The history of laparoscopic general surgery in the Caribbean.
The first world witnessed a laparoscopic revolution in the 1990s. At the start, laparoscopic surgery was heavily criticized and ridiculed. Despite this, the specialty has blossomed where almost any procedure can be done laparoscopically with the now obvious tremendous benefit to the patients. The objective of this paper is to examine where the Caribbean is placed relative to the rest of the world in terms of laparoscopic surgery and to understand why we are here. The literature written on laparoscopy in the region was reviewed and contributions were taken from key surgeons in three main islands, Trinidad and Tobago, Barbados and Jamaica. Though the first laparoscopic cholecystectomy in the Caribbean, in most islands, took place in the early 1990s like the rest of the world, there was relative dormancy for at least a decade in Trinidad and Tobago and even longer in other islands with regards to implementing advanced procedures or increasing case volumes. Reasons for this included lack of funding, lack of operating time in public facilities, lack of information of the public and the medical fraternity but most importantly lack of trained laparoscopic surgeons. This last factor was proven to be the key one in Trinidad and Tobago in 2003, Jamaica 2005 and Barbados 2011/12, when the return of trained personel engineered the transition from basic to advanced laparoscopy Despite the delay of approximately 10 years in Trinidad and Tobago and 15 years in other islands, the return of trained surgeons has seen a rapid increase in case variety and volumes in laparoscopy. The wheels of motion of the laparoscopic revolution in the Caribbean have finally begun.


Evaluation of an individualized education program in pituitary diseases: a pilot study.
The low prevalence of pituitary diseases makes patient autonomy crucial, and self-management programs should be more common. To assess the efficacy of an education program for patients with pituitary diseases in terms of patients' quality of life, satisfaction and goal attainment. Adult patients with pituitary disorders were recruited in a tertiary referral center and chose at least three of eight possible sessions on various topics, from disease management to psychosocial issues. Patients were included if they attended at least three sessions between 2012 and 2016 and completed the initial, final, and follow-up questionnaires. Data on quality of life (SF36), satisfaction and goal attainment were analyzed. Fifty-three patients were included (33 women; mean age, 53.5 years). There were a significant quality of life improvements in terms of physical and psychic limitation scores at the final assessment that persisted at follow-up evaluation. Most patients reached their objectives, especially those on sharing experiences and improving autonomy and self-confidence. More than half set new objectives at the end of the program, the most popular one being to reinforce their knowledge of their pituitary disease, its evolution and treatment (17.1% of patients). The mean overall satisfaction score was 3.75/4. At follow-up evaluation, patients reported improved self-management of pituitary disease (3.6/5) and improved self-efficacy (3.8/5). Individualizing the educational objectives of patients with pituitary disease improves the way they live with their disease. If confirmed in other cohorts, this approach could become the gold standard for education programs in rare endocrine diseases.


Nightmares and Suicide in Posttraumatic Stress Disorder: The Mediating Role of Defeat, Entrapment, and Hopelessness.
Although nightmares appear to be related to suicidal behaviors, the mechanisms which underpin this relationship are unknown. We sought to address this gap by examining a multiple mediation hypothesis whereby nightmares were predicted to have an indirect effect on suicidal behaviors through perceptions of defeat, entrapment, and hopelessness. Data were collected from 91 participants who had experienced trauma and symptoms of posttraumatic stress disorder (PTSD). Nightmares were measured by summing the frequency and intensity ratings of relevant items on the Clinician-Administered PTSD Scale. Participants also completed questionnaire measures of suicidal behavior, hopelessness, defeat, and entrapment. Given the interrelations between insomnia, PTSD, and suicide, a measure of insomnia was included as a covariate. Furthermore, analyses were conducted with and without those participants who had comorbid depression. Suicidal behaviors were higher in those participants who experienced nightmares (62%), in comparison to those who did not (20%). Bootstrapped analyses provided support for the hypothesized multistep mediational model. Specifically, nightmares were both directly and indirectly associated with suicidal behaviors, through perceptions of defeat, entrapment, and hopelessness, independent of comorbid insomnia and depression. For the first time we show that the relationship between nightmares and suicidal behaviors is partially mediated by a multistep pathway via defeat, entrapment, and hopelessness. Clinically, our work highlights the importance of monitoring and targeting nightmares and perceptions of defeat, entrapment, and hopelessness when working with clients who have experienced trauma. A commentary on this article appears in this issue on page 289.


Molecular epidemiology of diarrhoeagenic Escherichia coli associated with sporadic cases and outbreaks of diarrhoea between 2000 and 2001 in India.
Diarrhoeal infection caused by Escherichia coli is common in India with occasional outbreaks. However, association of different pathotypes of diarrhoeagenic E. coli (DEC) with the disease and its phenotypic and genotypic characteristics are not fully demonstrated. In this study, E. coli strains from sporadic cases and outbreaks of diarrhoea during 2000-2001 were confirmed as DEC by polymerase chain reaction (PCR) targeting the specific virulence genes. DEC represented by enterotoxigenic E. coli (ETEC), enteropathogenic E. coli (EPEC) and enteroaggregative E. coli (EAggEC) were mostly belonged to O serogroups 25, 86a, 114 and 146. The gene astA was frequently detected among ETEC and EAggEC than EPEC. After initial screening of 200 DEC strains with serology and antibiotic susceptibility test, 32 strains representing ETEC, EPEC, and EAggEC isolated from different areas of India were included in the pulsed-field gel electrophoresis (PFGE) analysis. Using the PFGE results, the hierarchical representation of different linkage levels between the DEC strains were determined by unweighed pair-group arithmetic mean (UPGAMA) method. Except for few strains, clonotyping by PFGE revealed no correlation between pathotypes and serogroups as well as the place of isolation of the DEC strains. The prevailing clonal diversity among the different categories of DEC strains suggests that the pathotypes of DEC belonged to diverse clones.


Plasmon-assisted terahertz imaging inside metal-filled media.
We present the application of THz plasmonics in imaging dielectric objects embedded in metal-filled media. By exploiting the time domain information from the transmitted pulse, signatures of the objects were observed. To enhance the low quality images acquired through THz time domain spectroscopy, a super-resolution image processing technique was applied. It is shown that pulse arrival time and phase magnitude information compared to the integrated instantaneous power of the transmitted pulse provides more detailed images of the embedded object.


Snoring as a risk factor for sleep-related brain infarction.
We studied 177 consecutive male patients aged 16-60 years with brain infarction verified by neuroradiology and analyzed the time of onset of stroke symptoms related to sleep and the role of possible or known risk factors for brain infarction. Brain infarction occurred relatively more often during the first 30 minutes after awakening than at any other time. In multiple stepwise logistic regression analyses, snoring was the only independent risk factor differentiating stroke occurring during sleep and stroke occurring either during sleep or during the first 30 minutes after awakening from stroke occurring at other times of the day. The risk ratios were 2.65 (95% confidence interval 1.32-5.29, p less than 0.005) and 3.16 (95% confidence interval 1.61-6.22, p less than 0.001), respectively. Other factors tested were age, arterial hypertension, diabetes mellitus, smoking, alcohol consumption, and body mass index. Arterial hypertension seemed to have an additive effect on the independent risk caused by snoring.


Novel Structured Reporting Systems for Theranostic Radiotracers.
Standardized reporting is more and more routinely implemented in clinical practice, and such structured reports have a major impact on a large variety of medical fields, such as laboratory medicine, pathology, and, recently, radiology. Notably, the field of nuclear medicine is constantly evolving as novel radiotracers for numerous clinical applications are developed. Thus, framework systems for standardized reporting in this field may increase clinical acceptance of new radiotracers, allow for inter- and intracenter comparisons for quality assurance, and be used in global multicenter studies to ensure comparable results and enable efficient data abstraction. In the last couple of years, several standardized framework systems for PET radiotracers with potential theranostic applications have been proposed. These include systems for prostate-specific membrane antigen-targeted PET agents to diagnose and treat prostate cancer, and systems for somatostatin receptor-targeted PET agents to diagnose and treat neuroendocrine neoplasia. In the present review, the framework systems for these 2 types of cancer will be briefly introduced, followed by an overview of their advantages and limitations. In addition, potential applications will be defined, approaches to validate such concepts will be proposed, and future perspectives will be discussed.


Who Supports Breastfeeding Mothers? : An Investigation of Kin Investment in the United States.
Breastfeeding is one important form of maternal investment that is influenced by support from kin and non-kin. This paper investigates who provides support for breastfeeding mothers and their children, what type of support they provide, and how support impacts breastfeeding duration. The data were derived from a survey of 594 American mothers and were analyzed using quantitative methods, including Cox regression. Analyses indicate that mothers receive significant support, particularly from spouses and maternal grandmothers. More frequent breastfeeding discussions with La Leche League and maternal grandfathers were associated with longer duration, whereas discussions with physicians were associated with shorter breastfeeding duration. Results indicate that consulting others specifically about breastfeeding may influence breastfeeding decisions. The results are consistent with the idea that social support may influence breastfeeding duration and that some types of support are more influential than others. Furthermore, support persons should be educated about breastfeeding to prevent early weaning.


Genetic analysis of Saccharomyces cerevisiae chromosome I: on the role of mutagen specificity in delimiting the set of genes identifiable using temperature-sensitive-lethal mutations.
In a previous attempt to identify as many as possible of the essential genes on Saccharomyces cerevisiae chromosome I, temperature-sensitive (Ts-) lethal mutations that had been induced by ethyl methane-sulfonate or nitrosoguanidine were analyzed. Thirty-two independently isolated mutations that mapped to chromosome I identified only three complementation groups, all of which had been known previously. In contrast, molecular analyses of segments of the chromosome have suggested the presence of numerous additional essential genes. In order to assess the degree to which problems of mutagen specificity had limited the set of genes detected using Ts- lethal mutations, we isolated a new set of such mutations after mutagenesis with UV or nitrogen mustard. Surprisingly, of 21 independently isolated mutations that mapped to chromosome I, 17 were again in the same three complementation groups as identified previously, and two of the remaining four mutations were apparently in a known gene involved in cysteine biosynthesis. Of the remaining two mutations, one was in one of the essential genes identified in the molecular analyses, and the other was too leaky to be mapped. These results suggest that only a minority of the essential genes in yeast can be identified using Ts- lethal mutations, regardless of the mutagen used, and thus emphasize the need to use multiple genetic strategies in the investigation of cellular processes.


