Phylogeny, genome evolution, and host specificity of single-stranded RNA bacteriophage (family Leviviridae).
Bacteriophage of the family Leviviridae have played an important role in molecular biology where representative species, such as Q beta and MS2, have been studied as model systems for replication, translation, and the role of secondary structure in gene regulation. Using nucleotide sequences from the coat and replicase genes we present the first statistical estimate of phylogeny for the family Leviviridae using maximum-likelihood and Bayesian estimation. Our analyses reveal that the coliphage species are a monophyletic group consisting of two clades representing the genera Levivirus and Allolevivirus. The Pseudomonas species PP7 diverged from its common ancestor with the coliphage prior to the ancient split between these genera and their subsequent diversification. Differences in genome size, gene composition, and gene expression are shown with a high probability to have changed along the lineage leading to the Allolevivirus through gene expansion. The change in genome size of the Allolevivirus ancestor may have catalyzed subsequent changes that led to their current genome organization and gene expression.


Cross-Sectional Observational Study of Typical in utero Fetal Movements Using Machine Learning.
Early variations of fetal movements are the hallmark of a healthy developing central nervous system. However, there are no automatic methods to quantify the complex 3D motion of the developing fetus in utero. The aim of this prospective study was to use machine learning (ML) on in utero MRI to perform quantitative kinematic analysis of fetal limb movement, assessing the impact of maternal, placental, and fetal factors. In this cross-sectional, observational study, we used 76 sets of fetal (24-40 gestational weeks [GW]) blood oxygenation level-dependent (BOLD) MRI scans of 52 women (18-45 years old) during typical pregnancies. Pregnant women were scanned for 5-10 min while breathing room air (21% O2) and for 5-10 min while breathing 100% FiO2 in supine and/or lateral position. BOLD acquisition time was 20 min in total with effective temporal resolution approximately 3 s. To quantify upper and lower limb kinematics, we used a 3D convolutional neural network previously trained to track fetal key points (wrists, elbows, shoulders, ankles, knees, hips) on similar BOLD time series. Tracking was visually assessed, errors were manually corrected, and the absolute movement time (AMT) for each joint was calculated. To identify variables that had a significant association with AMT, we constructed a mixed-model ANOVA with interaction terms. Fetuses showed significantly longer duration of limb movements during maternal hyperoxia. We also found a significant centrifugal increase of AMT across limbs and significantly longer AMT of upper extremities <31 GW and longer AMT of lower extremities >35 GW. In conclusion, using ML we successfully quantified complex 3D fetal limb motion in utero and across gestation, showing maternal factors (hyperoxia) and fetal factors (gestational age, joint) that impact movement. Quantification of fetal motion on MRI is a potential new biomarker of fetal health and neuromuscular development.


Referral patterns of patients presenting with chest pain at two rural emergency departments in Western Australia.
Coronary heart disease is the largest single cause of death in Australia. In Western Australia invasive diagnostics and therapies for acute coronary syndromes are only provided in the metropolitan hospitals of Perth. Patients in rural hospitals who need invasive cardiac care have to be transferred to Perth. The aim of our research was to determine which patient factors are associated with referral to advanced cardiac care at metropolitan level and how this compares to Australian guidelines for the management of acute coronary syndromes. Data was collected from patients presenting with chest pain to the rural emergency department, who were at least 18 years old and had given their consent. Exclusion criteria were chest pain accompanied or precipitated by significant co morbidity and prior enrolment in this study protocol. Socioeconomic and medical information of patients was collected from their medical records. Data was analysed using chi(2) tests, independent sample t-tests and multivariable logistic-regression models (stepwise backwards procedure). The study included 115 rural patients with chest pain with a mean age of 58 years: 66 (57%) men, 12 (10%) indigenous Australians and 38 (33%) transferred patients. Of all transferred patients 19 (50%) had a positive peak troponin-T, 13 (36%) a high peak creatine kinase (CK) and 12 (32%) persistent ST-elevation on their electrocardiogram, compared with 10 (14%), 12 (17%) and 11 (14%) respectively for non-transferred patients. Chi-square-tests showed significant differences between transfer groups in all three essential initial cardiac investigations and known dyslipidaemia. In multivariate analyses the positive peak troponin-T increased odds of transfer (OR6.40; 95% CI 2.55-16.08). This effect increased after adjustment for gender, serum creatinine and known dyslipidaemia (OR27.61; 95% CI 6.41-119.04). When adjusted for the peak troponin-T, neither ECG with persistent ST-elevation nor high peak CK remained significant. Known dyslipidaemia remained significant and serum creatinine became significant. Gender became significant when adjusted for troponin-T, known dyslipidaemia and serum creatinine. Peak troponin-T is an independent determinant associated with the transfer to advanced care at metropolitan level, but ECG with persistent ST-elevation and peak CK (other essential initial cardiac investigations) are not. Further investigation of the available and provided cardiac care in rural Western Australia is required.


The first decade of aortocoronary bypass grafting, 1967-1977. A review.
Despite a decade of experience with aortocoronary bypass grafting embracing 300,000 or more operations, indications for its use remain controversial. The controversy persists because of a lack of adequate controls with which to compare the clinical course of operated patients; only 1248 have been reported who have been studied in a carefully controlled and random manner. Benefit has been claimed frequently by comparing the course of patients treated surgically with medically treated patients followed the decade before. Such comparisons are not valid in view of the well documented changes in the natural history of coronary artery disease that have been occurring during the last decade. Despite a low operative mortality and rate of graft closure, available data in the literature do not indicate that initial symptomatic improvement necessarily persists, or that myocardial infarctions, arrhythmias, or congestive heart failure will be prevented, or that life will be prolonged in the vast majority of operated patients.


