice and Arabidopsis and these species share many common features. Interestingly, alternative splicing may play a role beyond creating novel combinations of transcripts that expand the proteome. Many isoforms will presumably have negative consequences for protein structure and function, suggesting that their biological role involves post-transcriptional regulation of gene expression.


Improving recombinant Rubisco biogenesis, plant photosynthesis and growth by coexpressing its ancillary RAF1 chaperone.
Enabling improvements to crop yield and resource use by enhancing the catalysis of the photosynthetic CO2-fixing enzyme Rubisco has been a longstanding challenge. Efforts toward realization of this goal have been greatly assisted by advances in understanding the complexities of Rubisco's biogenesis in plastids and the development of tailored chloroplast transformation tools. Here we generate transplastomic tobacco genotypes expressing Arabidopsis Rubisco large subunits (AtL), both on their own (producing tob(AtL) plants) and with a cognate Rubisco accumulation factor 1 (AtRAF1) chaperone (producing tob(AtL-R1) plants) that has undergone parallel functional coevolution with AtL. We show AtRAF1 assembles as a dimer and is produced in tob(AtL-R1) and Arabidopsis leaves at 10-15 nmol AtRAF1 monomers per square meter. Consistent with a postchaperonin large (L)-subunit assembly role, the AtRAF1 facilitated two to threefold improvements in the amount and biogenesis rate of hybrid L8(A)S8(t) Rubisco [comprising AtL and tobacco small (S) subunits] in tob(AtL-R1) leaves compared with tob(AtL), despite >threefold lower steady-state Rubisco mRNA levels in tob(AtL-R1). Accompanying twofold increases in photosynthetic CO2-assimilation rate and plant growth were measured for tob(AtL-R1) lines. These findings highlight the importance of ancillary protein complementarity during Rubisco biogenesis in plastids, the possible constraints this has imposed on Rubisco adaptive evolution, and the likely need for such interaction specificity to be considered when optimizing recombinant Rubisco bioengineering in plants.


Serratus muscle stimulation effectively treats notalgia paresthetica caused by long thoracic nerve dysfunction: a case series.
Currently, notalgia paresthetica (NP) is a poorly-understood condition diagnosed on the basis of pruritus, pain, or both, in the area medial to the scapula and lateral to the thoracic spine. It has been proposed that NP is caused by degenerative changes to the T2-T6 vertebrae, genetic disposition, or nerve entrapment of the posterior rami of spinal nerves arising at T2-T6. Despite considerable research, the etiology of NP remains unclear, and a multitude of different treatment modalities have correspondingly met with varying degrees of success. Here we demonstrate that NP can be caused by long thoracic nerve injury leading to serratus anterior dysfunction, and that electrical muscle stimulation (EMS) of the serratus anterior can successfully and conservatively treat NP. In four cases of NP with known injury to the long thoracic nerve we performed transcutaneous EMS to the serratus anterior in an area far lateral to the site of pain and pruritus, resulting in significant and rapid pain relief. These findings are the first to identify long thoracic nerve injury as a cause for notalgia paresthetica and electrical muscle stimulation of the serratus anterior as a possible treatment, and we discuss the implications of these findings on better diagnosing and treating notalgia paresthetica.


Vascular changes in workers exposed to carbon disulfide.
To assess the effects of occupational exposure to carbon disulfide (CS2) concentrations below the threshold limit value (31 mg/m3) on the structural and the functional properties of the arteries, heart rate, blood pressure and lipids. Study subjects were 85 male workers in the viscose industry and 35 men without such exposure. The CS2 concentration was determined by personal active sampling. From the common carotid artery diameter, the change in diameter (echography) during the heart cycle and the pulse pressure, local arterial distensibility and compliance were calculated. Global large and small artery elasticity were calculated from registrations of radial artery waveforms. Simultaneously, heart rate and blood pressure were recorded and blood samples were collected for lipid measurements. CS2 concentrations ranged from 2.34 to 32.4 mg/m3. No significant effect of CS2 on blood pressure, total cholesterol, HDL and LDL cholesterol or triglycerides was found. Among the vascular parameters under study, common carotid artery distensibility was significantly lower, and heart rate significantly higher in exposed workers compared to controls. The differences remained significant after adjustment for age, body mass index, smoking habits, alcohol consumption, heart rate and systolic blood pressure. Common carotid artery intima media thickness and global arterial indices did not differ significantly between the two groups. Exposure to CS2 under the current level may already cause alterations in common carotid artery elastic properties in apparently healthy individuals. Even before biochemical and clinical findings occur, important functional changes in the vessel wall were observed, at least in some vascular territories.


Refeeding risks in patients requiring intravenous nutrition support: Results of a two-centre, prospective, double-blind, randomised controlled trial.
Refeeding syndrome can result following excessive feeding of malnourished patients. The syndrome remains poorly defined but encompasses a range of adverse effects including electrolyte shifts, hyperglycaemia and other less well-defined phenomena. There are additional risks of underfeeding malnourished individuals. Studies of refeeding syndrome have generally focussed on critical care environments or patients with anorexia nervosa. Here we have conducted a two-centre, prospective, double-blind, randomised controlled trial amongst all patients referred to hospital nutrition support teams for intravenous nutrition support. We sought to determine whether electrolyte and other abnormalities suggestive of refeeding syndrome risk varied depending on initial rate of intravenous feeding. Patients at moderate or high risk of refeeding syndrome, as defined by United Kingdom National Institute of Health and Care Excellence guidelines, were screened for inclusion. Patients were randomised to receive either high (30 kcal/kg/day, 0.25 gN/kg/day) or low (15 kcal/day, 0.125 gN/kg/day) rate feeding for the first 48 h prior to escalation to standard parenteral nutrition regimens. The primary outcome was rates of potential refeeding risks within the first 7 days as defined by electrolyte imbalance or hyperglycaemia requiring insulin. Secondary outcomes included effects on QTc interval, infections and length of hospital stay. Statistical analysis was performed with χ2 or Wilcoxon rank sum tests and all analysis was intention-to-treat. Problems with study recruitment led to premature termination of the trial. Registered on the EU Clinical Trials Register (EudraCT number 2007-005547-17). 534 patients were screened and 104 randomised to either high or low rate feeding based on risk of refeeding syndrome. Seven patients were withdrawn prior to collection of baseline demographics and were excluded from analysis. 48 patients were analysed for the primary outcome with potential refeeding risks identified in 46%. No differences in risks were seen between high and low rate feeding (p > 0.99) or high and moderate risk feeding (p = 0.68). There were no differences in QTc abnormalities, infection rates, or hospital length of stay between groups. In this randomised trial of rates of refeeding risk, in patients pre-stratified as being at high or moderate risk, we found no evidence of increased refeeding related disturbances in those commenced on high rate feeding compared to low rate. No differences were seen in secondary endpoints including cardiac rhythm analysis, infections or length of stay. Our study reflects real world experience of patients referred for nutrition support and highlights challenges encountered when conducting clinical nutrition research.


Relationship between daily exposure to biomass fuel smoke and blood pressure in high-altitude Peru.
Household air pollution from biomass fuel use affects 3 billion people worldwide; however, few studies have examined the relationship between biomass fuel use and blood pressure. We sought to determine if daily biomass fuel use was associated with elevated blood pressure in high altitude Peru and if this relationship was affected by lung function. We analyzed baseline information from a population-based cohort study of adults aged ≥ 35 years in Puno, Peru. Daily biomass fuel use was self-reported. We used multivariable regression models to examine the relationship between daily exposure to biomass fuel smoke and blood pressure outcomes. Interactions with sex and quartiles of forced vital capacity were conducted to evaluate for effect modification. Data from 1004 individuals (mean age, 55.3 years; 51.7% women) were included. We found an association between biomass fuel use with both prehypertension (adjusted relative risk ratio, 5.0; 95% confidence interval, 2.6-9.9) and hypertension (adjusted relative risk ratio, 3.5; 95% confidence interval, 1.7-7.0). Biomass fuel users had a higher systolic blood pressure (7.0 mm Hg; 95% confidence interval, 4.4-9.6) and a higher diastolic blood pressure (5.9 mm Hg; 95% confidence interval, 4.2-7.6) when compared with nonusers. We did not find interaction effects between daily biomass fuel use and sex or percent predicted forced vital capacity for either systolic blood pressure or diastolic blood pressure. Biomass fuel use was associated with a higher likelihood of having hypertension and higher blood pressure in Peru. Reducing exposure to household air pollution from biomass fuel use represents an opportunity for cardiovascular prevention.


Alcohol consumption and metabolic syndrome: does the type of beverage matter?
To examine the association between total and beverage-specific alcohol consumption and the prevalence odds of metabolic syndrome (MS). Using a cross-sectional design, we studied 4510 white participants of the National Heart, Lung, and Blood Institute Family Heart Study. We used generalized estimating equations adjusting for age, education, risk group, smoking, physical activity, diabetes mellitus, coronary heart disease, energy intake, energy from fat, fruits, and vegetables, dietary cholesterol, dietary fiber, and use of multivitamins to estimate the prevalence odds of MS by alcohol intake. Compared with never-drinkers, multivariate odds ratios (95% confidence interval) for MS were 1.12 (0.85 to 1.49), 0.68 (0.36 to 1.28), 0.72 (0.50 to 1.03), 0.66 (0.44 to 0.99), and 0.80 (0.55 to 1.16) among men who were former drinkers and who were current drinkers of 0.1 to 2.5, 2.6 to 12.0, 12.1 to 24.0, and >24.0 g/d of alcohol, respectively (p for linear trend 0.018). Corresponding values for women were 0.86 (0.69 to 1.09), 0.80 (0.43 to 1.34), 0.47 (0.33 to 0.66), 0.47 (0.30 to 0.74), and 0.39 (0.21 to 0.74), respectively (p for trend < 0.0001). The reduced prevalence odds of MS was observed across all beverage types: compared with never-drinkers, multivariate adjusted odds ratios (95% confidence interval) of MS were 0.32 (0.14 to 0.73), 0.42 (0.23 to 0.77), 0.57 (0.30 to 1.09), and 0.56 (0.36 to 0.88) for subjects who consumed >7 drinks/wk of wine only, beer only, spirits only, and more than one type of beverage, respectively. Our data indicate that alcohol consumption is associated with a lower prevalence of MS irrespective of the type of beverage consumed. Prospective studies are needed to confirm these findings and to assess the influence of drinking patterns on the alcohol-MS association.