Information, communication, advocacy, and complaint: how the spouse of a man with aphasia managed his discharge from hospital.
Background: The impact of stroke and aphasia has been recognised as a family problem for many years with studies highlighting spouses' need for information at different times along the recovery journey, for practical and emotional support, recognition, and respite. In particular, the decision-making around discharge from hospital, or planning for rehabilitation, is not always collaborative even though family involvement assists family members to plan and adjust to their new caring role. Aims: This study aims to explore how the wife of a man with aphasia managed his discharge from hospital in the acute phase post-stroke. It provides an opportunity for health professional learning and sensitisation through the detailed analysis of a de-identified but a real case that happened to reflect key issues reported by families in previous research: lack of information, poor communication with healthcare professionals, and the need for advocacy. Methods and procedures: The data for this paper are drawn from two sources: a single in-depth interview with the wife collected as part of an earlier large multi-site study that included interviews with 48 family members of people with aphasia after stroke; and two complaint letters she wrote to the hospital and two letters received back. This study uses a narrative analysis of the interview, and a systemic functional linguistics (SFL) analysis of the letters in order to shed light on the key issues of information, communication, and advocacy. Outcomes and results: The narrative analysis of the interview and the SFL analysis of the letters together help to unpack the reasons why the wife felt motivated to write a complaint letter to the hospital where her husband had been admitted post-stroke. The letters themselves demonstrate careful choices of language for both parties, with the hospital discounting the wife's concerns and closing down the exchange. They also reflect a profound misunderstanding by the hospital about the functional consequences of aphasia and its impact on the family. Conclusions: It is important that family members, taking on a caring role for people with aphasia after stroke, are supported with clear information and good communication in acute settings. This may enable them to be engaged in the recovery process as partners with healthcare teams and more effectively support adjustments to post-stroke life in the longer term.


Dental disease and risk of coronary heart disease and mortality.
To investigate a reported association between dental disease and risk of coronary heart disease. National sample of American adults who participated in a health examination survey in the early 1970s. Prospective cohort study in which participants underwent a standard dental examination at baseline and were followed up to 1987. Proportional hazards analysis was used to estimate relative risks adjusted for several covariates. Incidence of mortality or admission to hospital because of coronary heart disease; total mortality. Among all 9760 subjects included in the analysis those with periodontitis had a 25% increased risk of coronary heart disease relative to those with minimal periodontal disease. Poor oral hygiene, determined by the extent of dental debris and calculus, was also associated with an increased incidence of coronary heart disease. In men younger than 50 years at baseline periodontal disease was a stronger risk factor for coronary heart disease; men with periodontitis had a relative risk of 1.72. Both periodontal disease and poor oral hygiene showed stronger associations with total mortality than with coronary heart disease. Dental disease is associated with an increased risk of coronary heart disease, particularly in young men. Whether this is a causal association is unclear. Dental health may be a more general indicator of personal hygiene and possibly health care practices.


Abundant and dynamic expression of G protein-coupled P2Y receptors in mammalian development.
Extracellular ATP mediates diverse biological effects by activating two families of receptors, the P2X and P2Y receptors. There is growing evidence to show that activation of G protein-coupled P2Y receptors can produce trophic effects in many cell types. Yet the expression and function of the P2Y receptors in development has rarely been studied and has never been investigated in mammalian development. This study used the reverse transcription-polymerase chain reaction and immunohistochemistry to demonstrate the abundant and dynamic expression of P2Y receptors in rat development. These receptors were expressed in a wide range of embryonic structures, notably somites, skeletal muscle, the central and peripheral nervous system, the heart, lung, and liver. All the P2Y receptors studied were expressed as early as embryonic day 11, when most embryonic organs were far from being functional and still in the process of being formed. P2Y receptor proteins were strongly expressed in temporary, developmental structures that do not have a correlate in the adult animal, including the somites (P2Y1, P2Y2, and P2Y4) and the floor plate of the neural tube (P2Y1). P2Y receptors were also dynamically expressed, with receptor mRNA and protein being both up- and down-regulated at different developmental stages. The down-regulation of the P2Y1, 2, and 4 receptor proteins in skeletal muscle and heart, and the disappearance of the P2Y4 receptor from the brainstem and ventral white matter of the spinal cord postnatally, demonstrated that many P2Y receptors were likely to be involved in functions specific to embryonic life. Thus, these findings strongly suggest that P2Y receptors play an important role in the development of many tissues, and pioneer further studies into the role of purinergic signalling in development.


Effect of IgG subclasses on in vivo bioavailability and metabolic fate of immune-complexed insulin in Lewis rats.
The bioavailability, distribution, and metabolic fate of 125I-labeled insulin complexed to antibodies in guinea pig antiserum, purified guinea pig IgG1, IgG2, a mixture of IgG1 and IgG2, and homologous Lou/m rat antiserum were studied in inbred Lewis rats. 125I-insulin complexed to purified guinea pig IgG2 antibodies was rapidly cleared from the blood and sequestered in increasing amounts with time in the liver. Large amounts of the 125I-insulin complexed to guinea pig IgG1 antibodies remained in the blood for at least 30 min. The bioavailability of 125I-insulin bound to IgG1 and IgG2 antibodies was inhibited for at least 30 min because significantly less was available for rapid binding to insulin receptors on hepatocytes and renal tubular cells and its subsequent rapid degradation. The bioavailability of 125I-insulin was further decreased when bound to antibodies in native guinea pig antiserum or a mixture of IgG1 and IgG2 antibodies compared with the 125I-insulin complexed to either purified IgG1 or IgG2 antibodies alone. The 125I-insulin bound to antibodies in native guinea pig antiserum or a mixture of IgG1 and IgG2 antibodies was distributed in vivo in a manner reflecting the relative concentrations of the IgG1 and IgG2 antibodies present. The bioavailability, distribution, and metabolic fate of 125I-insulin in immune complexes prepared with homologous Lou/m rat insulin antiserum was qualitatively similar to that observed with immune complexes prepared with guinea pig insulin antiserum. It appears that the Lewis rat can be used as an in vivo model to study the bioavailability,distribution,and metabolic fate of insulin bound to xenogenic or homologous insulin antibodies.


Cervical disease and cancer in HIV positive women. Recommendations for screening and diagnosis.
Cancer and cervical disease occur more frequently in HIV infected women than in HIV negative. HIV infection is associated with an increased prevalence and severity of Human Papilloma Virus (HPV) associated cervical intraepithelial lesions. Advanced HIV disease is the strongest independent risk factor for cancer associated HPV infection. Up to now, there have been limited and controversial data on the effect of High Active Antiretroviral Therapy (HAART) on the natural history of cervical lesions. The major risk factors associated with cervical cancer detection are similar in HIV positive and negative women and include lack of screening and prolonged duration of symptoms. HIV positive women should have a complete gynaecological examination, including a Pap test, which should be performed twice in the first year after the diagnosis of HIV infection. Referral for colposcopy and biopsy should be recommended in case of abnormal cytology.


Phase synchronization of baroclinic waves in a differentially heated rotating annulus experiment subject to periodic forcing with a variable duty cycle.
A series of laboratory experiments in a thermally driven, rotating fluid annulus are presented that investigate the onset and characteristics of phase synchronization and frequency entrainment between the intrinsic, chaotic, oscillatory amplitude modulation of travelling baroclinic waves and a periodic modulation of the (axisymmetric) thermal boundary conditions, subject to time-dependent coupling. The time-dependence is in the form of a prescribed duty cycle in which the periodic forcing of the boundary conditions is applied for only a fraction δ of each oscillation. For the rest of the oscillation, the boundary conditions are held fixed. Two profiles of forcing were investigated that capture different parts of the sinusoidal variation and δ was varied over the range 0.1≤δ≤1. Reducing δ was found to act in a similar way to a reduction in a constant coupling coefficient in reducing the width of the interval in forcing frequency or period over which complete synchronization was observed (the "Arnol'd tongue") with respect to the detuning, although for the strongest pulse-like forcing profile some degree of synchronization was discernible even at δ=0.1. Complete phase synchronization was obtained within the Arnol'd tongue itself, although the strength of the amplitude modulation of the baroclinic wave was not significantly affected. These experiments demonstrate a possible mechanism for intraseasonal and/or interannual "teleconnections" within the climate system of the Earth and other planets that does not rely on Rossby wave propagation across the planet along great circles.


Structures of Two Melanoma-Associated Antigens Suggest Allosteric Regulation of Effector Binding.
The MAGE (melanoma associated antigen) protein family are tumour-associated proteins normally present only in reproductive tissues such as germ cells of the testis. The human genome encodes over 60 MAGE genes of which one class (containing MAGE-A3 and MAGE-A4) are exclusively expressed in tumours, making them an attractive target for the development of targeted and immunotherapeutic cancer treatments. Some MAGE proteins are thought to play an active role in driving cancer, modulating the activity of E3 ubiquitin ligases on targets related to apoptosis. Here we determined the crystal structures of MAGE-A3 and MAGE-A4. Both proteins crystallized with a terminal peptide bound in a deep cleft between two tandem-arranged winged helix domains. MAGE-A3 (but not MAGE-A4), is predominantly dimeric in solution. Comparison of MAGE-A3 and MAGE-A3 with a structure of an effector-bound MAGE-G1 suggests that a major conformational rearrangement is required for binding, and that this conformational plasticity may be targeted by allosteric binders.