Optogenetic-mediated release of histamine reveals distal and autoregulatory mechanisms for controlling arousal.
Histaminergic neurons in the tuberomammillary nucleus (TMN) are an important component of the ascending arousal system and may form part of a "flip-flop switch" hypothesized to regulate sleep and wakefulness. Anatomical studies have shown that the wake-active TMN and sleep-active ventrolateral preoptic nucleus (VLPO) are reciprocally connected, suggesting that each region can inhibit its counterpart when active. In this study, we determined how histamine affects the two branches of this circuit. We selectively expressed channelrhodopsin-2 (ChR2) in TMN neurons and used patch-clamp recordings in mouse brain slices to examine the effects of photo-evoked histamine release in the ventrolateral TMN and VLPO. Photostimulation decreased inhibitory GABAergic inputs to the ventrolateral TMN neurons but produced a membrane hyperpolarization and increased inhibitory synaptic input to the VLPO neurons. We found that in VLPO the response to histamine was indirect, most likely via a GABAergic interneuron. Our experiments demonstrate that release of histamine from TMN neurons can disinhibit the TMN and suppresses the activity of sleep-active VLPO neurons to promote TMN neuronal firing. This further supports the sleep-wake "flip-flop switch" hypothesis and a role for histamine in stabilizing the switch to favor wake states.


Indexing events in memory: evidence for index dominance.
Research on narrative comprehension and autobiographical memory converge on three hypotheses which make different predictions about event organisation. The availability of different event components as indexes may explain the convergence on three hypotheses rather than one. In this paper, three experiments assessed event indexing in narratives with different available indexes. In Experiment 1, participants read event descriptions organised by character or time. In Experiment 2, event descriptions were organised by character or location. In Experiment 3, participants read event descriptions where events were grouped by activity. In each experiment, memory could be organised by any of the available components alone, by both components, or by using the organisation imposed by the discourse. Participants indexed events by character in Experiment 1, re-indexing information when necessary. Results of Experiment 2 indicated equal use of character and location indexes. In this case, participants used the discourse organisation. In Experiment 3, participants indexed events using activity groupings, again re-indexing events when necessary. Results are interpreted as indicating reliance on a single organising index with flexibility in the selection of different event components as indexes.


Food-web complexity, meta-community complexity and community stability.
What allows interacting, diverse species to coexist in nature has been a central question in ecology, ever since the theoretical prediction that a complex community should be inherently unstable. Although the role of spatiality in species coexistence has been recognized, its application to more complex systems has been less explored. Here, using a meta-community model of food web, we show that meta-community complexity, measured by the number of local food webs and their connectedness, elicits a self-regulating, negative-feedback mechanism and thus stabilizes food-web dynamics. Moreover, the presence of meta-community complexity can give rise to a positive food-web complexity-stability effect. Spatiality may play a more important role in stabilizing dynamics of complex, real food webs than expected from ecological theory based on the models of simpler food webs.


Early impact of 10-valent pneumococcal conjugate vaccine in childhood pneumonia hospitalizations using primary data from an active population-based surveillance.
In Brazil, 10-valent pneumococcal conjugate vaccine (PCV10) was introduced in 2010 in the childhood routine immunization program. We used primary data to evaluate the effect of PCV10 on the reduction of hospital admissions due to community-acquired pneumonia (CAP). Active population-based surveillance studies on pneumonia hospitalizations in children aged <36 months were conducted before and after PCV10 introduction in Central Brazil. The surveillances comprised all 17 pediatric hospitals of the study area, which provide assistance for public and private health insurances. Linear regression was performed to detect any trend in pneumonia monthly rates previously to vaccine introduction. PCV10 post-vaccination impact (Nov/2011 to Oct/2013) on clinical and X-Ray confirmed pneumonia was estimated as the relative and the absolute reduction (prevented burden) in pneumonia admission rates, taking as baseline the pre-vaccination period (May/2007 to Apr/2009). Overall, males presented higher rates of pneumonia hospitalization, compared to females. The relative rate reduction for clinical and X-Ray confirmed pneumonia was 13.1%, and 25.4%, respectively for children aged 2-23 months. The highest prevented burden was observed in age-groups 2-11 months, respectively 853/100,000 (from 6788/100,000 to 5935/100,000), and 729/100,000 (from 2871/100,000 to 2142/100,000), for clinical and X-Ray confirmed pneumonia. This study provides evidence for the impact of PCV10 in clinical and X-Ray confirmed pneumonia in routine vaccination program in Brazil, after 3 years of vaccine introduction. Extended follow-up studies should confirm the benefit of vaccination through herd effect given the high burden of pneumonia in our setting.