Changing aspirin use in patients with Type 2 diabetes in the UKPDS.
To examine the proportion of UK Prospective Diabetes Study (UKPDS) patients with Type 2 diabetes taking aspirin regularly for the primary and secondary prevention of cardiovascular disease (CVD) before and after publication of the 1997 American Diabetes Association (ADA) Clinical Practice Recommendations and the 1998 Joint British Recommendations on the Prevention of Coronary Disease in Clinical Practice. UKPDS annual review data from 1996/7 (n = 3190) and 2000/1 (n = 2467) were used to determine the prevalence of patients taking aspirin regularly in relation to known CVD risk factors and pre-existing CVD. Patients taking aspirin regularly were more often male than female (24 vs. 20%, P = 0.0033), older (66 +/- 8 vs. 62 +/- 9 years, P < 0.0001) and less often Afro-Caribbean than White Caucasian or Indian Asian (11 vs. 23 vs. 22%, respectively, P < 0.0001). Between 1996/7 and 2000/1 aspirin use in patients without pre-existing CVD increased from 17 to 31% (P < 0.0001) and for those with pre-existing CVD from 76 to 82% (P = 0.032). The majority of patients with pre-existing CVD were taking aspirin regularly. Although aspirin use in those without pre-existing CVD approximately doubled after publication of the ADA and Joint British Recommendations, less than two-thirds of these high-risk patients were being treated according to guidelines. This may relate to a lack of convincing evidence for primary CVD prevention or failure to adhere to guidelines. It may be that more trial data is needed to convince clinicians of the value of aspirin therapy in Type 2 diabetes.


Photo-isomerization fronts in dye-doped nematic liquid crystals.
An experimental study of the photo-isomerization dynamics in dye-doped nematic crystals is reported, which shows that, when the sample is illuminated by a Gaussian beam, and for high enough input power, a transition from the nematic to the isotropic phase takes place in the illuminated area. The two phases are spatially connected via a front propagating outward from the center of the beam and following the local intensity profile and thus inducing a photo-controlled optical aperture. The optical intensity and temperature fields on the sample follow the same dynamical profile. The front dynamics is described by a phenomenological bi-stable model with an inhomogeneous control parameter, directly related to the beam intensity profile.


The role of peroxiredoxin II in radiation-resistant MCF-7 breast cancer cells.
Although several signaling pathways have been suggested to be involved in the cellular response to ionizing radiation, the molecular basis of tumor resistance to radiation remains elusive. We have developed a unique model system based upon the MCF-7 human breast cancer cell line that became resistant to radiation treatment (MCF+FIR30) after exposure to chronic ionizing radiation. By proteomics analysis, we found that peroxiredoxin II (PrxII), a member of a family of peroxidases, is up-regulated in the radiation-derived MCF+FIR3 cells but not in the MCF+FIS4 cells that are relatively sensitive to radiation. Both MCF+FIR3 and MCF+FIS4 cell lines are from MCF+FIR30 populations. Furthermore, the resistance to ionizing radiation can be partially reversed by silencing the expression of PrxII by PrxII/small interfering RNA treatment of MCF+FIR3 resistant cells, suggesting that PrxII is not the sole factor responsible for the resistant phenotype. The relevance of this mechanism was further confirmed by the increased radioresistance in PrxII-overexpressing MCF+FIS4 cells when compared with vector control cells. The up-regulation of the PrxII protein in radioresistant cancer cells suggested that human peroxiredoxin plays an important role in eliminating the generation of reactive oxygen species by ionizing radiation. The present finding, together with the observation that PrxII is also up-regulated in response to ionizing radiation in other cell systems, strengthens the hypothesis that the PrxII antioxidant protein is involved in the cellular response to ionizing radiation and functions to reduce the intracellular reactive oxygen species levels, resulting in increased resistance of breast cancer cells to ionizing radiation.


Understanding CBHI hospitalisation patterns: a comparison of insured and uninsured women in Gujarat, India.
Community-based health insurance has been associated with increased hospitalisation in low-income settings, but with limited analysis of the illnesses for which claims are submitted. A review of claims submitted to VimoSEWA, an inpatient insurance scheme in Gujarat, India, found that fever, diarrhoea and hysterectomy, the latter at a mean age of 37 years, were the leading reasons for claims by adult women. We compared the morbidity, outpatient treatment-seeking and hospitalisation patterns of VimoSEWA-insured women with uninsured women. We utilised data from a cross-sectional survey of 1,934 insured and uninsured women in Gujarat, India. Multivariable logistic regression identified predictors of insurance coverage and the association of insurance with hospitalisation. Self-reported data on morbidity, outpatient care and hospitalisation were compared between insured and uninsured women. Age, marital status and occupation of adult women were associated with insurance status. Reported recent morbidity, type of illness and outpatient treatment were similar among insured and uninsured women. Multivariable analysis revealed strong evidence of a higher odds of hospitalisation amongst the insured (OR = 2.7; 95% ci. 1.6, 4.7). The leading reason for hospitalisation for uninsured and insured women was hysterectomy, at a similar mean age of 36, followed by common ailments such as fever and diarrhoea. Insured women appeared to have a higher probability of being hospitalised than uninsured women for all causes, rather than specifically for fever, diarrhoea or hysterectomy. Length of stay was similar while choice of hospital differed between insured and uninsured women. Despite similar reported morbidity patterns and initial treatment-seeking behaviour, VimoSEWA members were more likely to be hospitalised. The data did not provide strong evidence that inpatient hospitalisation replaced outpatient treatment for common illnesses or that insurance was the primary inducement for hysterectomy in the population. Rather, it appears that VimoSEWA members behaved differently in deciding if, and where, to be hospitalised for any condition. Further research is required to explore this decision-making process and roles, if any, played by adverse selection and moral hazard. Lastly, these hospitalisation patterns raise concerns regarding population health needs and access to quality preventive and outpatient services.


Effect of radio-frequency electromagnetic radiations (RF-EMR) on passive avoidance behaviour and hippocampal morphology in Wistar rats.
The interaction of mobile phone radio-frequency electromagnetic radiation (RF-EMR) with the brain is a serious concern of our society. We evaluated the effect of RF-EMR from mobile phones on passive avoidance behaviour and hippocampal morphology in rats. Healthy male albino Wistar rats were exposed to RF-EMR by giving 50 missed calls (within 1 hour) per day for 4 weeks, keeping a GSM (0.9 GHz/1.8 GHz) mobile phone in vibratory mode (no ring tone) in the cage. After the experimental period, passive avoidance behaviour and hippocampal morphology were studied. Passive avoidance behaviour was significantly affected in mobile phone RF-EMR-exposed rats demonstrated as shorter entrance latency to the dark compartment when compared to the control rats. Marked morphological changes were also observed in the CA(3) region of the hippocampus of the mobile phone-exposed rats in comparison to the control rats. Mobile phone RF-EMR exposure significantly altered the passive avoidance behaviour and hippocampal morphology in rats.


Supporting the clinical use of the ICF in Japan - development of the Japanese version of the simple, intuitive descriptions for the ICF Generic-30 set, its operationalization through a rating reference guide, and interrater reliability study.
The World Health Organization developed the International Classification of Functioning, Disability, and Health (ICF) in 2001 and has been in the process of implementing it in clinics since then. Current international efforts to implement ICF in rehabilitation clinics include the implementation of ICF Core Sets and the development of simple, intuitive descriptions for the ICF Generic-30 Set (also called Rehabilitation Set). The present study was designed to operationalize these ICF tools for clinical practice in Japan. This work included 1) the development of the Japanese version of the simple, intuitive descriptions for the ICF Generic-30 Set, 2) the development of a rating reference guide for Activity and Participation categories, and 3) the examination of the interrater reliability of rating Activity and Participation categories. The Japanese version of the simple, intuitive descriptions for the ICF Generic-30 Set was developed following the process employed to develop the Chinese and Italian versions. For further operationalization of this ICF Set in practice, a rating reference guide was developed. The development of the rating reference guide involved the following steps: 1) a trial of rating patients by several raters, 2) cognitive interviewing of the raters to analyse the thinking process involved in rating, 3) drafting of the rating reference guide, and 4) review by ICF specialists to confirm consistency with the original ICF concepts. After the rating reference guide was developed, interrater reliability of the rating with the reference guide was determined. Interrater reliability was examined using weighted kappa statistics with linear weight. Through the pre-defined process, the Japanese version of the simple, intuitive descriptions for 30 categories of the ICF Generic-30 Set and the rating reference guides for 21 Activity and Participation categories were successfully developed. The weighted kappa statistics ranged from 0.61 to 0.85, showing substantial to excellent agreement of the ratings between raters. The present study demonstrates that ICF categories can be translated into clinical practice. Collaboration between clinicians and researchers would further enhance the implementation of the ICF in Japan.