Appraisal of lignocellusoic biomass degrading potential of three earthworm species using vermireactor mediated with spent mushroom substrate: Compost quality, crystallinity, and microbial community structural analysis.
Spent mushroom substrate (SMS) is a recalcitrant lignocellulosic waste. Recycling of SMS through composting has been reported; however, the process is lengthy due to its complex biochemical composition. Although vermitechnology is known for its high efficiency, it has rarely been applied to recycle SMS. In this study, the qualitative value of vermicomposted SMS mediated by three earthworm species (i.e., Eisenia fetida, Eudrilus eugeniae, and Perionyx excavatus) was evaluated on the basis of nutrient availability, microbial activity, phospholipid fatty acid (PLFA) profiles, and seed germination assays. Degradation profiles of the lignocellulosic substrate in the vermireactors were assessed by monitoring the changes in crystallinity and distribution of functional groups using X-ray diffraction (XRD) and Fourier transform infrared spectroscopy, respectively. Total organic carbon decreased by 1.4-3.5 folds with approximately 2.1-2.4 folds increase in nitrogen and phosphorus availability in all vermibeds. Interestingly, pH declined in the Eisenia and Eudrilus systems but increased in the Perionyx-vermibeds. XRD-derived crystallinity index was reduced significantly by 1.37 folds in Perionyx-vermicompost with concurrent microbial enrichment. Further, profuse abundance of vital functional groups (CO, NH, and OH) was clearly observed in the vermicompost with Perionyx followed by that with Eisenia. Moreover, PLFA illustrated significant variations in fatty acid distributions and microbial communities of the three vermicomposting systems. The seed germination assay showed that the germination index and relative root-shoot vigor of Perionyx-vermicompost treated seeds were 1.05-1.30 times greater than those of Eisenia and Eudrilus vermicompost treated ones. The results suggest that SMS degradability was affected by the growth of a healthy microbial community through vermicomposting.


Alterations in central catecholamines associated with immune responding in adult and aged mice.
Central catecholamine alterations associated with immune activity are similar to those seen following stressor exposure. Inasmuch as aged animals exhibit more pronounced stressor-provoked alterations of central amines relative to younger animals, it was of interest to determine whether immune challenge would similarly induce more pronounced central amine variations in older animals. Fifteen-month old CD-1 mice challenged with 10(7) sheep red blood cells (SRBC) revealed an equivalent peak splenic plaque-forming cell response (4 days after antigen challenge) to that of 3-month-old mice challenged with 10(6) cells. Neither plasma adrenocorticotropic hormone (ACTH) nor corticosterone levels varied over days following immunization, although ACTH levels were generally higher in the older mice. In both age groups reductions of hypothalamic and locus coeruleus norepinephrine (NE) and increased accumulation of the metabolite MHPG coincided with (or preceded by 24 h) the peak immune response. However, increased accumulation of MHPG in the hypothalamus was greater and occurred earlier in the locus coeruleus of the aged mice. Likewise, at or about the time of peak immune responses nucleus accumbens dopamine (DA) levels were reduced and metabolites elevated in both age groups, while in the prefrontal cortex only DA metabolite levels were elevated. These data are commensurate with previous findings showing that SRBC inoculation may influence central neurotransmitters and that such effects correspond with the time of the peak immune responses. Moreover, in so far as hypothalamic NE utilization is concerned, it seems that the effects of SRBC inoculation are more pronounced in aged animals.


Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study.
Hypertension can be controlled adequately with existing drugs such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Nevertheless, treatment success is often restricted by patients not adhering to treatment. Immunisation against angiotensin II could solve this problem. We investigated the safety and efficacy of CYT006-AngQb-a vaccine based on a virus-like particle-that targets angiotensin II to reduce ambulatory blood pressure. In this multicentre, double-blind, randomised, placebo-controlled phase IIa trial, 72 patients with mild-to-moderate hypertension were randomly assigned with a computer-generated randomisation list to receive subcutaneous injections of either 100 mug CYT006-AngQb (n=24), 300 mug CYT006-AngQb (24), or placebo (24), at weeks 0, 4, and 12. 24-h ambulatory blood pressure was measured before treatment and at week 14. The primary outcomes were safety and tolerability. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00500786. Two patients in the 100 mug group, three in the 300 mug group, and none in the placebo group discontinued study treatment. All patients were included in safety analyses; efficacy analyses did not include the five dropouts, for whom no data were available at week 14. Five serious adverse events were reported (two in the 100 mug group, two in the 300 mug group, and one in the placebo group); none were deemed to be treatment related. Most side-effects were mild, transient reactions at the injection site. Mild, transient influenza-like symptoms were seen in three patients in the 100 mug group, seven in the 300 mug group, and none in the placebo group. In the 300 mug group, there was a reduction from baseline in mean ambulatory daytime blood pressure at week 14 by -9.0/-4.0 mm Hg compared with placebo (p=0.015 for systolic and 0.064 for diastolic). The 300 mug dose reduced the early morning blood-pressure surge compared with placebo (change at 0800 h -25/-13 mm Hg; p<0.0001 for systolic, p=0.0035 for diastolic). Immunisation with CYT006-AngQb was associated with no serious adverse events; most observed adverse events were consistent with local or systemic responses similar to those seen with other vaccines. The 300 mug dose reduced blood pressure in patients with mild-to-moderate hypertension during the daytime, especially in the early morning. Cytos Biotechnology AG.


Aberrations measurement of freeform spectacle lenses based on Hartmann wavefront technology.
Freeform spectacle lenses have been popularized in the past few years. Traditional evaluation methods only focused on the refractive power parameters. The inspection technology of wavefront aberration has been introduced to optometry. In this paper, the wavefront aberration is used to evaluate the freeform spectacle lenses. The Shack-Hartmann wavefront technology is used to measure the same zones on the lenses with different designed forms. It shows that the aberration distributions are different from each other. The design with the freeform surface on the back can obtain the smallest aberrations in the entire surface. The aberrations on different zones for the same lens are analyzed. The blending zones show the greatest aberrations. The aberration on the progressive corridor is greater than the other zones. The Hartmann wavefront technology can be used to measure the wavefront aberration of freeform spectacle lenses.


Erroneous sonographic identification of fetal lateral ventricles: relationship to the echogenic periventricular "blush".
We show, through correlation of fetal, neonatal, and necropsy brain sonography, that the three-parallel-echogenic-line configuration classically thought to represent fetal lateral ventricular margins on high axial images are actually extraventricular, lying within cerebral white matter. Accurate sonographic identification of fetal hydrocephalus is essential for appropriate patient management. Both qualitative and quantitative methods of determining ventriculomegaly have been described. The latter require identification of lateral ventricular walls for subsequent ventricular mensuration and comparison with hemispheric width. The parallel-line configuration, thought to represent ventricular margins, has been used for such measurements. We have--through careful fetal, neonatal, and necropsy specimen scanning in several planes--determined that the presumed ventricular wall echoes are actually extraventricular, arising from fibers within the cerebral white matter aligned perpendicular to the sonographic beam. This is identical to the etiology of the normal echogenic periventricular "blush" described in the neonate. Since these parallel echogenic lines do not represent actual ventricular margins, they should not be relied upon for the diagnosis of ventriculomegaly.


Patterns of alcohol use among Brazilian adolescents.
To describe patterns of alcohol consumption by adolescents in Brazil. From November 2005 to April 2006, a sample composed of 661 subjects aged between 14 to 17 years was rigorously selected in Brazil using a multistage probabilistic method to represent the profile of the adolescent Brazilian population. 34% of Brazilian adolescents drink alcoholic beverages. The mean age of drinking initiation was 14 years of age. Older adolescents, as well as those living in the southern part of Brazil, those who are not attending school and those who are working, and black individuals and those with personal income reported a higher frequency of drinking. Socio-demographic factors such as gender, income bracket, family income and student status do increase the amount of alcohol consumed. Males report a higher frequency of binge drinking than females. Moreover, more than half of the males that had drunk in the previous year reported having engaged in binge drinking on at least one occasion. Beer represents approximately half of all the drinks consumed by adolescents. There was no significant difference between genders in the kind of alcohol consumed. Among adolescents who drink, the consumption of several drinks is frequent. Alcohol consumption varies from region to region, social economic status (including self-generated income) and age. These findings are discussed in light of their importance for the development of alcohol prevention policies in Brazil.


Primary Tactile Thalamus Spiking Reflects Cognitive Signals.
Little is known about whether information transfer at primary sensory thalamic nuclei is modified by behavioral context. Here we studied the influence of previous decisions/rewards on current choices and preceding spike responses of ventroposterior medial thalamus (VPm; the primary sensory thalamus in the rat whisker-related tactile system). We trained head-fixed rats to detect a ramp-like deflection of one whisker interspersed within ongoing white noise stimulation. Using generative modeling of behavior, we identify two task-related variables that are predictive of actual decisions. The first reflects task engagement on a local scale ("trial history": defined as the decisions and outcomes of a small number of past trials), whereas the other captures behavioral dynamics on a global scale ("satiation": slow dynamics of the response pattern along an entire session). Although satiation brought about a slow drift from Go to NoGo decisions during the session, trial history was related to local (trial-by-trial) patterning of Go and NoGo decisions. A second model that related the same predictors first to VPm spike responses, and from there to decisions, indicated that spiking, in contrast to behavior, is sensitive to trial history but relatively insensitive to satiation. Trial history influences VPm spike rates and regularity such that a history of Go decisions would predict fewer noise-driven spikes (but more regular ones), and more ramp-driven spikes. Neuronal activity in VPm, thus, is sensitive to local behavioral history, and may play an important role in higher-order cognitive signaling.SIGNIFICANCE STATEMENT It is an important question for perceptual and brain functions to find out whether cognitive signals modulate the sensory signal stream and if so, where in the brain this happens. This study provides evidence that decision and reward history can already be reflected in the ascending sensory pathway, on the level of first-order sensory thalamus. Cognitive signals are relayed very selectively such that only local trial history (spanning a few trials) but not global history (spanning an entire session) are reflected.