More than just strand breaks: the recognition of structural DNA discontinuities by DNA-dependent protein kinase catalytic subunit.
The DNA-dependent protein kinase (DNA-PK) is a trimeric factor originally identified as an enzyme that becomes activated upon incubation with DNA. Genetic defects in either the catalytic subunit (DNA-PK(CS)) or the two Ku components of DNA-PK result in immunodeficiency, radiosensitivity, and premature aging. This combined phenotype is generally attributed to the requirement for DNA-PK in the repair of DNA double strand breaks during various biological processes. However, recent studies revealed that DNA-PK(CS), a member of the growing family of phosphatidylinositol 3-kinases, participates in signal transduction cascades related to apoptotic cell death, telomere maintenance and other pathways of genome surveillance. These manifold functions of DNA-PK(CS) have been associated with an increasing number of protein interaction partners and phosphorylation targets. Here we review the DNA binding properties of DNA-PK(CS) and highlight its ability to interact with an astounding diversity of nucleic acid substrates. This survey indicates that the large catalytic subunit of DNA-PK functions as a sensor of not only broken DNA molecules, but of a wider spectrum of aberrant, unusual, or specialized structures that interrupt the standard double helical conformation of DNA.


Sad dads: paternal postpartum depression.
The postpartum period is associated with many adjustments to fathers that pose risks for depression. Estimates of the prevalence of paternal postpartum depression (PPD) in the first two months postpartum vary in the postpartum period from 4 to 25 percent. Paternal PPD has high comorbidity with maternal PPD and might also be associated with other postpartum psychiatric disorders. Studies so far have only used diagnostic criteria for maternal PPD to investigate paternal PPD, so there is an urgent need to study the validity of these scales for men and develop accurate diagnostic tools for paternal PPD. Paternal PPD has negative impacts on family, including increasing emotional and behavioral problems among their children (either directly or through the mother) and increasing conflicts in the marital relationship. Changes in hormones, including testosterone, estrogen, cortisol, vasopressin, and prolactin, during the postpartum period in fathers may be biological risk factors in paternal PPD. Fathers who have ecological risk factors, such as excessive stress from becoming a parent, lack of social supports for parenting, and feeling excluded from mother-infant bonding, may be more likely to develop paternal PPD. Support from their partner, educational programs, policy for paid paternal leave, as well as consideration of psychiatric care may help fathers cope with stressful experiences during the postpartum period.


Genome measures used for quality control are dependent on gene function and ancestry.
The transition/transversion (Ti/Tv) ratio and heterozygous/nonreference-homozygous (het/nonref-hom) ratio have been commonly computed in genetic studies as a quality control (QC) measurement. Additionally, these two ratios are helpful in our understanding of the patterns of DNA sequence evolution. To thoroughly understand these two genomic measures, we performed a study using 1000 Genomes Project (1000G) released genotype data (N=1092). An additional two datasets (N=581 and N=6) were used to validate our findings from the 1000G dataset. We compared the two ratios among continental ancestry, genome regions and gene functionality. We found that the Ti/Tv ratio can be used as a quality indicator for single nucleotide polymorphisms inferred from high-throughput sequencing data. The Ti/Tv ratio varies greatly by genome region and functionality, but not by ancestry. The het/nonref-hom ratio varies greatly by ancestry, but not by genome regions and functionality. Furthermore, extreme guanine + cytosine content (either high or low) is negatively associated with the Ti/Tv ratio magnitude. Thus, when performing QC assessment using these two measures, care must be taken to apply the correct thresholds based on ancestry and genome region. Failure to take these considerations into account at the QC stage will bias any following analysis. email@example.com Supplementary data are available at Bioinformatics online.


Revision of medial Oxford unicompartmental knee replacement to a total knee replacement: similar to a primary?
Unicompartmental knee replacement (UKR) is an option for the treatment of isolated medial compartment osteoarthritis. A commonly perceived potential advantage is that revision of a UKR is straightforward. The purpose of this study was to determine the early outcomes and the level of complexity of revisions of Oxford UKRs performed at our hospital. A retrospective review of a prospective database of all phase III Oxford UKRs was undertaken. This identified 89 Oxford UKRs which were revised at our institution between 2002 and 2008. The median time from the primary procedure to revision was 19 months (interquartile range 2-73 months). Nine were revised to another UKR. Eighty were revised to a total knee replacement (TKR). Fifty-three were revised with primary TKR components. Twenty-seven were revised using stems and/or augments. The median overall tibial component thickness (including augments) was 15 mm. Forty-five knees had an overall tibial component thickness greater than 15 mm. A primary Oxford UKR bearing thickness of greater than 6mm was associated with an increased likelihood of requiring revision components. On the basis of this review, tibial bone defects were commonly encountered when revising UKRs. Reconstruction with either an augment and a stem, or thick polyethylene component was often required. We recommend that the potential complexity of revision for UKR failure should be borne in mind when considering a primary Oxford UKR.