A cross-linguistic study of early word meaning: universal ontology and linguistic influence.
This research concerns how children learn the distinction between substance names and object names. Quine (1969) proposed that children learn the distinction through learning the syntactic distinctions inherent in count/mass grammar. However, Soja et al. (1991) found that English-speaking 2-year-olds, who did not seem to have acquired count/mass grammar, distinguished objects from substances in a word extension task, suggesting a pre-linguistic ontological distinction. To test whether the distinction between object names and substance names is conceptually or linguistically driven, we repeated Soja et al.'s study with English- and Japanese-speaking 2-, 2.5-, and 4-year-olds and adults. Japanese does not make a count-mass grammatical distinction: all inanimate nouns are treated alike. Thus if young Japanese children made the object-substance distinction in word meaning, this would support the early ontology position over the linguistic influence position. We used three types of standards: substances (e.g., sand in an S-shape), simple objects (e.g., a kidney-shaped piece of paraffin) and complex objects (e.g., a wood whisk). The subjects learned novel nouns in neutral syntax denoting each standard entity. They were then asked which of the two alternatives--one matching in shape but not material and the other matching in material but not shape--would also be named by the same label. The results suggest the universal use of ontological knowledge in early word learning. Children in both languages showed differentiation between (complex) objects and substances as early as 2 years of age. However, there were also early cross-linguistic differences. American and Japanese children generalized the simple object instances and the substance instances differently. We speculate that children universally make a distinction between individuals and non-individuals in word learning but that the nature of the categories and the boundary between them is influenced by language.


Morbidity and associated factors in rural and urban populations of South Lebanon: a cross-sectional community-based study of self-reported health in 2000.
To assess self-reported morbidity and its determining factors in South Lebanon, with an emphasis on the influence of the habitat location (urban vs. rural) and gender. Cross-sectional survey in 2000 among 524 South Lebanon residents >/=14 years sampled from a random sample of households using a multi-level cluster sampling technique. Data on self-reported morbidity, lifestyle and socioeconomic status were collected through interviews, using a standardized questionnaire. To evaluate deprivation, a new index was created; the modified 'Living Conditions Index'. Stepwise logistic regression analysis was performed to test the effect of habitat and gender on self-reported morbidity. People in one-fifth of the households lived in precarious conditions. Illiteracy was significantly higher in rural than urban settings. Urban residents reported obesity, varicose veins, anxiety/depression and visual disorders more often. Illiteracy, headaches, lumbar pain, varicose veins and anxiety/depression were more frequently reported by women, whereas ulcers, hearing disorders, cardio-vascular diseases and their risk factors were more frequently reported by men. Precarious living conditions were associated with headaches, lumbar pains and insomnia. Individuals covered by a health insurance sought care more often than the uninsured. Habitat location had only a minor influence on self-reported morbidity; women perceived their health as poorer than men and a number of disease conditions were influenced by deprivation. Our study confirms that the epidemiological transition phenomenon had occurred in South Lebanon in 2000. Our community-based data can serve as a baseline for monitoring changes in health in South Lebanon in the future and especially those because of the war that emerged in July 2006.


Laparoscopic versus Open Surgery Catheter Placement in Peritoneal Dialysis Patients: A Meta-Analysis of Outcomes.
The peritoneal dialysis catheter (PDC) can be placed either through the laparoscopic technique, percutaneous technique, or surgical procedures. The utilization of these PDC placement procedures is based on the successful placement and reduced risk of development of complications. The main objective of this study was to compare the complications associated with the laparoscopic technique to those linked to open surgery during PDC placement. The literature for this review was obtained from the PubMed and Google Scholar databases. The literature search was limited to studies published in the period between 1998 and 2019. The meta-analysis was done using Stata Version 12. The results showed a significant difference in catheter malfunction rates between the laparoscopic and open surgery groups (relative risk [RR] = 0.58; 95% confidence interval [CI]: 0.42-0.8, P = 0.031). There was no statistically significant difference in dialysate leakage (RR = 0.77; 95% CI: 0.51-1.17, P = 0.116), peritonitis (RR = 0.8; 95% CI: 0.6-1.06, P = 0.349), and exit-site infection (RR = 0.84; 95% CI: 0.65-1.09, P = 0.834) between two groups. In conclusion, the laparoscopic PDC placement procedure was superior to open surgery with regard to catheter malfunction.


Design, construction and performance of a portable handheld electrohydrodynamic multi-needle spray gun for biomedical applications.
Electrohydrodynamic (EHD) processing has attracted substantial interest in the technological and pharmaceutical sectors in recent years. Given the complexity of the process, exploring new ideas for EHD electrospraying and electrospinning delivery is a challenge. In this article, the design, construction and testing of a portable handheld EHD multi-needle device are described to produce multifunctional particles and fibers. Solid and encapsulated polymer particles and fibers were generated in order to study the performance of the device. The intrinsic properties of the feed solution/suspension and the processing conditions were adjusted to ensure robustness of the process and give uniform and reproducible products, with diameters ranging from the sub-micrometer scale to a few micrometers. These products have a broad range of applications in many advanced industrial sectors e.g. drug delivery systems, wound dressing patches, low calorie food products and cosmetics.


Ecology of Jamestown Canyon virus (Bunyaviridae: California serogroup) in coastal California.
This paper reports the first isolation of Jamestown Canyon (JC) virus from coastal California and the results of tests for antibody to JC virus in mammals living in coastal California. The virus isolation was made from a pool of 50 Aedes dorsalis females collected as adults from Morro Bay, San Luis Obispo County, California. The virus isolate was identified by two-way plaque reduction-serum dilution neutralization tests done in Vero cell cultures. Sera from the mammals were tested for antibody to JC virus by a plaque-reduction serum dilution neutralization method. A high prevalence of JC virus-specific antibody was found in horses and cattle sampled from Morro Bay. This finding is additional evidence for the presence of a virus antigenically identical or closely related to JC virus in Morro Bay and indicates that the vectors of the virus in Morro Bay feed on large mammals. A high prevalence of virus-specific antibody was also found in horses sampled from Marin and San Diego counties. This finding suggests that viruses antigenically identical or closely related to JC virus are geographically widespread in coastal California.


Smad2 mediates Erk1/2 activation by TGF-beta1 in suspended, but not in adherent, gastric carcinoma cells.
Integrin-mediated cell adhesion enables cells to respond to extracellular stimuli for diverse cellular functions including proliferation, leading to differential biological activities from cells in suspension. Integrins can transduce signals (directly) to intracellular molecules and also collaborate with other membrane receptor-mediated signal pathways, including TGF-beta1 pathway. TGF-beta1 induces growth inhibition in epithelial cells and is known to transduce intracellular signaling in Smad-dependent or -independent manner. Currently effects of cell adhesion status on the TGF-beta1-mediated Erk1/2 regulation and on its Smad-(in)dependency are not known. In this study, we examined effects of cell adhesion status on the TGF-beta1-mediated Erk1/2 regulation, and roles of Smad proteins on the cell adhesion-mediated effects, using a gastric carcinoma cell variant. First, we found that cell adhesion-dependent Erk1/2 activation responded differentially to TGF-beta1, depending on cell adhesion status; TGF-beta1 treatment resulted in activation of Erk1/2 in suspended cells, whereas a decrease was noted in adherent cells. This activation of Erk1/2 by TGF-beta1 in suspension was more enhanced by an overexpression of Smad2, but not of other Smads 2, 4, and 7, but abolished by a Smad2 reduction via an introduction of its siRNA. In contrast, PKB/Akt regulation by TGF-beta1 was not different in suspension or in adhesion, and Smad7, but not the other Smads, activated PKB/Akt phosphorylation on TGF-beta1 treatment, indicating a specificity of Smad2-mediated and cell adhesion status-dependent activation of Erk1/2 activity.


Antioxidant activity of proteins extracted from red alga dulse harvested in Japan.
In this study, we investigated antioxidant activity of proteins from the red alga dulse (Palmaria sp.) harvested in Hokkaido, Japan. The dulse proteins that contain phycoerythrin (PE) as the main component showed a high radical scavenging activity. To clarify the key constituent of antioxidant activity in dulse proteins, we prepared recombinant dulse PE β-subunit (rPEβ) (apoprotein) and chromophores from the dulse proteins. As a result, the rPEβ showed lower radical scavenging activity than that of dulse proteins. On the other hand, the dulse chromophores composed mainly of phycoerythrobilin (PEB) indicated extremely higher radical scavenging activity (90.4% ± 0.1%) than that of dulse proteins (17.9% ± 0.1%) on ABTS assay. In addition, on cell viability assay using human neuroblastoma SH-SY5Y cells, the dulse chromophores showed extracellular and intracellular cytoprotective effects against H2 O2 -induced cell damage. From these data, we concluded that the dulse proteins have antioxidant ability and the activity principally derives from the chromophores. PRACTICAL APPLICATION: Dulse is an abundant and underused resource, which contains a lot of proteins, especially phycoerythrin. We here demonstrated that the practically prepared dulse proteins possessed antioxidant activity and clarified that chromophores from the dulse proteins were the key components. Therefore, the dulse proteins have a potential for functional material.