Application of Fourier transform infrared (FT-IR) spectroscopy to the study of the modification of epoxidized sunflower oil by acrylation.
Commercial sunflower oil was epoxidized at the laboratory-scale. The epoxidized sunflower oil (ESFO) was modified following the acrylation reaction. Modification was carried out simultaneously using acrylic acid (AA) and triethylamine (TEA). To optimize the reaction conditions, the effects of four temperatures (40, 60, 80, and 100 °C), the ESFO:AA (100:100) ratio, and 0.2% TEA were investigated. The rate of conversion was analyzed with both FT-IR and titration of the oxirane ring. After that, the temperature with the highest conversion was selected and used throughout for all modification reactions. Then, four ratios (100:100, 100:90, 100:80, and 100:75) of ESFO:AA were analyzed at four different concentrations of TEA (0.2, 0.3, 0.4, and 0.5%) to determine the best estimate for both the ESFO:AA ratio and the catalyst concentration. Conversion rate was analyzed using FT-IR spectroscopy by measuring the concentrations of ester, carbonyl, and alcohol groups. Moreover, oxirane-ring concentration was estimated using the titration method (with gentian violet as indicator) and FT-IR spectroscopy (epoxy ring absorptions at 1270 cm(-1) and 877 cm(-1)). Based on conversion yield, the optimum ESFO:AA ratio corresponds to 100:80; the best temperature reaction was at 60 °C, and the best TEA concentration was 0.2%. The critical amounts of reactants needed to reach maximum conversion were established. The final acid value of the acrylated ESFO after washing (pH = 7) was 2.1 mg potassium hydroxide (KOH)·g(-1). All results show that FT-IR spectroscopy is a simple, low-cost, rapid method for investigating the kinetics of a reaction.


Is there cognitive decline 1 year after CABG? Comparison with surgical and nonsurgical controls.
It is widely assumed that decline in cognition after coronary artery bypass grafting (CABG) is related to use of the cardiopulmonary bypass pump. Because most studies have not included comparable control groups, it remains unclear whether postoperative cognitive changes are specific to cardiopulmonary bypass, general aspects of surgery, or vascular pathologies of the aging brain. This nonrandomized study included four groups: CABG patients (n = 140); off-pump coronary surgery (n = 72); nonsurgical cardiac controls (NSCC) with diagnosed coronary artery disease but no surgery (n = 99); and heart healthy controls (HHC) with no cardiac risk factors (n = 69). Subjects were evaluated at baseline (preoperatively), 3 months, and 12 months. Eight cognitive domains and a global cognitive score, as well as depressive and subjective symptoms were analyzed. At baseline, patients with coronary artery disease (CABG, off-pump, and NSCC) had lower performance than the HHC group in several cognitive domains. By 3 months, all groups had improved. From 3 to 12 months, there were minimal intrasubject changes for all groups. No consistent differences between the CABG and off-pump patients were observed. Compared with heart healthy controls (HHC), the groups with coronary artery disease had lower cognitive test scores at baseline. There was no evidence that the cognitive test performance of coronary artery bypass grafting (CABG) patients differed from that of control groups with coronary artery disease over a 1-year period. This study emphasizes the need for appropriate control groups for interpreting longitudinal changes in cognitive performance after CABG.


Mechanical and degradation properties of advanced platelet-rich fibrin (A-PRF), concentrated growth factors (CGF), and platelet-poor plasma-derived fibrin (PPTF).
Fibrin clot membranes prepared from advanced platelet-rich fibrin (A-PRF) or concentrated growth factors (CGF), despite their relatively rapid biodegradability, have been used as bioactive barrier membranes for alveolar bone tissue regeneration. As the membranes degrade, it is thought that the growth factors are gradually released. However, the mechanical and degradable properties of these membranes have not well been characterized. The purpose of this study was to mechanically and chemically characterize these membranes. A-PRF and CGF clots were prepared from blood samples collected from non-smoking, healthy donors and were compressed to form 1-mm-thick membranes. Platelet-poor plasma-derived fibrin (PPTF) clots were prepared by adding bovine thrombin to platelet-poor plasma. A tensile test was performed at the speed of 1 mm/min. Morphology of the fibrin fibers was examined by SEM. A digestion test was performed in PBS containing trypsin and EDTA. In the tensile test, statistical difference was not observed in Young's modulus, strain at break, or maximum stress between A-PRF and CGF. In strain at break, PPTF was significantly weaker than CGF. Likewise, fibrin fiber thickness and crosslink density of PPTF were less than those of other membranes, and PPTF degraded faster than others. Although the centrifugal conditions are different, A-PRF and CGF are prepared by essentially identical mechanisms. Therefore, it is conceivable that both membranes have similar mechanical and chemical properties. Only PPTF, which was prepared by a different mechanism, was characterized as mechanically weaker and enzymatically more degradable.


'Linkage analysis of thyroid antibody production: evidence for shared susceptibility to clinical autoimmune thyroid disease.
Epidemiological data suggest a genetic susceptibility to thyroid antibody (TAb) production. The objective of the study was to identify genetic loci that are linked with TAb production. The design of the study was a whole genome linkage study in families with clustering of thyroid autoimmunity. The study took place at an academic medical center. Participants included 102 multigenerational families (540 individuals) multiplex for autoimmune thyroid disease (AITD) and TAb production. We computed two-point logarithm of odds (LOD) scores and multipoint heterogeneity LOD scores for 400 microsatellite markers spanning the entire human genome at an average distance of 10 cm (approximately 10 Mb). Three loci showed evidence for linkage with TAb production: 1) 2q locus, which gave a maximum multipoint heterogeneity LOD score (HLOD) of 2.8 and contained the CTLA-4 gene, previously reported to be linked and associated with clinical AITD; (2) 6p locus (HLOD 2.5), which was the same AITD-1 locus found to be linked with clinical AITD; and (3) 8q locus (HLOD 2.2), which contained the thyroglobulin gene, also previously reported to be linked and associated with AITD. All loci that were linked to TAb were also linked to AITD, suggesting that TAb and AITD share the same genetic predisposition. We conclude that: 1) some of the genes/loci predisposing to TAb and AITD are shared, whereas distinct genes/loci also exist; (2) the presence of TAb in relatives of AITD patients may be associated with increased risk for the development of clinical AITD; and (3) further studies are needed to determine the predictive value of TAb levels for the development of clinical AITD in relatives of patients with familial AITD.


Long-term results of intraoperative electron beam irradiation (IOERT) for patients with unresectable pancreatic cancer.
To analyze the effects of a treatment program of intraoperative electron beam radiation therapy (IOERT) and external beam radiation therapy and chemotherapy on the outcome of patients with unresectable or locally advanced pancreatic cancer. From 1978 to 2001, 150 patients with unresectable and nonmetastatic pancreatic cancer received IOERT combined with external beam radiation therapy and 5-fluorouracil-based chemotherapy for definitive treatment. The 1-, 2-, and 3-year actuarial survival rates of all 150 patients were 54%, 15%, and 7%, respectively. Median and mean survival rates were 13 and 17 months, respectively. Long-term survival has been observed in 8 patients. Five patients have survived beyond 5 years and 3 more between 3 and 4 years. There was a statistically significant correlation of survival to the diameter of treatment applicator (a surrogate for tumor size) used during IOERT. For 26 patients treated with a small-diameter applicator (5 cm or 6 cm), the 2- and 3-year actuarial survival rates were 27% and 17%, respectively. In contrast, none of the 11 patients treated with a 9-cm-diameter applicator survived beyond 18 months. Intermediate survival rates were seen for patients treated with a 7- or 8-cm-diameter applicator. Operative mortality was 0.6%, and postoperative and late complications were 20% and 15%, respectively. A treatment strategy employing IOERT has resulted in long-term survival in 8 of 150 patients with unresectable pancreatic cancer. Survival benefit was limited to patients with small tumors. Enrollment of selected patients with small tumors into innovative protocols employing this treatment approach is appropriate.


[Routine outcome monitoring in anxiety disorders: diagnosis-specific versus generic assessment instruments].
Mental health institutions increasingly utilise routine outcome monitoring (rom) in order to assess treatment effectiveness. It remains unclear which instruments are more sensitive to change with regard to rom in patients with an anxiety disorder: diagnosis-specific or generic instruments.
 AIM: To compare the sensitivity of diagnosis-specific versus generic rom-instruments in patients with an anxiety disorder.
 METHOD: 160 adults with an anxiety disorder received cognitive behavioural therapy at the Altrecht Academic Anxiety Centre. Approximately half of the population also received medication. Patients completed an assessment both before and after treatment. This consisted of two generic instruments (Outcome Questionnaire (oq-45) and Brief Symptom Inventory (bsi)) and two diagnosis-specific instruments, determined by the main diagnosis.
 RESULTS: The differences between pre- and post-treatment assessments were generally larger for the generic bsi and diagnosis-specific instruments than for the generic oq-45.
 CONCLUSION: When assessed after cognitive behavioural therapy, the (generic) bsi and diagnosis-specific instruments indicated larger progress than the oq-45. The bsi might be a relatively diagnosis-specific measure for anxiety disorders. when selecting an instrument for assessment, both the intended goal of treatment (symptom reduction or improvement in quality of life) and other reasons for assessment should be taken into consideration. The bsi or diagnosis-specific instruments are preferred if the goal is to assess the change in specific anxiety symptoms.


Genetic architecture of host proteins involved in SARS-CoV-2 infection.
Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).