Characterization of the rat vasoactive intestinal polypeptide receptor gene 5' region.
The broad spectrum of vasoactive intestinal polypeptide (VIP) cellular functions are mediated by high-affinity binding sites. To determine regulation of the VIP receptor gene expression, we have isolated and characterized two genomic clones that contain the first three exons and the 5' flanking region of the VIP receptor gene. Using RNase protection assays, receptor gene expression was detected in adult rat lung, liver and intestine, but not in fetal lung, indicating that VIP receptor is expressed in diverse tissues, and its expression is differentially regulated during lung development. The transcription start site of the gene was mapped to a cytosine residue, 76 bp upstream from the ATG initiation codon. Transfection into rat lung cell lines shows that although 126 bp of the VIP receptor 5' DNA sequences are capable of activating VIP receptor gene basal transcription 30-fold over a promoterless control, 488 bp of the 5' sequences further induce this activation to 97-fold over control. However, inclusion of up to 859 bp 5' sequences results in a decrease in basal promoter activity (31-fold over control), indicating that while sequences between -126 and -488 bp contain potential enhancer sequences, sequences between -488 and -859 bp may include a transcriptional repressor sequence. Deletion analysis shows that transcription factor Sp1 plays an important role in activating basal promoter of the VIP receptor gene. DNase I footprinting and gel-mobility-shift assays show that Sp1 binds to its consensus binding sites in the VIP receptor promoter, suggesting that interaction of Sp1 with VIP receptor promoter transactivates this gene.


Identification of the core domain and the secondary structure of the transcriptional coactivator MBF1.
Multiprotein bridging factor 1 (MBF1) is a transcriptional coactivator necessary for transcriptional activation caused by DNA binding activators, such as FTZ-F1 and GCN4. MBF1 bridges the DNA-binding regions of these activators and the TATA-box binding protein (TBP), suggesting that MBF1 functions by recruiting TBP to promoters where the activators are bound. In addition, MBF1 stimulates DNA binding activities of the activators to their recognition sites. To date, little is known about structures of coactivators that bind to TBP. The two-dimensional (2D) 1H-15N correlation spectrum of 15N labeled MBF1 indicated that MBF1 consists of both flexible and well structured parts. Limited digestion of MBF1 by alpha-chymotrypsin yielded a approximately 9 kDa fragment. N-terminal sequence analysis and NMR measurements revealed that this fragment originates from the C-terminal 80 residues of MBF1 and form a well structured C-terminal domain of MBF1, MBF1CTD. As previous deletion analyses have shown that MBF1CTD is capable of binding to TBP, it is suggested that MBF1CTD is the TBP binding domain of MBF1. Sequential assignments have been obtained by means of three-dimensional (3D) and four dimensional (4D) heteronuclear correlation spectroscopies, and then the secondary structure of MBF1CTD was determined. As a result, MBF1CTD was shown to contain four amphipathic helices and a conserved C-terminal region. Asp106 which is assumed to be responsible for the binding to TBP is located at the hydrophilic side of the third helix. Structural analyses revealed that MBF1 consists of two structurally different domains. A N-terminal region is indispensable for the binding to activators, and does not form a well defined structure. In contrast, the C-terminal 80 residues, which is capable of binding to TBP by itself, form a well-structured domain, MBF1CTD. MBF1CTD is made up of four amphipathic helices and a conserved C-terminal tail. A putative TBP binding residue is located on the hydrophilic surface of the third helix.


Improving implementation of evidence-based practice in mental health service delivery: protocol for a cluster randomised quasi-experimental investigation of staff-focused values interventions.
There is growing acceptance that optimal service provision for individuals with severe and recurrent mental illness requires a complementary focus on medical recovery (i.e., symptom management and general functioning) and personal recovery (i.e., having a 'life worth living'). Despite significant research attention and policy-level support, the translation of this vision of healthcare into changed workplace practice continues to elude. Over the past decade, evidence-based training interventions that seek to enhance the knowledge, attitudes, and skills of staff working in the mental health field have been implemented as a primary redress strategy. However, a large body of multi-disciplinary research indicates disappointing rates of training transfer. There is an absence of empirical research that investigates the importance of worker-motivation in the uptake of desired workplace change initiatives. 'Autonomy' is acknowledged as important to human effectiveness and as a correlate of workplace variables like productivity, and wellbeing. To our knowledge, there have been no studies that investigate purposeful and structured use of values-based interventions to facilitate increased autonomy as a means of promoting enhanced implementation of workplace change. This study involves 200 mental health workers across 22 worksites within five community-managed organisations in three Australian states. It involves cluster-randomisation of participants within organisation, by work site, to the experimental (values) condition, or the control (implementation). Both conditions receive two days of training focusing on an evidence-based framework of mental health service delivery. The experimental group receives a third day of values-focused intervention and 12 months of values-focused coaching. Well-validated self-report measures are used to explore variables related to values concordance, autonomy, and self-reported implementation success. Audits of work files and staff work samples are reviewed for each condition to determine the impact of implementation. Self-determination theory and theories of organisational change are used to interpret the data. The research adds to the current knowledge base related to worker motivation and uptake of workplace practice. It describes a structured protocol that aims to enhance worker autonomy for imposed workplace practices. The research will inform how best to measure and conceptualise transfer. These findings will apply particularly to contexts where individuals are not 'volunteers' in requisite change processes. ACTRN12613000353796.


How families manage chronic conditions: an analysis of the concept of normalization.
Concept analysis entails the systematic examination of the attributes or characteristics of a given concept for the purpose of clarifying the meaning of that concept. The term "normalization" appears frequently in reports of how families respond to the illness or disability of a member. While most authors agree that families who have an ill or disabled member attempt to normalize their family life, definitions and applications of the concept vary considerably across investigators. Following guidelines for concept analysis proposed by Chinn and Jacobs (1983), the origin and development of the concept normalization are traced and criteria are presented for distinguishing between normalization and other responses families make to a member's illness or disability. Three case examples are presented: a model (normalization) case, a contrary (disassociation) case, and a related (denial) case.