General anaesthesia as fragmentation of selfhood: insights from electroencephalography and neuroimaging.
Selfhood is linked to brain processes that enable the experience of a person as a distinct entity, capable of agency. This framework naturally incorporates a continuum of both non-conscious and conscious self-related information processing, and includes a hierarchy of components, such as awareness of existence (core self), embodied self (sentience), executive self (agency/volition), and various other higher-order cognitive processes. Consciousness relates to, but is not congruent, with selfhood; understanding the processes required for selfhood can explain the partial consciousness seen in anaesthesia. Functional-brain-imaging and electroencephalographic studies in sleep and general anaesthesia have shown differential effects of anaesthetic drugs on various specific self-related functional brain networks. In particular, drug-induced selective impairment of anterior insula function suggests there might be a crucial difference between anaesthesia and natural sleep when it comes to the salience network. With increasing concentrations of anaesthetics, it is not uncommon for patients to become depersonalised (i.e. to lose sentience and agency), but retain many higher-order functions and a disembodied self-awareness, until quite high concentrations are reached. In this respect, general anaesthesia differs significantly from physiological sleep, where it appears that loss of agency and sentience parallels, or lags behind, the decrease in self-awareness. Interestingly, connectivity within the posterior brain regions is maintained even to quite high concentrations of anaesthetics, potentially representing a pathognomonic marker of the core self that possibly is involved in maintaining a reduced energy state of homeostasis.


Acute and chronic cardiac adaptations in adults born preterm.
What is the topic of this review? Studies using cardiovascular magnetic resonance imaging and echocardiography to investigate cardiac alterations at rest and during exercise-induced physiological stress in adults born preterm. What advances does it highlight? People born preterm have a greater long-term cardiovascular risk, which may be explained in part by their cardiac structural and functional alterations. They have potentially adverse alterations in left and right ventricular structure and function that worsens with blood pressure elevation; an impaired myocardial functional reserve; and an increase in diffuse myocardial fibrosis that may drive their lower diastolic function. Preterm birth accounts for more than 10% of births worldwide and associates with a long-term increase in cardiovascular disease risk. The period around preterm birth is a rapid and critical phase of cardiovascular development, which might explain why changes in multiple components of the cardiovascular system have been observed in individuals born preterm. These alterations include reduced microvascular density, increased macrovascular stiffness, and higher systolic and diastolic blood pressure. Cardiac alterations have been observed in people born preterm as early as neonatal life and infancy, with potentially adverse changes in both left and right ventricular structure and function extending into adulthood. Indeed, studies using cardiovascular magnetic resonance imaging and echocardiography have demonstrated that preterm-born individuals have structural cardiac changes and functional impairments. Furthermore, myocardial tissue characterization by cardiovascular magnetic resonance imaging has demonstrated an increase in left ventricular diffuse myocardial fibrosis in young adults born preterm, and under acute physiological stress, their myocardial functional reserve assessed by echocardiography is reduced. The preterm heart is also more susceptible to chronic systolic blood pressure elevation, with a significantly greater increase in left ventricular mass as systolic blood pressure rises observed in preterm-born compared to term-born young adults. Given these known, potentially adverse acute and chronic cardiac adaptations in the preterm-born population, primary prevention strategies are needed to reduce long-term cardiovascular disease risk in this subgroup of the population.


The acute effect of psychosocial stress on the level of oxidative stress in children.
The effect of chronic stress on oxidative stress (OS) is commonly discussed while the effect of acute stress situation is not fully examined yet. The present study was aimed to analyse whether acute psychosocial strain causes changes in OS and antioxidant status. Unstimulated saliva was collected from 46 healthy prepubertal children during the control and stress day. On the stress day, collection was performed before and after a stress situation induced by the Trier social stress test. Saliva collection during the control day imitated the stress day without the stress strain. Samples were used for analysis of lipid peroxidation, thiobarbituric acid reactive substances (TBARS), advanced glycation end products (AGEs) and markers of antioxidant status, total antioxidant capacity (TAC) and ferric reducing antioxidant power (FRAP). On the stress day, increased level of FRAP was observed in the second saliva collection in comparison with the first collection. Within the same day, no significant changes in the levels of TBARS, AGEs and TAC were observed in samples taken before and after stress strain. Significantly higher levels of TBARS were observed on stress day in comparison to control day. In summary, acute psychosocial stress caused increase of FRAP during the stress day. TBARS did not increase during the stress day in the second sample but it was higher compared to the control day. None of the interactions with gender were statistically significant. It appears the short-term exposure to stress could potentially stimulate antioxidant activity.


Quantitative Analysis of Shock Wave Dynamics in a Fluid of Light.
We report on the formation of a dispersive shock wave in a nonlinear optical medium. We monitor the evolution of the shock by tuning the incoming beam power. The experimental observations for the position and intensity of the solitonic edge of the shock, as well as the location of the nonlinear oscillations are well described by recent developments of Whitham modulation theory. Our work constitutes a detailed and accurate benchmark for this approach. It opens exciting possibilities to engineer specific configurations of optical shock wave for studying wave-mean flow interaction.


Accurate dried blood spots collection in the community using non-medically trained personnel could support scaling up routine viral load testing in resource limited settings.
Regular plasma HIV-RNA testing for persons living with HIV on antiretroviral therapy (ART) is now the global standard, but as many as 60% of persons in Africa today on ART do not have access to standard laboratory HIV-RNA assays. As a result, patients in Zambia often receive treatment without any means of determining true virologic failure, which poses a risk of premature switch of ART regimens and widespread HIV drug resistance. Dry blood spots (DBS) on the other hand require unskilled personnel and less complex storage supply chain so are ideal to capture viral-load results from HIV patients outside clinic settings. We assess collection of DBS in the community using non-medically trained personnel (NMP) and documented challenges. We trained 23 NMP to collect DBS from lost to follow-up (LTFU) patients in 4 rural and urban Zambian districts. We developed a phlebotomy box to transport DBS without contamination at ambient temperature and concomitant training and standard operating procedures. We evaluated this through field observations, bi-weekly meetings, reports, and staff meetings. The laboratory assessed DBS quality for testing validity. We attempted to collect DBS from 357 participants in the community. Though individual reasons for refusal from the remaining 37% were not collected, NMPs reported privacy concerns, awkward box-size which drew attention in the community and fears of undisclosed uses of samples related to witchcraft and circulating narratives about past research. Successful DBS collection was not associated with patient gender, age, time on ART, enrolment CD4, facility. DBS viral-load collection by NMP is feasible in Zambia. Our training approach and assessments of NMP not part of the health system can be extended to patients by giving them more responsibility to manage their own differentiated care groups. Concerted efforts that compare collection of DBS by NMP to those collected by skilled-medical personnel are needed.


Accelerated simulation of evolutionary trajectories in origin-fixation models.
We present an accelerated algorithm to forward-simulate origin-fixation models. Our algorithm requires, on average, only about two fitness evaluations per fixed mutation, whereas traditional algorithms require, per one fixed mutation, a number of fitness evaluations of the order of the effective population size, Ne Our accelerated algorithm yields the exact same steady state as the original algorithm but produces a different order of fixed mutations. By comparing several relevant evolutionary metrics, such as the distribution of fixed selection coefficients and the probability of reversion, we find that the two algorithms behave equivalently in many respects. However, the accelerated algorithm yields less variance in fixed selection coefficients. Notably, we are able to recover the expected amount of variance by rescaling population size, and we find a linear relationship between the rescaled population size and the population size used by the original algorithm. Considering the widespread usage of origin-fixation simulations across many areas of evolutionary biology, we introduce our accelerated algorithm as a useful tool for increasing the computational complexity of fitness functions without sacrificing much in terms of accuracy of the evolutionary simulation.


Preservation of cardiomyocytes from the adult heart.
Cardiomyocytes represent one of the most useful models to conduct cardiac research. A single adult heart yields millions of cardiomyocytes, but these cells do not survive for long after isolation. We aimed to determine whether inhibition of myosin II ATPase that is essential for muscle contraction may preserve fully differentiated adult cardiomyocytes. Using inhibitors of the myosin II ATPase, blebbistatin and N-benzyl-p-toluene sulphonamide (BTS), we preserved freshly isolated fully differentiated adult primary cardiomyocytes that were stored at a refrigerated temperature. Specifically, preserved cardiomyocytes stayed viable for a 2-week period with a stable expression of cardiac genes and retained the expression of key markers characteristic of cardiomyocytes. Furthermore, voltage-clamp, action potential, calcium transient and contractility studies confirmed that the preserved cardiomyocytes are comparable to freshly isolated cells. Long-term exposure of preserved cardiomyocytes to four tyrosine kinase inhibitors, sunitinib malate, dasatinib, sorafenib tosylate and imatinib mesylate, revealed their potential to induce cardiac toxicity that was manifested with a decrease in contractility and induction of cell death, but this toxicity was not observed in acute experiments conducted over the time course amenable to freshly prepared cardiomyocytes. This study introduces the concept that the inhibition of myosin II ATPase safeguards the structure and function of fully differentiated adult cardiomyocytes. The fact that these preserved cardiomyocytes can be used for numerous days after preparation makes them a robust and versatile tool in cardiac research and allows the investigation of long-term exposure to novel drugs on cardiomyocyte function.


Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma.
The strong male predominance in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) remains inadequately explained, but sex hormones might be involved. We hypothesized that single nucleotide polymorphisms (SNPs) in the androgen pathway influence risk of developing BE and EAC. This genetic-epidemiological analysis included 14 studies from Australia, Europe and North America. Polymorphisms in 16 genes coding for the androgen pathway were analyzed using a gene-based approach: versatile gene-based test association study. This method evaluates associations between a trait and all SNPs within a specific gene rather than each SNP marker individually as in a conventional GWAS. The data were stratified for sex, body-mass index, waist-to-hip ratio, tobacco smoking and gastroesophageal reflux status. Included were data from 1,508 EAC patients, 2,383 BE patients and 2,170 control participants. SNPs within the gene CYP17A1 were associated with risk of BE in the sexes combined (p = 0.002) and in males (p = 0.003), but not in females separately (p = 0.3). This association was found in tobacco smokers (p = 0.003) and in BE patients without reflux (p = 0.004), but not in nonsmokers (p = 0.2) or those with reflux (p = 0.036). SNPs within JMJD1C were associated with risk of EAC in females (p = 0.001). However, none of these associations replicated in a subsequent sample. Fourteen other genes studied did not reach statistically significant levels of association with BE, EAC or the combination of BE and EAC, after correcting for the number of genes included in the analysis. In conclusion, genetic variants in the androgen-related genes CYP17A1 and JMJD1C might be associated with risk of BE and EAC, respectively, but replication data with larger sample sizes are needed.


Vascular prostaglandin and thromboxane production in a canine model of myocardial ischemia.
Whereas numerous studies have investigated the role of prostacyclin and thromboxane A2 in the maintenance of coronary blood flow, most of these have focused on normal vessels. In the present investigation, we examined the prostaglandin- and thromboxane-synthesizing capacity of isolated coronary artery segments obtained from the site of a critical coronary artery stenosis. Cyclic flow variations were produced by placing a hard cylindrical constrictor on the proximal left anterior descending coronary artery in open-chest, anesthetized dogs. Cyclic flow variations are characterized by progressive declines in coronary blood flow, interrupted by sudden spontaneous restorations of flow. After cyclic flow variations had been induced, the hearts were removed, and the left anterior descending and circumflex coronary arteries were dissected. The vessels were cut into segments and incubated in the presence of increasing concentrations of arachidonic acid (10(-4)-10(-6) M). The synthesis of prostaglandin E2, thromboxane B2, and 6-keto prostaglandin F1 alpha by the coronary segments was measured by radioimmunoassay. When incubated in the presence of 10(-5) M arachidonic acid, coronary artery segments obtained from the left anterior descending coronary artery undergoing cyclic flow variations produced substantially more thromboxane B2 (142 +/- 27 vs. 29 +/- 3 pg/mg P less than 0.01) and less 6-keto prostaglandin F1alpha (125 +/- 12 vs. 350 +/- 30 pg/mg, P less than 0.01) than control circumflex coronary artery segments. Circumflex coronary vessels in which the endothelium was removed ex vivo produced 6-keto prostaglandin F1alpha levels comparable to those found in the left anterior descending coronary artery (147 +/- 17 pg/mg), but did not synthesize thromboxane B2 (23 +/- 2.6 pg/mg).(ABSTRACT TRUNCATED AT 250 WORDS)


Hand locomotor functions, body structure, and epidermal ridge patterns: preliminary study.
The purpose of this study was to determine whether any relationships exist between hand locomotor functions and dermatoglyphic characteristics and body structure. The pilot sample consisted of 71 adult normal individuals (30 males and 41 females). The locomotor function tests included a power grip and two precision grips; dermatoglyphic features were represented by finger and palmar pattern intensities and ridge counts, and body structure by 35 head, face, trunk, and limb anthropometric measurements. Univariate and multivariate correlation analyses reveal that on average half of the variance in the locomotor hand-function tests can be accounted for by a set of body and/or dermatoglyphic variables in males; this contribution is appreciably lower in females. Body longitudinal measurements and some facial measures, such as jaw length, were found to be the main correlates of either a power grip or a simple thumb-index squeeze, especially in males; head and face measurements and the size and intensity of patterns on fingers 1 and 2 were the main correlates of more complex precision tests involving complicated manipulation of objects using the thumb and index finger. These preliminary results identify some previously unknown sources of variation in dermatoglyphic patterns and contribute to a better understanding of the evolutionary aspects of the relationships between specific functional and morphologic traits in humans.


On the reversibility of parasitism: adaptation to a free-living lifestyle via gene acquisitions in the diplomonad Trepomonas sp. PC1.
It is generally thought that the evolutionary transition to parasitism is irreversible because it is associated with the loss of functions needed for a free-living lifestyle. Nevertheless, free-living taxa are sometimes nested within parasite clades in phylogenetic trees, which could indicate that they are secondarily free-living. Herein, we test this hypothesis by studying the genomic basis for evolutionary transitions between lifestyles in diplomonads, a group of anaerobic eukaryotes. Most described diplomonads are intestinal parasites or commensals of various animals, but there are also free-living diplomonads found in oxygen-poor environments such as marine and freshwater sediments. All these nest well within groups of parasitic diplomonads in phylogenetic trees, suggesting that they could be secondarily free-living. We present a transcriptome study of Trepomonas sp. PC1, a diplomonad isolated from marine sediment. Analysis of the metabolic genes revealed a number of proteins involved in degradation of the bacterial membrane and cell wall, as well as an extended set of enzymes involved in carbohydrate degradation and nucleotide metabolism. Phylogenetic analyses showed that most of the differences in metabolic capacity between free-living Trepomonas and the parasitic diplomonads are due to recent acquisitions of bacterial genes via gene transfer. Interestingly, one of the acquired genes encodes a ribonucleotide reductase, which frees Trepomonas from the need to scavenge deoxyribonucleosides. The transcriptome included a gene encoding squalene-tetrahymanol cyclase. This enzyme synthesizes the sterol substitute tetrahymanol in the absence of oxygen, potentially allowing Trepomonas to thrive under anaerobic conditions as a free-living bacterivore, without depending on sterols from other eukaryotes. Our findings are consistent with the phylogenetic evidence that the last common ancestor of diplomonads was dependent on a host and that Trepomonas has adapted secondarily to a free-living lifestyle. We believe that similar studies of other groups where free-living taxa are nested within parasites could reveal more examples of secondarily free-living eukaryotes.


Characterizing Trends in Human Papillomavirus Vaccine Discourse on Reddit (2007-2015): An Observational Study.
Despite the introduction of the human papillomavirus (HPV) vaccination as a preventive measure in 2006 for cervical and other cancers, uptake rates remain suboptimal, resulting in preventable cancer mortality. Social media, widely used for information seeking, can influence users' knowledge and attitudes regarding HPV vaccination. Little is known regarding attitudes related to HPV vaccination on Reddit (a popular news aggregation site and online community), particularly related to cancer risk and sexual activity. Examining HPV vaccine-related messages on Reddit may provide insight into how HPV discussions are characterized on forums online and influence decision making related to vaccination. We observed how the HPV vaccine is characterized on Reddit over time and by user gender. Specifically, this study aimed to determine (1) if Reddit messages are more related to cancer risks or sexual behavior and (2) what other HPV vaccine-related discussion topics appear on Reddit. We gathered all public Reddit comments from January 2007 to September 2015. We manually annotated 400 messages to generate keywords and identify salient themes. We then measured the similarity between each comment and lists of keywords associated with sexual behavior and cancer risk using Latent Semantic Analysis (LSA). Next, we used Latent Dirichlet Allocation (LDA) to characterize remaining topics within the Reddit data. We analyzed 22,729 messages containing the strings hpv or human papillomavirus and vaccin. LSA findings show that HPV vaccine discussions are significantly more related to cancer compared with sexual behavior from 2008 to 2015 (P<.001). We did not find a significant difference between genders in discussions of cancer and sexual activity (P>.05). LDA analyses demonstrated that although topics related to cancer risk and sexual activity were both frequently discussed (16.1% and 14.5% of word tokens, respectively), the majority of online discussions featured other topics. The most frequently discussed topic was politics associated with the vaccine (17.2%). Other topics included HPV disease and/or immunity (13.5%), the HPV vaccine schedule (11.5%), HPV vaccine side effects (9.7%), hyperlinks to outside sources (9.1%), and the risks and benefit of HPV vaccination (8.5%). Reddit discourse on HPV vaccine encompasses a broad range of topics among men and women, with HPV political debates and cancer risk making up the plurality of the discussion. Our findings demonstrated that women and men both discussed HPV, highlighting that Reddit users do not perceive HPV as an issue that only pertains to women. Given the increasing use of social media as a source of health information, these results can inform the development of targeted online health communication strategies to promote HPV vaccination to young adult users of Reddit. Analyzing online discussions on Reddit can inform health communication efforts by identifying relevant, important HPV-related topics among online communities.


Perspectives of speech and language therapists in paediatric palliative care: an international exploratory study.
The involvement of speech and language therapists (SLTs) within paediatric palliative care (PPC) settings has been recognized within the extant literature. However, there is little understanding of SLT's specific roles and practices when working with this vulnerable cohort of children and their families. As part of a larger body of work to develop consensus-based recommendations for SLTs working in PPC, it is important to investigate demographic and caseload characteristics. This exploratory study aimed to gather previously undocumented international demographic data pertaining to SLT service provision, caseload and training in PPC. Additionally, it sought to ascertain the current treatment and assessment approaches of SLTs, and if variations exist in beliefs and practices. An anonymous cross-sectional survey was designed and reported according to the Checklist for Reporting Results of Internet E-Surveys (CHERRIES). The online survey consisted of 40 items spanning four domains: (1) demographic information, (2) caseload information, (3) service provision and (4) training and education. SLTs from Australia, Canada, New Zealand, the UK, Ireland and the United States were recruited using a purposive snowball sampling approach. Descriptive analysis of closed-ended survey responses and content analysis of open-ended responses are presented. A total of 52 respondents completed the survey. SLTs worked in a variety of PPC settings, with patients of varying age and disease groups. Over 50% of participants reported working in PPC for ≤ 4 years. Genetic disorders (34%), oncology (27%) and neurological conditions (21%) made up a significant portion of respondents' caseloads. Reported treatments and assessment approaches used by SLTs are not unique to a PPC population. Barriers and enablers for practice were identified. A portion of participants did not feel trained and prepared to assess (19.2%) or treat (15.4%) PPC clients. This study confirms that SLTs internationally have a role in the management of communication and swallowing impairments in a PPC context. However, whether current training and resources adequately support SLTs in this role remains questionable. This paper helps to provide SLTs, administrators, professional associations and tertiary institutions with foundational data to help inform workforce planning, advocacy efforts and training priorities. What this paper adds What is already known on the subject The published multidisciplinary literature has identified that SLTs have a role in PPC. However, there has been no targeted research investigating the professional characteristics of clinicians in this context, nor any detailed information regarding associated clinician beliefs or management approaches. What this paper adds to existing knowledge This study is a snapshot of attributes, practice patterns and beliefs of SLTs who work with a PPC population. It highlights SLT perspectives of education and training, as well as meta-perceptions of themselves within the multidisciplinary team. What are the potential or actual clinical implications of this work? Data presented in this paper will help to enable SLTs, organizations and associations to augment service provision and determine future professional development priorities within the field of PPC.