Dopamine/neuroleptic receptors in basal hypothalamus and pituitary.
In order to determine whether the basal hypothalamus or the pituitary (or both) is the likely locus of action of the tuberoinfundibular (TI) dopamine neurons, these regions were examined for dopamine and neuroleptic receptors. High affinity receptors for haloperidol and dopamine were found in the rat pituitary while none were detected in rat basal hypothalamus. The relative ability of two neuroleptics, chlorpromazine and haloperidol, to displace (3H)haloperidol from the receptor in monkey pituitary is similar to that for rat striatum. The lack of receptors capable of binding (3H)haloperidol or (3H)dopamine in the basal hypothalamus strongly suggests that the TI neurons do not produce postsynaptic effects in this region. The pituitary receptors for (3H)haloperidol and (3H)dopamine have the characteristics of a functional system. The presence of neuroleptic/dopamine receptors in the pituitary and lack of such receptors in the basal hypothalamus supports the hypothesis that dopamine may act directly as a prolactin release inhibiting factor (PIF) rather than releasing PIF from adjacent nerve terminals in the median eminence.


aHSCT is superior to alemtuzumab in maintaining NEDA and improving cognition in multiple sclerosis.
Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly recognized as a potential therapy for patients with highly active multiple sclerosis (MS). This study aims to assess outcome differences in disease activity in MS patients treated either with aHSCT or alemtuzumab. We conducted a monocentric registry-based cohort study by recording the clinical course (EDSS and relapses), MRI parameters (new T2 lesions), and neuropsychological assessment in all 19 MS patients receiving aHSCT, and all 21 patients receiving alemtuzumab between 2007 and 2018. We used survival analyses of no evidence of disease activity (NEDA) as the primary objective which was defined by no EDSS progression, no relapse, and no new T2 lesion on MRI. Secondary objectives were EDSS improvement and neurocognitive performance. Both treatment groups were similar in respect of age, gender, disability, and neurocognitive performance except for significantly longer disease duration in the alemtuzumab group. Mean follow-up was 58.8 [range 29-140] months in the aHSCT group compared to 27.6 [range 11-52] months in the alemtuzumab-treated group. We observed significantly more patients maintaining NEDA in the aHSCT group (p = 0.048) compared to the alemtuzumab-treated patients. Furthermore, 37% of the aHSCT patients showed an improvement of EDSS compared to none in the alemtuzumab-treated group (p = 0.033). It is of note that cognitive function was significantly improved in the aHSCT-treated patients. aHSCT suppresses inflammatory activity more effectively than alemtuzumab and might enable improvement of overall disability and cognition in MS.


GM-CSF Primes Proinflammatory Monocyte Responses in Ankylosing Spondylitis.
Objectives: GM-CSF is a pro-inflammatory cytokine with multiple actions predominantly on myeloid cells. Enhanced GM-CSF expression by lymphocytes from patients with Ankylosing Spondylitis (AS) has recently been described, however, its potential pathogenic role(s) in AS are unknown. Methods: The effects of GM-CSF on TNF, IL-23, and CCL17 production by blood, PBMCs and isolated CD14+ monocytes from AS patients and healthy controls (HCs) were studied using ELISA. Serum CCL17 and GM-CSF and T cell GM-CSF production were studied in AS patients including pre-and on TNFi therapy. Results: GM-CSF markedly increased TNF production by LPS-stimulated whole blood, peripheral blood mononuclear cells (PBMC) and purified monocytes from AS patients, with 2 h GM-CSF exposure sufficient for monocyte "priming." Blocking of GM-CSF significantly reduced the production of TNF by whole blood from AS patients but not HCs. GM-CSF priming increased IL-23 production from LPS-stimulated AS and HC whole blood 5-fold, with baseline and stimulated IL-23 levels being significantly higher in AS whole blood. GM-CSF also stimulated CCL17 production from AS and HC blood and CCL17 levels were elevated in AS plasma. GM-CSF could be detected in plasma from 14/46 (30%) AS patients compared to 3/18 (17%) HC. Conclusion: We provide evidence that GM-CSF primes TNF and IL-23 responses in myeloid cells from AS patients and HC. We also show CCL17 levels, downstream of GM-CSF, were elevated in plasma samples of AS patients. Taken together these observations are supportive of GM-CSF neutralization as a potential novel therapeutic approach for the treatment of AS.


Regulation of alveolar epithelial cell phenotypes in fetal sheep: roles of cortisol and lung expansion.
Our aim was to determine whether cortisol's effect on alveolar epithelial cell (AEC) phenotypes in the fetus is mediated via a sustained alteration in lung expansion. Chronically catheterized fetal sheep were exposed to 1) saline infusion, 2) cortisol infusion (122-131 days' gestation, 1.5-4.0 mg/day), 3) saline infusion plus reduced lung expansion, or 4) cortisol infusion plus reduced lung expansion. The proportions of type I and II AECs were determined by electron microscopy, and surfactant protein (SP)-A, -B, and -C mRNA levels were determined by Northern blot analysis. Cortisol infusions significantly increased type II AEC proportions (to 38.2 +/- 2.2%), compared with saline-infused fetuses (23.8 +/- 2.4%), and reduced type I AEC proportions (to 59.0 +/- 2.2%), compared with saline-infused fetuses (70.4 +/- 2.4%). Reduced lung expansion also increased type II AEC proportions (to 52.9 +/- 3.5%) and decreased type I AEC proportions (to 34.2 +/- 3.7%), compared with control, saline-infused fetuses. The infusion of cortisol into fetuses exposed to reduced lung expansion tended to further increase type II (to 60.3 +/- 2.1%, P = 0.066) and reduce type I AEC (to 26.6 +/- 2.3%, P = 0.07) proportions. SP-A, -B, and -C mRNA levels changed in parallel with the changes in type II AEC proportions. These results indicate that cortisol alters the proportion of type I and type II AECs via a mechanism unrelated to the degree of fetal lung expansion. However, reductions in fetal lung expansion appear to have a greater impact on the proportion of AECs than cortisol.


It feels real: physiological responses to a stressful virtual reality environment and its impact on working memory.
Virtual reality (VR) is increasingly used to study and treat psychiatric disorders. Its fidelity depends in part on the extent to which the VR environment provides a convincing simulation, for example whether a putatively stressful VR situation actually produces a stress response. We studied the stress response in 28 healthy men exposed either to a stressor VR elevator (which simulated travelling up the outside of a tall building and culminated in the participant being asked to step off the elevator platform), or to a control elevator. We measured psychological and physiological (salivary cortisol and alpha-amylase, blood pressure, pulse, skin conductance) stress indices. We also measured subsequent performance on the N-back task because acute stress has been reported to impact on working memory. Compared to participants in the control elevator, those in the external elevator had increases in skin conductance, pulse and subjective stress and anxiety ratings, altered heart rate variability, and a delayed rise in cortisol. N-back performance was unaffected. A putatively stressful VR elevator produces a physiological as well as a psychological stress response, supporting its use in the investigation and treatment of stress-related disorders, and its potential value as an experimental laboratory stressor.


Oncology nurses' perceptions about palliative care.
To explore oncology nurses' perceptions about palliative care. Descriptive study with narrative data analysis. Oncology units in three midwestern hospitals. 33 actively practicing oncology nurses. Oncology nurses participated in focus groups that elicited concrete experiences and reflections about palliative care. Researchers identified subtexts by which to sort data, worked inductively in each subtext to identify categories, resorted the text according to the categories, carefully examined the category narratives, and established narrative descriptors that captured the essence of each category. Data matrices were constructed to examine the emerging categories more closely. Oncology nurses' perceptions about palliative care. Narratives revealed 14 descriptors about palliative care. Considerable agreement occurred in nurses' descriptions about the nature of palliative care. Divergent viewpoints were evident as nurses described how palliative care intersects with other practice areas. Three descriptors of the healthcare context in which palliative care occurs were identified: limited time for addressing complex palliative care issues, health care's emphasis on prolonging life, and the challenge of coordinating care across disciplines. Participants clearly comprehend palliative care goals. However, divergent perspectives about the intersections of palliative care with oncology nursing may limit timely consultation with specialty palliative care teams. The current acute care context poses challenges to implementing palliative care. Palliative care teams and oncology nurses need to develop partnership models that clearly illustrate how both partners contribute to palliative care across the continuum of oncology care. Furthermore, the partnership models must address barriers that the acute care context poses to quality palliative care.


Admittance matrix of a trapezoidal piezoelectric heterogeneous bimorph.
Bimorph structures are a standard method for transforming the high force of piezoelectric materials into a large deflection. In micro electromechanical systems (MEMS) applications, it is preferable to use structures consisting of a passive substrate (usually silicon) and one or more piezoelectric layers on the top. Such structures are called heterogeneous bimorphs or enakemesomorphs. In some MEMS applications- for example, for use as acoustic transducers-it is desirable to arrange such heterogeneous bimorphs in a circular shape, which results in trapezoidal cantilever structures. In this paper, an analytic dynamic description of such actuators is obtained. The resulting model is proved to be compatible with existing models for heterogeneous bimorphs with constant width. A comparison to a finite element analysis model of an exemplary layout shows divergences wholly within the same range as found for published models for constant-width structures.


Endocytic structures and synaptic vesicle recycling at a central synapse in awake rats.
The synaptic vesicle (SV) cycle has been studied extensively in cultured cells and slice preparations, but not much is known about the roles and relative contributions of endocytic pathways and mechanisms of SV recycling in vivo, under physiological patterns of activity. We employed horseradish peroxidase (HRP) as an in vivo marker of endocytosis at the calyx of Held synapse in the awake rat. Ex vivo serial section scanning electron microscopy and 3D reconstructions revealed two categories of labelled structures: HRP-filled SVs and large cisternal endosomes. Inhibition of adaptor protein complexes 1 and 3 (AP-1, AP-3) by in vivo application of Brefeldin A (BFA) disrupted endosomal SV budding while SV recycling via clathrin-mediated endocytosis (CME) remained unaffected. In conclusion, our study establishes cisternal endosomes as an intermediate of the SV cycle and reveals CME and endosomal budding as the predominant mechanisms of SV recycling in a tonically active central synapse in vivo.