Septic sialoadenitis in equids: a retrospective study of 18 cases (1998-2010).
Septic sialoadenitis, although uncommonly reported in equids, is a significant cause of pain, inappetence, dysphagia and discomfort. There are currently few reported cases possibly as a result of its infrequent occurrence. To review cases presenting with sialoadenitis and describe the presenting complaints, results of diagnostic tests, treatment and outcome. Retrospective case series. Records were reviewed for equids presenting to the UC Davis William R. Pritchard Veterinary Medical Teaching Hospital between 1998 and 2010 for salivary gland swelling. Equids were included if a diagnosis of septic sialoadenitis was made based on a combination of oral examination and/or ultrasonographic findings and/or microbial culture. Data collected included age, breed, presenting complaints, diagnostic results, treatment and outcome. Eighteen equids were diagnosed with septic sialoadenitis affecting the parotid gland (11) or the mandibular salivary gland (7). Ultrasound was useful to differentiate whether the mandibular or parotid salivary gland was involved. Affected equids ranged in age from 4 to 30 years (mean 17.7 years). Fourteen of 15 (93.3%) equids that underwent a complete oral examination had dental or other oral abnormalities. Six of 18 cases had evidence of sialolithiasis. Culture of the infected salivary gland or secretions was performed in 9 equids and all yielded growth of Fusobacterium sp. along with other aerobic and anaerobic bacteria. Infection resolved in 15/18 cases (83.3%) and 2/18 (11.1%) were subjected to euthanasia. Dental disease and sialolith formation may play important roles in the development of septic sialoadenitis in equids. Anaerobic infection should be assumed in all cases and affected horses should be treated for this until culture and sensitivity results are available. Prognosis is favourable (83.3%) with appropriate treatment.


Changes in the Prevalence of Tobacco Consumption and the Profile of Spanish Smokers after a Comprehensive Smoke-Free Policy.
A partial smoke-free regulation in Spain was introduced on January 1, 2006, which was subsequently amended to introduce a comprehensive smoke-free policy from 2 January 2011 onward. The objective of this study was to compare the prevalence of tobacco consumption in Spain and the profile of smokers before (2006) and after (2011) the comprehensive smoking ban passed in 2010. Two independent, cross-sectional, population-based surveys were carried out among the adult (≥ 18 years old) Spanish population in 2006 and 2011 through telephone interviews. Both surveys used the same methods and questionnaire. Nicotine dependence was assessed with the Fagerström Test for nicotine dependence and readiness to quit according to the stages of change. The prevalence of tobacco consumption showed a nonsignificant decrease from 23.4% in 2006 to 20.7% in 2011. No changes were observed in nicotine dependence or readiness to quit. In 2011, most smokers (76%) showed low nicotine dependence and were mainly in the precontemplation stage (72%). The prevalence of smokers has slightly decreased since the introduction of the total smoking ban in Spain. No differences were found in nicotine dependence or readiness to quit.


[Dialogues between Clio and Asclepius: Ivolino de Vasconcellos and the Revista Brasileira de História da Medicina].
The Brazilian Institute for the History of Medicine was founded on 1945 by the physician Ivolino de Vasconcellos. Because the movement intended to be of national scope, the Federação Nacional de História da Medicina e Ciências Afins was also created (National Federation for the History of Medicine and Related Sciences). The latter group had a humanistic understanding of medicine, wherein the history of medicine played a central role; since this subject honored great names and achievements in medicine, members of the federation felt it was a prime tool in the ethical and humanistic training of healthcare professionals. Thus was born the Revista Brasileira de História da Medicina, which fostered scientific and academic production and events in the field of history of medicine and also registered the Federation's activities and scientific output.


Effect of cholecystectomy on bowel function: a prospective, controlled study.
Published estimates of the prevalence of postcholecystectomy diarrhoea derive from retrospective or uncontrolled data. They ignore functional bowel syndromes and possible changes in diet and drug use. To determine prospectively whether and how often cholecystectomy leads to changes in bowel function and bowel symptoms, especially to liquid stools, over and above any non-specific effect of laparoscopic surgery. 106 adults undergoing laparoscopic cholecystectomy (85 women, 21 men). 37 women undergoing laparoscopic sterilisation. Before and 2-6 months after surgery patients were administered questionnaires about bowel frequency, bowel symptoms, diet, and drugs, and kept records of five consecutive defecations with assessment of stool form or appearance on a seven point scale. In cholecystectomised women, stated bowel frequency increased, on average by one movement a week, and fewer subjects felt that they became constipated. However, records showed no consistent change in bowel frequency, stool form, or defecatory symptoms. Six women reported diarrhoea after the operation but in only one was it clearly new and in her it was mild. Change in dietary fibre intake did not associate with change in bowel function but stopping constipating drugs did in a minority. In women being sterilised there was no consistent change in bowel function. In men having cholecystectomy no consistent changes were observed. In women, cholecystectomy leads to the perception of less constipation and slightly more frequent defecations but short term recordings show no consistent change in bowel function. Clinical diarrhoea develops rarely and is not severe.


Psychiatric test assessment of patients with psychomotor epilepsy.
The authors evaluated the psychiatric status of 31 patients who had temporal lobectomies and 6 patients who received implantation of depth electrodes for relief of epileptic seizures. Results showed a general postoperative improvement in overall psychopathology (measured by the Brief Psychiatric Rating Scale) and in depression in particular; however, depression tended to recur with the passage of time after lobectomy.