Laboratory measures of methylphenidate effects in cocaine-dependent patients receiving treatment.
Two experiments examined the effects of methylphenidate in male and female patients enrolled in an outpatient treatment program for primary cocaine dependence. The first study was a component of a double-blind efficacy trial wherein 57 patients were first tested in a human laboratory for their initial responsiveness to medication. Patients were randomly assigned to receive either placebo or methylphenidate treatment and received their first dose in the human laboratory environment before continuing in outpatient treatment. Methylphenidate was given as a 20-mg sustained-release dose (twice daily) plus an additional 5-mg immediate-release dose combined with the morning dose. Methylphenidate increased heart rate and subjective ratings; however, the subjective effects were primarily of a "dysphoric" nature, and significant effects were limited to increases in anxiety, depression, and anger on the Profile of Mood States; shaky/jittery ratings on a visual analog scale; and dysphoria on the lysergic acid diethylamide (LSD) scale of the Addiction Research Center Inventory. Methylphenidate did not increase cocaine craving nor ratings suggesting abuse potential (i.e., Morphine-Benzedrine Group or drug-liking scores, etc.). None of the drug effects observed in the human laboratory was of clinical concern, and no subject was precluded from continuing in the outpatient study. After outpatient treatment completion, 12 patients were brought back into a second double-blind human laboratory study in which three doses (15, 30, and 60 mg) of immediate-release methylphenidate were administered in an ascending series preceded and followed by placebo. Methylphenidate produced dose-related increases in heart rate, subjective ratings of shaky/jittery, and LSD/dysphoria without significantly altering cocaine craving or stimulant euphoria ratings. These results suggest that stimulant substitution-type approaches to the treatment of cocaine dependence are not necessarily contraindicated because of cardiovascular toxicity or medication abuse potential. However, they also suggest that the subjective effects of methylphenidate may not be positive enough for an adequate replacement approach.


Chemotherapy-induced nausea and vomiting: which antiemetic for which therapy?
Chemotherapy-induced nausea and vomiting (CINV) remains an important and common toxicity of cancer treatment. Recent guideline revisions have classified chemotherapeutic agents into four categories of emesis risk without the use of preventive agents: high (> 90%), moderate (30%--90%), low (10%-30%), and minimal (< 10%). Currently available antiemetic agents, including corticosteroids, 5-hydroxytryptamine (HT)3 receptor antagonists, and neurokinin (NK)-1 antagonists are used alone or in combination depending on the level of emetogenic potential as prophylaxis against the development of CINVduring the acute period (up to 24 hours after chemotherapy) and the delayed period (up to 5 days after treatment). Newer agents, including the second-generation 5-HT3 receptor antagonist palonosetron (Aloxi) and the NK-1 antagonist aprepitant (Emend), offer additional clinical benefit in highly and moderately emetogenic therapy. However, delayed nausea and vomiting continue to occur frequently in many patients and have an impact on quality of life. Other classes of agents including the benzodiazepines and cannabinoids offer the potential for additional protective benefit. Continued research with new drugs and combinations is necessary to meet this significant unmet need of cancer patients.


Neural mechanisms of tolerance to the effects of cocaine.
Chronic use of cocaine in high doses can produce tolerance as assessed by various behavioral, neurochemical, cellular and molecular measures in specific brain regions. Tolerance to cocaine is indicated by drug discrimination and intracranial self-stimulation models, which show the development of tolerance after approximately 1 week of frequent cocaine treatment, with recovery after a similar period of cocaine abstinence. Tolerance to the reinforcing properties of cocaine depends on dose, duration and frequency of cocaine self-administered by experimental animal or human subjects. The mechanism underlying this effect may involve an absolute or relative attenuation of dopamine response to cocaine challenge after frequent or repeated treatment in the nucleus accumbens (NAc). Similarly, afferent and efferent NAc circuits exhibit reduced metabolic activity, which lasts throughout the early period of withdrawal following repeated treatment. Attenuation of immediate early gene response also occurs, which might be related to a functional desensitization of dopamine D1-like receptors. Furthermore, intracellular adaptive responses to chronic cocaine exposure induce striatal dynorphin expression decreasing the behavioral potency of subsequent drug treatment. Thus, a combination of various pharmacodynamic mechanisms and the attenuation of dopamine response induced by sufficient dose, duration and frequency of cocaine exposure ultimately invoke the transient development of tolerance to the reinforcing effects of cocaine.


Identification of transcription factors potential related to brown planthopper resistance in rice via microarray expression profiling.
Brown planthopper (BPH), Nilaparvata lugens Stål, is one of the most destructive insect pests of rice. The molecular responses of plants to sucking insects resemble responses to pathogen infection. However, the molecular mechanism of BPH-resistance in rice remains unclear. Transcription factors (TF) are up-stream regulators of various genes that bind to specific DNA sequences, thereby controlling the transcription from DNA to mRNA. They are key regulators for transcriptional expression in biological processes, and are probably involved in the BPH-induced pathways in resistant rice varieties. We conducted a microarray experiment to analyze TF genes related to BPH resistance in a Sri Lankan rice cultivar, Rathu Heenati (RHT). We compared the expression profiles of TF genes in RHT with those of the susceptible rice cultivar Taichun Native 1 (TN1). We detected 2038 TF genes showing differential expression signals between the two rice varieties. Of these, 442 TF genes were probably related to BPH-induced resistance in RHT and TN1, and 229 may be related to constitutive resistance only in RHT. These genes showed a fold change (FC) of more than 2.0 (P<0.05). Among the 442 TF genes related to BPH-induced resistance, most of them were readily induced in TN1 than in RHT by BPH feeding, for instance, 154 TF genes were up-regulated in TN1, but only 31 TF genes were up-regulated in RHT at 24 hours after BPH infestation; 2-4 times more TF genes were induced in TN1 than in RHT by BPH. At an FC threshold of >10, there were 37 induced TF genes and 26 constitutive resistance TF genes. Of these, 13 were probably involved in BPH-induced resistance, and 8 in constitutive resistance to BPH in RHT. We explored the molecular mechanism of resistance to BPH in rice by comparing expressions of TF genes between RHT and TN1. We speculate that the level of gene repression, especially for early TF genes, plays an important role in the defense response. The fundamental point of the resistance strategy is that plants protect themselves by reducing their metabolic level to inhibit feeding by BPH and prevent damage from water and nutrient loss. We have selected 21 TF genes related to BPH resistance for further analyses to understand the molecular responses to BPH feeding in rice.


The unusual antibacterial activity of medical-grade Leptospermum honey: antibacterial spectrum, resistance and transcriptome analysis.
There is an urgent need for new, effective agents in topical wound care, and selected honeys show potential in this regard. Using a medical-grade honey, eight species of problematic wound pathogens, including those with high levels of innate or acquired antibiotic resistance, were killed by 4.0-14.8% honey, which is a concentration that can be maintained in the wound environment. Resistance to honey could not be induced under conditions that rapidly induced resistance to antibiotics. Escherichia coli macroarrays were used to determine the response of bacterial cells to a sub-lethal dose of honey. The pattern of gene expression differed to that reported for other antimicrobial agents, indicating that honey acts in a unique and multifactorial way; 78 (2%) genes were upregulated and 46 (1%) genes were downregulated more than two-fold upon exposure to the medical-grade honey. Most of the upregulated genes clustered into distinct functional regulatory groups, with many involved in stress responses, and the majority of downregulated genes encoded for products involved in protein synthesis. Taken together, these data indicate that honey is an effective topical antimicrobial agent that could help reduce some of the current pressures that are promoting antibiotic resistance.


Pharmacovigilance in China: current situation, successes and challenges.
With the integration of the global pharmaceutical economy and the gradual transformation of the healthcare insurance system in China, the legislative framework for a comprehensive regulatory system monitoring the whole process including drug development, manufacture, distribution and use has been established by the China Food and Drug Administration (CFDA) to ensure the safety and effectiveness of medication use. China has established a relatively comprehensive pharmacovigilance system covering regulation, organisation and technology from 1989 to 2014. As of 2013, one national centre, 34 provincial centres and more than 400 municipal centres for adverse drug reaction (ADR) monitoring were included in the four-level pharmacovigilance network (national, provincial, municipal and county) with more than 200,000 grassroot organisation users. The China Adverse Drug Reaction Monitoring System (CADRMS) is an online spontaneous reporting system which connects the four-level pharmacovigilance network. By 2013, CADRMS had received over 6.6 million ADR case reports. After integrating and analysing pharmacovigilance data, the National Centre for ADR Monitoring (NCADRM) publishes medication safety information by releasing ADR bulletins, National ADR Annual Reports and International Pharmacovigilance Newsletters. The NCADRM also routinely provides CADRMS data feedback to manufacturers. The CFDA implemented risk management through several approaches, including arranging 'manufacturer communication meetings', modification of medication package inserts, and restriction, suspension or withdrawal of marketing authorisations. Seamless information exchange with overseas regulatory authorities and organisations remains an area for improvement. Further development of the China pharmacovigilance system in terms of signal generation, post-marketing pharmacoepidemiology research and education is also needed.