Perillyl alcohol is an angiogenesis inhibitor.
Aberrant angiogenesis is essential for the progression of solid tumors and hematological malignancies. Thus, antiangiogenic therapy is one of the most promising approaches to control cancer. In the present work, we examined the ability of perillyl alcohol (POH), a dietary monoterpene with well-established tumor chemopreventive and chemotherapeutic activity, to interfere with the process of angiogenesis. POH remarkably prevented new blood vessel growth in the in vivo chicken embryo chorioallantoic membrane assay and proved to be effective in inhibiting the morphogenic differentiation of cultured endothelial cells into capillary-like networks both in collagen gel and Matrigel models. In addition, POH reduced the cell number in a proliferation assay and induced apoptosis of endothelial cells as indicated by the POH-mediated increase of caspase-3 activity and DNA fragmentation. Consistent with the observed antisurvival effect, POH treatment resulted in a significant inhibition of Akt phosphorylation in endothelial cells. Finally, POH was able to differentially modulate the release of two important angiogenic regulators: vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2). POH decreased the release of VEGF from cancer cells but stimulated the expression of Ang2 by endothelial cells, indicating that it might suppress neovascularization and induce vessel regression. Overall, these data underscore the antiangiogenic potential of POH and suggest that POH, in addition to its anticancer activity, may be an effective agent in the treatment of angiogenesis-dependent diseases.


PCAT1 is a poor prognostic factor in endometrial carcinoma and associated with cancer cell proliferation, migration and invasion.
Long non-coding RNAs (lncRNAs) are emerging as important modulators of cancer progression, among which prostate cancer-associated transcript 1 (PCAT1) has been shown to be an oncogene in several tumors. However, the clinical significance and biological function of PCAT1 in endometrial carcinoma (EC) remain unclear. In this study, we used 89 EC tissues and HEC-1B, Ishikawa, RL95-2 and AN3CA EC cell lines. We found elevated expression levels of PCAT1 in EC tissues and cell lines using reverse transcription qPCR (RT-qPCR). The prognostic value of PCAT1 was determined using Kaplan-Meier survival and Cox regression analysis. The results showed that higher PCAT1 expression was positively correlated with FIGO stage, myometrial invasion, lymph node metastasis, and a shorter overall survival. A series of functional assays showed that the knockdown of PCAT1 by small interfering RNA (siRNA) targeting PCAT1 (siPCAT1) suppressed cell proliferation, migration and invasion, but promoted apoptosis. Western blot analysis further showed that B-cell lymphoma 2 (Bcl-2), vimentin and N-cadherin were downregulated, but E-cadherin and Bcl-2-associated death promoter (Bad) were upregulated in PCAT1-silenced EC cells. Taken together, our results underscore the oncogenic role of PCAT1 in EC and show that PCAT1 may be a potential therapeutic target in EC treatment.


DSM-5: a teachable moment.
The rollout of DSM-5 is both a challenge and an opportunity for psychiatrists and particularly for trainees. Psychiatric education in the wake of DSM-5 will go beyond memorizing lists of new criteria. Teachers and learners alike will seize the "teachable moment" to learn new content, model how to approach and apply new understanding, think about how new knowledge is developed, and appreciate the importance of public dialogue.We can capitalize on this moment to improve the teaching of assessment skills as a central focus of residency training.


The genome of a songbird.
The zebra finch is an important model organism in several fields with unique relevance to human neuroscience. Like other songbirds, the zebra finch communicates through learned vocalizations, an ability otherwise documented only in humans and a few other animals and lacking in the chicken-the only bird with a sequenced genome until now. Here we present a structural, functional and comparative analysis of the genome sequence of the zebra finch (Taeniopygia guttata), which is a songbird belonging to the large avian order Passeriformes. We find that the overall structures of the genomes are similar in zebra finch and chicken, but they differ in many intrachromosomal rearrangements, lineage-specific gene family expansions, the number of long-terminal-repeat-based retrotransposons, and mechanisms of sex chromosome dosage compensation. We show that song behaviour engages gene regulatory networks in the zebra finch brain, altering the expression of long non-coding RNAs, microRNAs, transcription factors and their targets. We also show evidence for rapid molecular evolution in the songbird lineage of genes that are regulated during song experience. These results indicate an active involvement of the genome in neural processes underlying vocal communication and identify potential genetic substrates for the evolution and regulation of this behaviour.


On the contributions of topological features to transcriptional regulatory network robustness.
Because biological networks exhibit a high-degree of robustness, a systemic understanding of their architecture and function requires an appraisal of the network design principles that confer robustness. In this project, we conduct a computational study of the contribution of three degree-based topological properties (transcription factor-target ratio, degree distribution, cross-talk suppression) and their combinations on the robustness of transcriptional regulatory networks. We seek to quantify the relative degree of robustness conferred by each property (and combination) and also to determine the extent to which these properties alone can explain the robustness observed in transcriptional networks. To study individual properties and their combinations, we generated synthetic, random networks that retained one or more of the three properties with values derived from either the yeast or E. coli gene regulatory networks. Robustness of these networks were estimated through simulation. Our results indicate that the combination of the three properties we considered explains the majority of the structural robustness observed in the real transcriptional networks. Surprisingly, scale-free degree distribution is, overall, a minor contributor to robustness. Instead, most robustness is gained through topological features that limit the complexity of the overall network and increase the transcription factor subnetwork sparsity. Our work demonstrates that (i) different types of robustness are implemented by different topological aspects of the network and (ii) size and sparsity of the transcription factor subnetwork play an important role for robustness induction. Our results are conserved across yeast and E Coli, which suggests that the design principles examined are present within an array of living systems.


A new concept for bisphosphonate therapy: a rationale for the development of monthly oral dosing of ibandronate.
Oral daily and weekly bisphosphonates represent the current mainstay of treatment for postmenopausal osteoporosis (PMO). However, the inconvenience of frequent dosing is known to negatively affect adherence to therapy in the long term. This has prompted the development of convenient oral bisphosphonate regimens that feature simple, less frequent dosing schedules. Such regimens require high potency agents, which can be given at low effective doses and that also have good tolerability. Ibandronate is a potent, nitrogen-containing bisphosphonate with proven efficacy when given intermittently to estrogen-depleted beagle dogs, rats and cynomolgus monkeys. Clinically, a pivotal prospective study has established that oral ibandronate has significant vertebral fracture efficacy in PMO, whether given daily (2.5 mg) or intermittently (20 mg every other day for 12 doses every 3 months; extended between-dose interval>2 months). Both oral regimens were well tolerated, which is noteworthy as patients with a history of gastrointestinal (GI) disturbance were not specifically excluded. As a result of these findings, a large, multinational, randomized, double-blind study (Monthly Oral iBandronate In LadiEs: MOBILE) is currently exploring the non-inferiority of once-monthly oral ibandronate (100 or 150 mg) to the oral daily ibandronate (2.5 mg) regimen with proven anti-fracture efficacy, in terms of lumbar spine bone mineral density (BMD) change. As with the trials investigating the weekly administration of other bisphosphonates, vertebral fracture efficacy will be inferred if the study demonstrates the non-inferiority of once-monthly ibandronate to the proven oral daily regimen in terms of spinal BMD change. The availability of this once-monthly ibandronate regimen is expected to offer benefits in terms of convenience (by having to follow dosing recommendations once a month vs. once daily or weekly) and potentially tolerability (by reducing the potential for upper GI irritation that can result from frequent, repeated exposure). Greater convenience and tolerability may enhance the therapy adherence and, hence, improve long-term therapeutic outcomes in PMO.


Direct selection at the blossom level on floral reward by pollinators in a natural population of Dalechampia schottii: full-disclosure honesty?
• Both floral rewards and advertisements can be important in the attraction of pollinators, but few studies have separated the individual contributions of rewards and advertisements to fitness. • Here, we investigated selection by pollinators on individual blossoms in Dalechampia schottii. This Neotropical vine, endemic to the Yucatán Peninsula, rewards bees by secreting fully visible, deep-blue resin from a gland subtended by two conspicuous petaloid bracts that may play the role of advertisement. • We used contextual analysis to build a fitness function for four morphological traits of individual blossoms: the amount of the reward as measured by gland area; the size of the advertisement trait as measured by bract length; the flower-pollinator fit as measured by the shortest distance between reward and stigma; and the potential for self-pollination as measured by the shortest distance between anthers and stigma. • Larger gland area and increased potential for self-pollination directly increased the seed production of individual blossoms. However, bract size or flower-pollinator fit did not influence the number of seeds produced by blossoms. Therefore, in this Dalechampia species, pollinators seem to select directly on the reward of individual blossoms but not on the advertising bracts.


Ocean warming and acidification have complex interactive effects on the dynamics of a marine fungal disease.
Diseases threaten the structure and function of marine ecosystems and are contributing to the global decline of coral reefs. We currently lack an understanding of how climate change stressors, such as ocean acidification (OA) and warming, may simultaneously affect coral reef disease dynamics, particularly diseases threatening key reef-building organisms, for example crustose coralline algae (CCA). Here, we use coralline fungal disease (CFD), a previously described CCA disease from the Pacific, to examine these simultaneous effects using both field observations and experimental manipulations. We identify the associated fungus as belonging to the subphylum Ustilaginomycetes and show linear lesion expansion rates on individual hosts can reach 6.5 mm per day. Further, we demonstrate for the first time, to our knowledge, that ocean-warming events could increase the frequency of CFD outbreaks on coral reefs, but that OA-induced lowering of pH may ameliorate outbreaks by slowing lesion expansion rates on individual hosts. Lowered pH may still reduce overall host survivorship, however, by reducing calcification and facilitating fungal bio-erosion. Such complex, interactive effects between simultaneous extrinsic environmental stressors on disease dynamics are important to consider if we are to accurately predict the response of coral reef communities to future climate change.