Effectiveness of restricting access to a suicide jump site: a test of the method substitution hypothesis.
Reducing access to lethal means can prevent suicides. However, substitution of a suicide method remains a concern. Until 1986, the Ellington Bridge was the site of one-half of all Washington, DC bridge suicides. An antisuicide fence was installed in 1986, creating a naturalistic case-control design for testing the substitution hypothesis with the adjacent and equally as lethal jump site, the Taft Bridge. We found that suicide deaths from the Ellington Bridge were reduced by 90% (p=0.001) following barrier construction, without changes in rates of jumps from either the Taft Bridge or any other bridge in the city. Suicides by all methods decreased significantly across the study period. While the decline in suicides from the Ellington Bridge may reflect a broader decline in suicide, the decline in bridge suicide without persistent shifts in deaths to other bridges provides evidence that restricting access to one highly lethal method is effective.


The beneficial and adverse effects of hypnotics.
Findings from a four-city study of the beneficial and adverse effects of hypnotics are reported. The study employed a new volunteer call-in method for monitoring drug effects outside of the clinical setting. Respondents were recruited through newspaper advertisements. They were invited to complete a short telephone interview if, during the past 12 months, they (1) had significant trouble with insomnia or (2) had taken a medication to induce sleep. Comparison groups were flurazepam, temazepam, triazolam, and over-the-counter (OTC) sleep medications. An untreated insomnia group also was included. Results indicate that most users of prescription hypnotics attributed positive effects to their sleep medications and that adverse effects were infrequent. OTC hypnotics were less effective and more likely to produce negative effects. The untreated insomnia group was more symptomatic than any of the medication groups.


The association of cigarette smoking with disease outcome in patients with early inflammatory polyarthritis.
Cigarette smoking is known to increase rheumatoid factor (RF) and nodule formation in patients with rheumatoid arthritis (RA). In this study, we examined the influence of smoking on disease outcome at 3 years among patients newly presenting with inflammatory polyarthritis (IP). We studied 486 patients with IP who were referred to the Norfolk Arthritis Register, of whom 323 (67%) satisfied the American College of Rheumatology 1987 criteria for RA. Smoking status was assessed at baseline. Disease outcome was assessed at 3 years, using measures of joint inflammation, functional disability, and radiologic damage. The influence of smoking on disease outcome was explored using logistic regression techniques, with patients who had never smoked as the referent group. Results are expressed as odds ratios (ORs), with their 95% confidence intervals (95% CIs). Current smokers were significantly more likely to be RF positive at baseline (47%) than were ex-smokers (34%) and never smokers (31%). After 3 years, rheumatoid nodules were significantly more common in smokers (13%) compared with ex-smokers/never smokers (4%), a relationship which persisted after adjusting for age and sex (OR 4.07, 95% CI 1.38-12). In contrast, after adjusting for age and sex, current smokers had significantly fewer swollen joints (OR 0.61, 95% CI 0.37-0.98). However, smoking status had no influence on the development of erosions or functional disability. Despite smokers being more likely to develop nodules and to be RF positive, current smokers did not have higher levels of radiologic damage, and had fewer swollen joints. We hypothesize that this could be due to either the effect of cigarette smoking on the inflammatory response or other factors (e.g., reduced physical activity in smokers) which may limit joint inflammation and damage.


Entomofauna resource distribution associated with pig cadavers in Bogotá DC.
A cadaver represents a temporal energy-loaded resource, which provides arthropods with food, protection and a place in which to find a mate. Insects are usually the first organisms to discover and colonize a cadaver; as decomposition progresses, insects colonize cadavers in a predictable sequence. This work aimed to establish cadaverous entomofauna relationships with regard to stages of decomposition and environmental conditions using multiple correspondence analysis and thereby to identify the way in which insects distribute a perishable and changing resource. Entomofauna were thus collected in a semi-rural area near Bogotá from the cadavers of three pigs (Sus scrofa L.) which had been shot. Environmental variables were recorded for each sampling. Multiple correspondence analyses were carried out for adult forms belonging to Diptera and Coleoptera families and stages of decomposition, and for Diptera and Coleoptera adult forms and environmental conditions. Stages of decomposition were a primary determining factor for structuring four guilds of entomofauna. However, environmental conditions influenced insect activity and were therefore a relevant factor in the structure of the entomofauna community. The results showed that the insects' distribution of available resources was related to changes in the stage of decomposition.


The relationship between head circumference and the development of communicating hydrocephalus in infants following intraventricular hemmorrhage.
Rapidly enlarging head circumference is a standard clinical sign of progressive hydrocephalus in an infant. Six neonates 29 to 36 weeks gestational age, with intraventricular hemorrhage, confirmed by ventricular tap, had head circumferences measured at intervals from birth. The sudden appearance of rapidly expanding head size, not associated with changing clinical status, occurred 9 to 20 days after the estimated time of hemorrhage in all of the infants. Air ventriculography within three days of abnormal acceleration of head circumference growth demonstrated moderately to severely dilated ventricles. The ventricles were probably enlarging slowing from the time of hemorrhage because there was no associated clinical deterioration in the infants coincident with the rapid increase in head circumference. After intraventricular hemorrhage, enlarging head circumference appears to be an insensitive sign of hydrocephalus in premature infants.