Epidemiological overview of multidimensional chromosomal and genome toxicity of cannabis exposure in congenital anomalies and cancer development.
Cannabis and cannabinoids are implicated in multiple genotoxic, epigenotoxic and chromosomal-toxic mechanisms and interact with several morphogenic pathways, likely underpinning previous reports of links between cannabis and congenital anomalies and heritable tumours. However the effects of cannabinoid genotoxicity have not been assessed on whole populations and formal consideration of effects as a broadly acting genotoxin remain unexplored. Our study addressed these knowledge gaps in USA datasets. Cancer data from CDC, drug exposure data from National Survey of Drug Use and Health 2003-2017 and congenital anomaly data from National Birth Defects Prevention Network were used. We show that cannabis, THC cannabigerol and cannabichromene exposure fulfill causal criteria towards first Principal Components of both: (A) Down syndrome, Trisomies 18 and 13, Turner syndrome, Deletion 22q11.2, and (B) thyroid, liver, breast and pancreatic cancers and acute myeloid leukaemia, have mostly medium to large effect sizes, are robust to adjustment for ethnicity, other drugs and income in inverse probability-weighted models, show prominent non-linear effects, have 55/56 e-Values > 1.25, and are exacerbated by cannabis liberalization (P = 9.67 × 10-43, 2.66 × 10-15). The results confirm experimental studies showing that cannabinoids are an important cause of community-wide genotoxicity impacting both birth defect and cancer epidemiology at the chromosomal hundred-megabase level.


Nomenclature and diagnosis of gluten-related disorders: A position statement by the Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO).
"Gluten-related disorders" is a term that encompasses different diseases induced by the ingestion of gluten-containing food. Because of their incidence the scientific community has been intensively studying them. To support gastroenterologists with a correct nomenclature and diagnostic approach to gluten-related disorders in adulthood. The Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO) commissioned a panel of experts to prepare a position statement clarifying the nomenclature and diagnosis of gluten-related disorders, focusing on those of gastroenterological interest. Each member was assigned a task and levels of evidence/recommendation have been proposed. The panel identified celiac disease, wheat allergy and non-celiac gluten sensitivity as the gluten-related disorders of gastroenterological interest. Celiac disease has an autoimmune nature, wheat allergy is IgE-mediated while the pathogenesis of non-celiac gluten sensitivity is still unknown as is the case of non-IgE mediated allergy. Diagnosis should start with the serological screening for celiac disease and wheat allergy. In case of normal values, the response to a gluten-free diet should be evaluated and a confirmatory blind food challenge carried out. Gluten-related disorders are clinically heterogeneous. Patients should be carefully managed and specific protocols applied for a correct differential diagnosis in gastroenterological setting.


Design of the Del-1 for therapeutic angiogenesis trial (DELTA-1), a phase II multicenter, double-blind, placebo-controlled trial of VLTS-589 in subjects with intermittent claudication secondary to peripheral arterial disease.
The objective of this phase II investigation is to assess the safety and efficacy of a plasmid mediated approach to induce angiogenesis/arteriogenesis with the angiomatrix protein Del-1 (developmentally regulated endothelial locus 1), in subjects with intermittent claudication (IC) secondary to peripheral arterial disease (PAD). VLTS-589 is an investigational nonviral therapeutic comprising a plasmid-expressing Del-1 formulated with poloxamer 188 (facilitating agent). One hundred subjects with bilateral PAD and IC will be randomized after careful screening to bilateral intramuscular delivery of VLTS-589 or placebo. A total of 84 mg of plasmid or placebo will be delivered as 42 intramuscular injections (2 ml per injection, 21 injections or 42 ml in each extremity of either plasmid or placebo) in both lower extremities. The subjects in the study will be followed at regular intervals for a year after study drug administration (days 30, 90, 180, and 365) with the primary endpoint being the safety and tolerability of VLTS-589 and change in peak walking time (PWT) at day 90. The secondary endpoints include percent and absolute change in resting ankle brachial Index, claudication onset time, and quality of life measured at various time points. DELTA-1 represents the largest plasmid-based gene transfer trial designed to test the efficacy of a Del-1 as a therapeutic approach in patients with IC caused by PAD. The novel aspects of the protocol include the usage of a Del-1 plasmid-polaxamer formulation to enhance gene transfer at doses that are an order of magnitude different than other comparable trials in a unique bilateral intramuscular dosing pattern to maximize transfection/clinical efficacy and general applicability to patients with PAD.


Palmitoylethanolamide, a Natural Retinoprotectant: Its Putative Relevance for the Treatment of Glaucoma and Diabetic Retinopathy.
Retinopathy is a threat to the eyesight, and glaucoma and diabetes are the main causes for the damage of retinal cells. Recent insights pointed out a common pathogenetic pathway for both disorders, based on chronic inflammation. Palmitoylethanolamide (PEA) is an endogenous cell protective lipid. Since its discovery in 1957 as a biologically active component in foods and in many living organisms, around 500 scientific papers have been published on PEA's anti-inflammatory and neuron-protective properties. PEA has been evaluated for glaucoma, diabetic retinopathy, and uveitis, pathological states based on chronic inflammation, respiratory disorders, and various pain syndromes in a number of clinical trials since the 70s of 20th century. PEA is available as a food supplement (PeaPure) and as diet food for medical purposes in Italy (Normast, PeaVera, and Visimast). These products are notified in Italy for the nutritional support in glaucoma and neuroinflammation. PEA has been tested in at least 9 double blind placebo controlled studies, among which two studies were in glaucoma, and found to be safe and effective up to 1.8 g/day, with excellent tolerability. PEA therefore holds a promise in the treatment of a number of retinopathies. We discuss PEA as a putative anti-inflammatory and retinoprotectant compound in the treatment of retinopathies, especially related to glaucoma and diabetes.


PlaScope: a targeted approach to assess the plasmidome from genome assemblies at the species level.
Plasmid prediction may be of great interest when studying bacteria of medical importance such as Enterobacteriaceae as well as Staphylococcus aureus or Enterococcus. Indeed, many resistance and virulence genes are located on such replicons with major impact in terms of pathogenicity and spreading capacities. Beyond strain outbreak, plasmid outbreaks have been reported in particular for some extended-spectrum beta-lactamase- or carbapenemase-producing Enterobacteriaceae. Several tools are now available to explore the 'plasmidome' from whole-genome sequences with various approaches, but none of them are able to combine high sensitivity and specificity. With this in mind, we developed PlaScope, a targeted approach to recover plasmidic sequences in genome assemblies at the species or genus level. Based on Centrifuge, a metagenomic classifier, and a custom database containing complete sequences of chromosomes and plasmids from various curated databases, PlaScope classifies contigs from an assembly according to their predicted location. Compared to other plasmid classifiers, PlasFlow and cBar, it achieves better recall (0.87), specificity (0.99), precision (0.96) and accuracy (0.98) on a dataset of 70 genomes of Escherichia coli containing plasmids. In a second part, we identified 20 of the 21 chromosomal integrations of the extended-spectrum beta-lactamase coding gene in a clinical dataset of E. coli strains. In addition, we predicted virulence gene and operon locations in agreement with the literature. We also built a database for Klebsiella and correctly assigned the location for the majority of resistance genes from a collection of 12 Klebsiella pneumoniae strains. Similar approaches could also be developed for other well-characterized bacteria.


Control of a Supernumerary Robotic Hand by Foot: An Experimental Study in Virtual Reality.
In the operational theater, the surgical team could highly benefit from a robotic supplementary hand under the surgeon's full control. The surgeon may so become more autonomous; this may reduce communication errors with the assistants and take over difficult tasks such as holding tools without tremor. In this paper, we therefore examine the possibility to control a third robotic hand with one foot's movements. Three experiments in virtual reality were designed to assess the feasibility of this control strategy, the learning curve of the subjects in different tasks and the coordination of foot movements with the two natural hands. Results show that the limbs are moved simultaneously, in parallel rather than serially. Participants' performance improved within a few minutes of practice without any specific difficulty to complete the tasks. Subjective assessment by the subjects indicated that controlling a third hand by foot has been easy and required only negligible physical and mental efforts. The sense of ownership was reported to improve through the experiments. The mental burden was not directly related to the level of motion required by a task, but depended on the type of activity and practice. The most difficult task was moving two hands and foot in opposite directions. These results suggest that a combination of practice and appropriate tasks can enhance the learning process for controlling a robotic hand by foot.