Temporal lobe rating scale: application to Alzheimer's disease and frontotemporal dementia.
Temporal lobe atrophy as assessed by MRI can be measured in several ways. Volumetric measurements are quantitative but very time consuming and require extensive training to perform, so are not easily transferable to clinical practice. Visual rating scales, by contrast, are quick and widely applicable. Although medial temporal lobe atrophy is well described in Alzheimer's disease (AD), it is uncertain how early these changes can be detected and whether they discriminate AD from other neurodegenerative diseases, most notably frontotemporal dementia (FTD). The objectives were (1) to develop a widely applicable temporal lobe rating scale, and (2) to characterise and quantify the patterns of temporal lobe atrophy in AD versus temporal and frontal variants of FTD. The temporal lobe assessments were made using an established hippocampal rating scale extended to incorporate additional temporal regions. This was firstly validated with volumetric analysis and then applied to 30 probable AD, 30 FTD (consisting of 17 temporal variant (semantic dementia) and 13 frontal variant) and 18 control coronal MRI images. Bilateral hippocampal atrophy was found in 50% of the patients with AD. Contrary to expectations, patients with semantic dementia also had hippocampal atrophy, which for the left side exceeded that seen in AD; other regions (temporal pole, parahippocampal gyrus, and lateral temporal lobe), spared in AD, were severely atrophied in this group. The patients with frontal variant FTD occupied an intermediate position and were largely indistinguishable from AD. Hippocampal atrophy is, therefore, not specific for AD. Semantic dementia can be distinguished from AD, by the presence of severe bilateral atrophy of the temporal pole, parahippocampal and lateral regions. These findings have implications for the differential diagnosis of dementias.


Different levels of Ras activity can specify distinct transcriptional and morphological consequences in early Drosophila embryos.
The terminal portions of the Drosophila body pattern are specified by the localized activity of the receptor tyrosine kinase Torso (Tor) at each pole of the early embryo. Tor activity elicits the transcription of two 'gap' genes, tailless (tll) and huckebein (hkb), in overlapping but distinct domains by stimulating the Ras signal transduction pathway. Here, we show that quantitative variations in the level of Ras activity can specify qualitatively distinct transcriptional and morphological responses. Low levels of Ras activity at the posterior pole direct tll but not hkb transcription; higher levels drive transcription of both genes. Correspondingly, low levels of Ras activity specify a limited subset of posterior terminal structures, whereas higher levels specify a larger subset. However, we also show that the response to Ras activity is not uniform along the body. Instead, levels of Ras activity which suffice to drive tll and hkb transcription at the posterior pole fail to drive their expression in more central portions of the body, apparently due to repression by other gap gene products. We conclude that tll and hkb transcription, as well as the terminal structures, are specified by two inputs: a gradient of Ras activity which emanates from the pole, and the opposing influence of more centrally deployed gap genes which repress the response to Ras.


Electrostatic effects on deposition of multiple phospholipid bilayers at oxide surfaces.
We investigated electrostatic effects on the formation of multiple supported phospholipid bilayers (SPB) by varying the oxide substrate, ionic strength, the presence of divalent Ca(2+), and phospholipid (PL) headgroup charge. Whereas the current understanding of processes and forces controlling SPB formation is based primarily on studies involving planar substrates, we report results from experiments using aqueous suspensions of quartz (α-SiO(2)) and corundum (α-Al(2)O(3)) particles. Using fluorescent dye-loaded dipalmitoylphosphatidylcholine (DPPC) vesicles, we determined that the vesicles underwent oxide particle-induced rupture and formed supported planar bilayers rather than a supported vesicle layer. Adsorption isotherms of DPPC at pH 7.2 in solutions of varying ionic strength set by NaCl, and with or without 2 mM Ca(2+), support our hypotheses that van der Waals forces predominantly account for two DPPC bilayers, and that adsorption beyond the second bilayer occurs at low ionic strength due to extension of the electric double-layer near the oxide surface. In contrast, adsorption isotherms of anionic dipalmitoylphosphatidylserine (DPPS) and cationic dipalmitoylethylphosphatidylcholine (DPEPC) show that adsorption of highly charged bilayers is decreased or prevented altogether due to bilayer-oxide and/or bilayer-bilayer repulsion. Results have potential implications for biomedical, industrial, and environmental remediation applications involving SPBs and for proto-cell stability in origin-of-life hypotheses.


Surgery in patients with von Willebrand disease.
Von Willebrand disease (vWD) is the most common inherited bleeding disorder. The biggest challenge in the management of vWD is the difficulty in performing surgical procedures because of bleeding. Treatment guidelines recommend the use of pure von Willebrand factor or von Willebrand factor/factor VIII (vWF/FVIII) concentrate in patients with type 2 or type 3 vWD undergoing surgery, in patients with type 1 vWD undergoing surgery who are unresponsive, and in patients for whom desmopressin acetate is contraindicated. However, there is no consensus on the dosage and optimum levels of these factors to date. The aim of this study was to evaluate the perioperative management of patients with vWD during surgical procedures. Data pertaining to surgical procedures performed at our center from 2003 to 2014 were analyzed retrospectively. All operations, except one appendectomy, were elective, and a plan for the management of hemostasis was prepared for each patient. During this period, 37 surgical procedures (major, minor, and dental) were performed in 23 patients with vWD. Complications occurred in four out of 37 procedures (10.8%). No deaths or life-threatening bleeding occurred during any of the operations and no thromboembolic events were observed. The results from this retrospective study indicate that surgery can be safely performed by providing adequate and timely hemostasis during and after the procedure in patients with vWD. Perioperative and postoperative bleeding complications are rare when patients are closely and carefully monitored.


Homologous Basal Ganglia Network Models in Physiological and Parkinsonian Conditions.
The classical model of basal ganglia has been refined in recent years with discoveries of subpopulations within a nucleus and previously unknown projections. One such discovery is the presence of subpopulations of arkypallidal and prototypical neurons in external globus pallidus, which was previously considered to be a primarily homogeneous nucleus. Developing a computational model of these multiple interconnected nuclei is challenging, because the strengths of the connections are largely unknown. We therefore use a genetic algorithm to search for the unknown connectivity parameters in a firing rate model. We apply a binary cost function derived from empirical firing rate and phase relationship data for the physiological and Parkinsonian conditions. Our approach generates ensembles of over 1,000 configurations, or homologies, for each condition, with broad distributions for many of the parameter values and overlap between the two conditions. However, the resulting effective weights of connections from or to prototypical and arkypallidal neurons are consistent with the experimental data. We investigate the significance of the weight variability by manipulating the parameters individually and cumulatively, and conclude that the correlation observed between the parameters is necessary for generating the dynamics of the two conditions. We then investigate the response of the networks to a transient cortical stimulus, and demonstrate that networks classified as physiological effectively suppress activity in the internal globus pallidus, and are not susceptible to oscillations, whereas parkinsonian networks show the opposite tendency. Thus, we conclude that the rates and phase relationships observed in the globus pallidus are predictive of experimentally observed higher level dynamical features of the physiological and parkinsonian basal ganglia, and that the multiplicity of solutions generated by our method may well be indicative of a natural diversity in basal ganglia networks. We propose that our approach of generating and analyzing an ensemble of multiple solutions to an underdetermined network model provides greater confidence in its predictions than those derived from a unique solution, and that projecting such homologous networks on a lower dimensional space of sensibly chosen dynamical features gives a better chance than a purely structural analysis at understanding complex pathologies such as Parkinson's disease.


Efficacy of microneedling plus human stem cell conditioned medium for skin rejuvenation: a randomized, controlled, blinded split-face study.
The use of growth factors in skin rejuvenation is emerging as a novel anti-aging treatment. While the role of growth factors in wound healing is well established, their use in skin rejuvenation has only recently been to be studied and no controlled trials have been performed. We evaluated the anti-aging effects of secretory factors of endothelial precursor cells differentiated from human embryonic stem cells (hESC-EPC) in Asian skin. A total of 25 women were included in this randomized, controlled split-face study. The right and left sides of each participant's face were randomly allocated to hESC-EPC conditioned medium (CM) or saline. To enhance epidermal penetration, a 0.25-mm microneedle roller was used. Five treatment sessions were repeated at 2-week intervals. Physician's global assessment of pigmentation and wrinkles after treatment revealed statistically significant effects of microneedling plus hESC-EPC CM compared to microneedling alone (p<0.05). Skin measurements by Mexameter and Visiometer also revealed statistically significant effects of microneedling plus hESC-EPC CM on both pigmentation and wrinkles (p<0.05). The only minimal adverse event was mild desquamation in one participant. Secretory factors of hESC-EPC improve the signs of skin aging and could be a potential option for skin rejuvenation.


Ketamine impairs recognition memory consolidation and prevents learning-induced increase in hippocampal brain-derived neurotrophic factor levels.
The non-competitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine has been shown to produce cognitive deficits. However, the effects of ketamine on the consolidation phase of memory remain poorly characterized. Here we show that systemic administration of ketamine immediately after training dose-dependently impairs long-term retention of memory for a novel object recognition (NOR) task in rats. Control experiments showed that the impairing effects of ketamine could not be attributed to an influence on memory retrieval or sensorimotor effects. In addition, ketamine prevented the increase in hippocampal brain-derived neurotrophic factor (BDNF) levels induced by NOR learning. Our results show for the first time that ketamine disrupts the consolidation phase of long-term recognition memory. In addition, the findings suggest that the amnestic effects of ketamine might be at least partially mediated by an influence on BDNF signaling in the hippocampus.