The need for supportive mental wellbeing interventions in bladder cancer patients: A systematic review of the literature.
There is an increased awareness of the effect of a bladder cancer diagnosis and its treatments on the mental wellbeing of patients. However, few studies have evaluated the efficacy, feasibility and acceptability of interventions to improve this mental wellbeing. This systematic review is the first phase of the Medical Research Council Framework for developing complex interventions and provides an overview of the published mental wellbeing interventions that could be used to design an intervention specific for BC patients. This review was conducted in accordance with the PRISMA guidelines in January 2019 and studies were identified by conducting searches for Medline, the Cochrane Central Register of Controlled Trials and Ovid Gateway. All included studies met the following criteria: mental wellbeing interventions of adults with medically confirmed diagnosis of any type of urological cancer, reported outcomes for specific HRQoL domains including psychological factors. The quality of evidence was assessed according to Down and Black 27-item checklist. A total of 15,094 records were collected from the literature search and 10 studies matched the inclusion and exclusion criteria. Of these, nine interventions were for patients with prostate cancer and one for patients with kidney cancer. No studies were found for other urological cancers. Depression was the most commonly reported endpoint measured. Of the included studies with positive efficacy, three were group interventions and two were couple interventions. In the group interventions, all showed a reduction in depressive symptoms and in the couple interventions, there was a reduction in depressive symptoms and a favourable relationship cohesion. The couple interventions were the most feasible and acceptable, but further research was required for most of the studies. While awareness of the importance of mental wellbeing in bladder cancer patients is growing, this systematic literature review highlights the gap of feasible and acceptable interventions for this patient population.


On EMDR: Measuring the working memory taxation of various types of eye (non-)movement conditions.
A recent, large randomized controlled trial employing different forms of eye (non-)movements in eye movement desensitization and reprocessing (EMDR) showed that fixating the eyes either on a therapist's moving or non-moving hand led to equal reductions in symptoms of post-traumatic stress disorder (PTSD). However, numerous EMDR lab analogue studies found that eye movements produce larger memory effects than eyes stationary. These beneficial effects are typically explained by differences in working memory (WM) taxation. We tested the degree of WM taxation of several eye (non-)movement conditions used in the clinical trial. All participants (N = 40) performed: (1) eyes moving by following the experimenter's moving finger, (2) eyes fixed on the experimenter's stationary finger, (3) eyes closed, or (4) looking unfocused into the room. Simultaneously they performed a simple reaction time task. Reaction times are an objective index of the extent to which different dual attention tasks tax WM. Eyes moving is more taxing than eyes fixed, while eyes fixed did not differ from eyes unfocused. All conditions were more taxing than eyes closed. We studied WM taxation in a laboratory setting; no clinical interventions were applied. In line with previous lab studies, making eye movements was more taxing than eyes fixed. We discuss why this effect was not observed for reductions in PTSD symptoms in the clinical trial (e.g., differences in dependent variables, sample population, and intervention duration). For more comprehensive future insights, we recommend integration of mechanistically focused lab analogue studies and patient-oriented clinical studies.


A randomized trial of the effect of patient race on physicians' intensive care unit and life-sustaining treatment decisions for an acutely unstable elder with end-stage cancer.
To test whether hospital-based physicians made different intensive care unit and life-sustaining treatment decisions for otherwise identical black and white patients with end-stage cancer and life-threatening hypoxia. We conducted a randomized trial of the relationship between patient race and physician treatment decisions using high-fidelity simulation. We counterbalanced the effects of race and case by randomly alternating their order using a table of random permutations. Physicians completed two simulation encounters with black and white patient simulator patients with prognostically identical end-stage gastric or pancreatic cancer and life-threatening hypoxia and hypotension, followed by a self-administered survey of beliefs regarding treatment preferences by race. We conducted within-subjects analysis of each physician's matched-pair simulation encounters, adjusting for order and case effects, and between-subjects analysis of physicians' first encounter, adjusting for case. Peter M. Winter Institute for Simulation Education and Research at the University of Pittsburgh, Pennsylvania. Thirty-three hospital-based attending physicians, including 12 emergency physicians, eight hospitalists, and 13 intensivists from Allegheny County, Pennsylvania. Race of patient simulator. Measurements included physician treatment decisions recorded during the simulation and documented in the chart and beliefs about treatment preference by race. When faced with a black vs. a white patient, physicians did not differ in their elicitation of intubation preferences (within-subject comparison, 28/32 [88%] vs. 28/32 [88%]; p = .589; between-subject comparison, 13/17 [87%] vs. 13/17 [76%]; p = .460), intensive care unit admission (within-subject comparison, 14/32 [44%] vs. 12/32 [38%]; p = .481; between-subject comparison, 8/15 (53%) vs. 7/17 (41%); p = .456), intubation (within-subject comparison, 5/32 [16%] vs. 4/32 [13%]; p = .567; between-subject comparison: 1/15 [7%] vs. 4/17 [24%]; p = .215), or initiation of comfort measures only (within-subject comparison: 16/32 [50%] vs. 19/32 [59%]; p = .681; between-subject comparison: 6/15 [40%] vs. 8/17 [47%]; p = .679). Physicians believed that a black patient with end-stage cancer was more likely than a similar white patient to prefer potentially life-prolonging chemotherapy over treatment focused on palliation (67% vs. 64%; z = -1.79; p = .07) and to want mechanical ventilation for 1 wk of life extension (43% vs. 34%; z = -2.93; p = .003), and less likely to want a do-not-resuscitate order if hospitalized (51% vs. 60%; z = 3.03; p = .003). In this exploratory study, hospital-based physicians did not make different treatment decisions for otherwise identical terminally ill black and white elders despite believing that black patients are more likely to prefer intensive life-sustaining treatment, and they grossly overestimated the preference for intensive treatment for both races.