Role of different pathways of the complement cascade in experimental bullous pemphigoid.
Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease associated with autoantibodies directed against the hemidesmosomal proteins BP180 and BP230 and inflammation. Passive transfer of antibodies to the murine BP180 (mBP180) induces a skin disease that closely resembles human BP. In the present study, we defined the roles of the different complement activation pathways in this model system. Mice deficient in the alternative pathway component factor B (Fb) and injected with pathogenic anti-mBP180 IgG developed delayed and less intense subepidermal blisters. Mice deficient in the classical pathway component complement component 4 (C4) and WT mice pretreated with neutralizing antibody against the first component of the classical pathway, C1q, were resistant to experimental BP. These mice exhibited a significantly reduced level of mast cell degranulation and polymorphonuclear neutrophil (PMN) infiltration in the skin. Intradermal administration of compound 48/80, a mast cell degranulating agent, restored BP disease in C4(-/-) mice. Furthermore, C4(-/-) mice became susceptible to experimental BP after local injection of PMN chemoattractant IL-8 or local reconstitution with PMNs. These findings provide the first direct evidence to our knowledge that complement activation via the classical and alternative pathways is crucial in subepidermal blister formation in experimental BP.


Visual Field Reconstruction in Hemianopia Using fMRI Based Mapping Techniques.
A stroke that includes the primary visual cortex unilaterally leads to a loss of visual field (VF) representation in the hemifield contralateral to the damage. While behavioral procedures for measuring the VF, such as perimetry, may indicate that a patient cannot see in a particular area, detailed psychophysical testing often detects the ability to perform detection or discrimination of visual stimuli ("blindsight"). The aim of this study was to determine whether functional magnetic resonance imaging (fMRI) could be used to determine whether perimetrically blind regions of the VF were still represented in VF maps reconstructed on the basis of visually evoked neural activity. Thirteen patients with hemianopia and nine control participants were scanned using 3T MRI while presented with visual stimulation. Two runs of a dynamic "wedge and ring" mapping stimulus, totaling approximately 10 min, were performed while participants fixated centrally. Two different analysis approaches were taken: the conventional population receptive field (pRF) analysis and micro-probing (MP). The latter is a variant of the former that makes fewer assumptions when modeling the visually evoked neural activity. Both methods were used to reconstruct the VF by projecting modeled activity back onto the VF. Following a normalization step, these "coverage maps" can be compared to the VF sensitivity plots obtained using perimetry. While both fMRI-based approaches revealed regions of neural activity within the perimetrically "blind" sections of the VF, the MP approach uncovered more voxels in the lesioned hemisphere in which a modest degree of visual sensitivity was retained. Furthermore, MP-based analysis indicated that both early (V1/V2) and extrastriate visual areas contributed equally to the retained sensitivity in both patients and controls. In hemianopic patients, fMRI-based approaches for reconstructing the VF can pick up activity in perimetrically blind regions of the VF. Such regions of the VF may be particularly amenable for rehabilitation to regain visual function. Compared to conventional pRF modeling, MP reveals more voxels with retained visual sensitivity, suggesting it is a more sensitive approach for VF reconstruction.


Effects of cycling bouts performed with different intensities and amounts of energy expended on central pressure and pulse wave reflection in normotensive and hypertensive men.
This study investigated pulse wave analysis in normotensive and hypertensive men after cycling bouts with different intensities and amounts of energy expended. Twenty-four men were assigned into normotensive (n = 14; age: 40.7 ± 2.8 years; 24-h ambulatory SBP/DBP:121 ± 2/74 ± 1 mmHg) and hypertensive (n = 10; age: 39.2 ± 2.3 years; 24-h ambulatory SBP/DBP:139 ± 3/86 ± 2 mmHg) groups. Participants undertook a maximal cardiopulmonary exercise test, a nonexercise control session (CTL) and three cycling bouts [two prolonged bouts expending 300 kcal at 50% (i.e. P-MOD) and 70% (i.e. P-VIG) oxygen uptake reserve (VO2R) and one short bout expending 150 kcal at 50% VO2R (i.e. S-MOD)] performed in a randomized order. Central SBP (cSBP), pulse pressure (cPP), augmentation pressure, augmentation index (AIx), heart rate (HR) and AIx adjusted for HR (AIx@75) were determined 10 min before, and 30- and 70-min postintervention. Compared to CTL, only the P-VIG changed the cSBP [70-min (Δ -11.7 mmHg)], cPP [70-min (Δ:-7.4 mmHg)], augmentation pressure [30-min (Δ:-5.7 mmHg); 70-min (Δ:-7.3 mmHg)], AIx [30-min (Δ:-15.3 %); 70-min (Δ:-16.4 %)], AIx@75 [30-min (Δ:-12.8 %); 70-min (Δ:-13.9 %)] and HR [70-min (Δ: 9.9 bpm)] in the hypertensive group. However, all exercise bouts mitigated the increased cSBP responses post-CTL in the hypertensive group. The present study provides evidence that vigorous-intensity aerobic exercise reduces acute central pressure and pulse wave reflection in hypertensive men.


Use of 2-aminopurine fluorescence to examine conformational changes during nucleotide incorporation by DNA polymerase I (Klenow fragment).
We have investigated conformational transitions in the Klenow fragment polymerase reaction by stopped-flow fluorescence using DNA substrates containing the fluorescent reporter 2-aminopurine (2-AP) on the template strand, either at the templating position opposite the incoming nucleotide (designated the 0 position) or 5' to the templating base (the +1 position). By using both deoxy- and dideoxy-terminated primers, we were able to distinguish steps that accompany ternary complex formation from those that occur during nucleotide incorporation. The fluorescence changes revealed two extremely rapid steps that occur early in the pathway for correct nucleotide incorporation. The first, detectable with the 2-AP reporter at the 0 position, occurs within the first few milliseconds and is associated with dNTP binding. This is followed by a rapid step involving relative movement of the +1 base, detectable when the 2-AP reporter is at the +1 position. Finally, when the primer had a 3'-OH, a fluorescence decrease with a rate equal to the rate of nucleotide incorporation was observed with both 0 and +1 position reporters. When the primer was dideoxy-terminated, the only change observed at the rate expected for nucleotide incorporation had a very small amplitude, suggesting that the rate-limiting conformational change does not produce a large fluorescence change, and is therefore unlikely to involve a significant change in the environment of the fluorophore. Fluorescence changes observed during misincorporation were substantially different from those observed during correct nucleotide incorporation, implying that the conformations adopted during correct and incorrect nucleotide incorporation are distinct.


The effects of vitamin D plus calcium supplementation on metabolic profiles, biomarkers of inflammation, oxidative stress and pregnancy outcomes in pregnant women at risk for pre-eclampsia.
The present study was designed to examine the effects of vitamin D plus calcium administration on metabolic profiles and pregnancy outcomes among women at risk for pre-eclampsia. In a prospective, double-blind, placebo-controlled trial, 60 women at risk for pre-eclampsia were randomised to take either 50 000 IU vitamin D3 every 2 weeks plus 1000 mg day(-1) calcium supplements (as calcium carbonate) (n = 30) or to receive placebos at the same times (n = 30) from 20 to 32 weeks of gestation. Fasting blood samples were taken at baseline and 12 weeks after intervention to determine related variables. Newborn anthropometric measurements were determined. Taking combined cholecalciferol and calcium supplements, compared to placebo, led to significant reductions in fasting plasma glucose (FPG) [mean (SD)] [-5.7 (5.5) versus -0.6 (12.6) mg dL(-1) , P = 0.04], serum insulin concentrations [-2.8 (6.0) versus +7.7 (9.8) μIU mL(-1) , P < 0.001], homeostasis model of assessment-insulin resistance [-0.8 (1.3) versus +1.6 (2.2), P < 0.001], homeostatic model assessment-beta cell function [-8.2 (25.8) versus +32.6 (41.3, P < 0.001] and a significant rise in quantitative insulin sensitivity check index score [+0.02 (0.02) versus -0.02 (0.02, P < 0.001]. Additionally, pregnant women who received cholecalciferol plus calcium supplements had increased serum high-density lipoprotein (HDL)-cholesterol [+4.6 (8.3) versus -2.9 (7.7) mg dL(-1) , P = 0.001] and plasma total glutathione (GSH) concentrations [+23.4 (124.0) versus -94.8 (130.2) μm, P = 0.001] compared to placebo. However, after adjustment for the baseline levels, maternal age and baseline body mass index, the effects on FPG levels (P = 0.13) and systolic blood pressure (P = 0.13) disappeared. Vitamin D plus calcium administration for 12 weeks had beneficial effects on glycaemic status, HDL-cholesterol, GSH and blood pressure among women at risk for pre-eclampsia.


Facultative symbiont infections affect aphid reproduction.
Some bacterial symbionts alter their hosts reproduction through various mechanisms that enhance their transmission in the host population. In addition to its obligatory symbiont Buchnera aphidicola, the pea aphid Acyrthosiphon pisum harbors several facultative symbionts influencing several aspects of host ecology. Aphids reproduce by cyclical parthenogenesis whereby clonal and sexual reproduction alternate within the annual life cycle. Many species, including the pea aphid, also show variation in their reproductive mode at the population level, with some lineages reproducing by cyclical parthenogenesis and others by permanent parthenogenesis. While the role of facultative symbionts has been well studied during the parthenogenetic phase of their aphid hosts, very little is known on their possible influence during the sexual phase. Here we investigated whether facultative symbionts modulate the capacity to produce sexual forms in various genetic backgrounds of the pea aphid with controlled symbiont composition and also in different aphid genotypes from natural populations with previously characterized infection status and reproductive mode. We found that most facultative symbionts exhibited detrimental effects on their hosts fitness under sex-inducing conditions in comparison with the reference lines. We also showed that the loss of sexual phase in permanently parthenogenetic lineages of A. pisum was not explained by facultative symbionts. Finally, we demonstrated that Spiroplasma infection annihilated the production of males in the host progeny by inducing a male-killing phenotype, an unexpected result for organisms such as aphids that reproduce primarily through clonal reproduction.