Deguelin inhibits the migration and invasion of U-2 OS human osteosarcoma cells via the inhibition of matrix metalloproteinase-2/-9 in vitro.
Osteosarcoma is the most common malignant primary bone tumor in children and young adults and lung metastasis is the main cause of death in those patients. Deguelin, a naturally occurring rotenoid, is known to be an Akt inhibitor and to exhibit cytotoxic effects, including antiproliferative and anticarcinogenic activities, in several cancers. In the present study, we determined if deguelin would inhibit migration and invasion in U-2 OS human osteosarcoma cells. Deguelin significantly inhibited migration and invasion of U-2 OS human osteosarcoma cells which was associated with a reduction of activities of matrix metalloproteinases-2 (MMP-2) and matrix metalloproteinases-9 (MMP-9). Furthermore, results from western blotting indicated that deguelin decreased the cell proliferation and cell growth-associated protein levels, such as SOS1, PKC, Ras, PI3K, p-AKT(Ser473), IRE-1α, MEKK3, iNOS, COX2, p-ERK1/2, p-JNK1/2, p-p38; the cell motility and focal adhesion-associated protein levels, such as Rho A, FAK, ROCK-1; the invasion-associated protein levels, such as TIMP1, uPA, MMP-2. MMP-9, MMP-13, MMP-1 and VEGF in U-2 OS cells. Confocal microscopy revealed that deguelin reduced NF-κB p65, Rho A and ROCK-1 protein levels in cytosol. MMP-7, MMP-9 and Rho A mRNA levels were suppressed by deguelin. These in vitro results provide evidence that deguelin may have potential as a novel anti-cancer agent for the treatment of osteosarcoma and provides the rationale for in vivo studies in animal models.


The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression.
Retinoblastoma (RB; encoded by RB1) is a tumor suppressor that is frequently disrupted in tumorigenesis and acts in multiple cell types to suppress cell cycle progression. The role of RB in tumor progression, however, is poorly defined. Here, we have identified a critical role for RB in protecting against tumor progression through regulation of targets distinct from cell cycle control. In analyses of human prostate cancer samples, RB loss was infrequently observed in primary disease and was predominantly associated with transition to the incurable, castration-resistant state. Further analyses revealed that loss of the RB1 locus may be a major mechanism of RB disruption and that loss of RB function was associated with poor clinical outcome. Modeling of RB dysfunction in vitro and in vivo revealed that RB controlled nuclear receptor networks critical for tumor progression and that it did so via E2F transcription factor 1-mediated regulation of androgen receptor (AR) expression and output. Through this pathway, RB depletion induced unchecked AR activity that underpinned therapeutic bypass and tumor progression. In agreement with these findings, disruption of the RB/E2F/nuclear receptor axis was frequently observed in the transition to therapy resistance in human disease. Together, these data reveal what we believe to be a new paradigm for RB function in controlling prostate tumor progression and lethal tumor phenotypes.


Examination of Age Variations in the Predictive Validity of Self-Rated Health.
The high predictive validity of self-rated health (SRH) is a major strength of this widely used population health measure. Recent studies, however, noted that the predictive validity varies across population subgroups. The aim of this study is to examine respondents' age as a moderator of SRH predictive validity with respect to subsequent mortality risk. Using data from the National Health Interview Survey-Linked Mortality Files (NHIS-LMF) 1986-2006, we estimate Cox proportional hazard models of all-cause and cause-specific mortality for adults aged 45-84 years as a function of their health ratings (N = 574,008). The data show significant age moderation of the predictive validity of SRH across all levels of ratings: the hazard ratios for mortality decline by about a half between the ages of 50 and 80 years. This attenuation appears primarily among earlier birth cohorts; there is no significant age attenuation in more recent cohorts-however, this may be in part attributed to the earlier ages when the respondents are observed. The findings of declining predictive validity of SRH across age imply that individuals may evaluate their health differently as they age. The results also suggest caution in using SRH to capture age-related health changes in the older population.


Rituximab for treating inhibitors in people with inherited severe hemophilia.
Hemophilia A and B are inherited coagulation disorders characterized by a reduced or absent level of factor VIII or factor IX respectively. The severe form is characterized by a factor level less than 0.01 international units (IU) per milliliter. The development of inhibitors in hemophilia is the main complication of treatment, because the presence of these antibodies, reduces or even nullifies the efficacy of replacement therapy, making it very difficult to control the bleeding. People with inhibitors continue to have significantly higher risks of morbidity and mortality, with considerable treatment costs. Given the wide 'off-label' use of rituximab for treating people with hemophilia and inhibitors, its efficacy and safety need to be evaluated. To assess the efficacy and safety of rituximab for treating inhibitors in people with inherited severe hemophilia A or B. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, complied from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews and also searched for ongoing or unpublished studies.Date of last search: 27 January 2015. Randomized controlled trials and controlled clinical trials investigating the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. No randomized controlled trials matching the selection criteria were eligible for inclusion. No randomized controlled trials on rituximab for treating inhibitors in people with hemophilia were identified. We were unable to identify any relevant trials on the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. The research evidence available is from case reports and case series. Randomized controlled trials are needed to evaluate the efficacy and safety of rituximab for this condition. However, prior to the publication of any possible future randomized controlled trials, meta-analysis of case reports and case series may provide some evidence.


RNAi in Plants: An Argonaute-Centered View.
Argonaute (AGO) family proteins are effectors of RNAi in eukaryotes. AGOs bind small RNAs and use them as guides to silence target genes or transposable elements at the transcriptional or posttranscriptional level. Eukaryotic AGO proteins share common structural and biochemical properties and function through conserved core mechanisms in RNAi pathways, yet plant AGOs have evolved specialized and diversified functions. This Review covers the general features of AGO proteins and highlights recent progress toward our understanding of the mechanisms and functions of plant AGOs.


Absence of evidence of xenotropic murine leukemia virus-related virus infection in persons with chronic fatigue syndrome and healthy controls in the United States.
XMRV, a xenotropic murine leukemia virus (MuLV)-related virus, was recently identified by PCR testing in 67% of persons with chronic fatigue syndrome (CFS) and in 3.7% of healthy persons from the United States. To investigate the association of XMRV with CFS we tested blood specimens from 51 persons with CFS and 56 healthy persons from the US for evidence of XMRV infection by using serologic and molecular assays. Blinded PCR and serologic testing were performed at the US Centers for Disease Control and Prevention (CDC) and at two additional laboratories. Archived blood specimens were tested from persons with CFS defined by the 1994 international research case definition and matched healthy controls from Wichita, Kansas and metropolitan, urban, and rural Georgia populations. Serologic testing at CDC utilized a Western blot (WB) assay that showed excellent sensitivity to MuLV and XMRV polyclonal or monoclonal antibodies, and no reactivity on sera from 121 US blood donors or 26 HTLV-and HIV-infected sera. Plasma from 51 CFS cases and plasma from 53 controls were all WB negative. Additional blinded screening of the 51 cases and 53 controls at the Robert Koch Institute using an ELISA employing recombinant Gag and Env XMRV proteins identified weak seroreactivity in one CFS case and a healthy control, which was not confirmed by immunofluorescence. PCR testing at CDC employed a gag and a pol nested PCR assay with a detection threshold of 10 copies in 1 ug of human DNA. DNA specimens from 50 CFS patients and 56 controls and 41 US blood donors were all PCR-negative. Blinded testing by a second nested gag PCR assay at the Blood Systems Research Institute was also negative for DNA specimens from the 50 CFS cases and 56 controls. We did not find any evidence of infection with XMRV in our U.S. study population of CFS patients or healthy controls by using multiple molecular and serologic assays. These data do not support an association of XMRV with CFS.


Helicobacter pylori reinfection with identical organisms: transmission by the patients' spouses.
Reinfection with Helicobacter pylori after eradication is responsible for the recurrence of duodenal ulcer disease. The mode of transmission has not yet been established. In this study, 18 patients with chronic duodenal ulcers in whom H pylori had been eradicated with amoxicillin and metronidazole were entered into a prospective follow up study. Control endoscopies were performed 4, 8, 14, 27, and 43 months after starting treatment and the results of direct tests were compared with the kinetics of H pylori specific IgG titres. After eradication there was a noticeable and consistent fall in anti-H pylori IgG, while reinfections were characterised by a significant increase in specific titres. Reinfection was detected in two patients after 14 and 43 months, respectively. The H pylori strains responsible for these reinfections, the corresponding pretreatment isolates, and the strains isolated from the spouses of these patients were examined by polymerase chain reaction based DNA fingerprinting. Analysis showed that reinfection had been caused by the same H pylori strain and identified the spouses of these patients as carriers of the identical strain. Considering the genomic diversity and the interpatient heterogeneity of H pylori these results suggest a person to person transmission of H pylori reinfection. By the end of the observation period reflux oesophagitis had developed in 10 of the 16 patients who had not been reinfected. This surprising finding may be explained by the changed eating habits of patients after healing of duodenal ulcer disease.


Integrating weight bias awareness and mental health promotion into obesity prevention delivery: a public health pilot study.
Promoting healthy weight is a top priority in Canada. Recent federal guidelines call for sustained, multisectoral partnerships that address childhood obesity on multiple levels. Current healthy weight messaging does not fully acknowledge the influence of social determinants of health on weight. An interactive workshop was developed and implemented by a team of academic researchers and health promoters from the psychology and public health disciplines to raise awareness about 1) weight bias and its negative effect on health, 2) ways to balance healthy weight messaging to prevent the triggering of weight and shape preoccupation, and 3) the incorporation of mental health promotion into healthy weight messaging. We conducted a full-day workshop with 342 Ontario public health promoters and administered a survey at preintervention, postintervention, and follow-up. Participation in the full-day workshop led to significant decreases in antifat attitudes and the internalization of media stereotypes and to significant increases in self-efficacy to address weight bias. Participants reported that the training heightened their awareness of their own personal weight biases and the need to broaden their scope of healthy weight promotion to include mental health promotion. There was consensus that additional sessions are warranted to help translate knowledge into action. Buy-in and resource support at the organizational level was also seen as pivotal. Professional development training in the area of weight bias awareness is associated with decreases in antifat attitudes and the internalization of media stereotypes around thinness. Health promoters' healthy weight messaging was improved by learning to avoid messages that trigger weight and shape preoccupation or unhealthful eating practices among children and youth. Participants also learned ways to integrate mental health promotion and resiliency-building into daily practice.