Evaluation of the harmonizing effect of ylang-ylang oil on humans after inhalation.
Scientific evaluations of the effects of fragrances on humans are rather scarce. The aim of this investigation was to study the effects of ylang-ylang oil (Cananga odorata, Annonaceae) on hu-man physiological parameters and self-evaluation. Twenty-four healthy volunteers participated in the experiments. Fragrances were administered by inhalation. Physiological parameters recorded were skin temperature, pulse rate, breathing rate and blood pressure. Self-evaluation was assessed in terms of alertness, attentiveness, calmness, mood, relaxation and vigor. Additionally, fragrances were rated in terms of pleasantness, intensity and effect. The present investigation showed that ylang-ylang oil may be characterized by the concept of "harmonization" rather than relaxation/sedation. Compared to an odorless placebo, ylang-ylang oil caused significant decreases in blood pressure and pulse rate as well as significant increases of subjective attentiveness and alertness. Correlational analyses revealed that the observed effects are mainly due to a subjective odor experience.


Multiracial competence in social work: recommendations for culturally attuned work with multiracial people.
According to the 2010 U.S. census, approximately 9 million individuals report multiracial identities. By the year 2050, as many as one in five Americans could claim a multiracial background. Despite this population growth, a review of recent empirical and theoretical literature in social work suggests a disproportionate lack of attention to issues ofmultiraciality. Instead, social work practice models remain embedded in traditional societal discourses of race and culture that often exclude or marginalize the experiences of multiracial individuals and families.This article summarizes recommendations following the domains of awareness, knowledge, and skills in the NASW Standards for Cultural Competence in Social Work Practice to support culturally attuned social work practice with multiracial people. The authors argue that a culturally attuned practice approach--one that is inclusive of multiraciality--is not only timely, but also consistent with the profession's ethical obligation to provide culturally relevant services to all consumers and clients.


Mechanism of calcite co-orientation in the sea urchin tooth.
Sea urchin teeth are remarkable and complex calcite structures, continuously growing at the forming end and self-sharpening at the mature grinding tip. The calcite (CaCO(3)) crystals of tooth components, plates, fibers, and a high-Mg polycrystalline matrix, have highly co-oriented crystallographic axes. This ability to co-orient calcite in a mineralized structure is shared by all echinoderms. However, the physico-chemical mechanism by which calcite crystals become co-oriented in echinoderms remains enigmatic. Here, we show differences in calcite c-axis orientations in the tooth of the purple sea urchin ( Strongylocentrotus purpuratus ), using high-resolution X-ray photoelectron emission spectromicroscopy (X-PEEM) and microbeam X-ray diffraction (muXRD). All plates share one crystal orientation, propagated through pillar bridges, while fibers and polycrystalline matrix share another orientation. Furthermore, in the forming end of the tooth, we observe that CaCO(3) is present as amorphous calcium carbonate (ACC). We demonstrate that co-orientation of the nanoparticles in the polycrystalline matrix occurs via solid-state secondary nucleation, propagating out from the previously formed fibers and plates, into the amorphous precursor nanoparticles. Because amorphous precursors were observed in diverse biominerals, solid-state secondary nucleation is likely to be a general mechanism for the co-orientation of biomineral components in organisms from different phyla.


Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis.
Increases in lipid levels and cancers with tofacitinib prompted a trial of major adverse cardiovascular events (MACE) and cancers in patients with rheumatoid arthritis receiving tofacitinib as compared with a tumor necrosis factor (TNF) inhibitor. We conducted a randomized, open-label, noninferiority, postauthorization, safety end-point trial involving patients with active rheumatoid arthritis despite methotrexate treatment who were 50 years of age or older and had at least one additional cardiovascular risk factor. Patients were randomly assigned in a 1:1:1 ratio to receive tofacitinib at a dose of 5 mg or 10 mg twice daily or a TNF inhibitor. The coprimary end points were adjudicated MACE and cancers, excluding nonmelanoma skin cancer. The noninferiority of tofacitinib would be shown if the upper boundary of the two-sided 95% confidence interval for the hazard ratio was less than 1.8 for the combined tofacitinib doses as compared with a TNF inhibitor. A total of 1455 patients received tofacitinib at a dose of 5 mg twice daily, 1456 received tofacitinib at a dose of 10 mg twice daily, and 1451 received a TNF inhibitor. During a median follow-up of 4.0 years, the incidences of MACE and cancer were higher with the combined tofacitinib doses (3.4% [98 patients] and 4.2% [122 patients], respectively) than with a TNF inhibitor (2.5% [37 patients] and 2.9% [42 patients]). The hazard ratios were 1.33 (95% confidence interval [CI], 0.91 to 1.94) for MACE and 1.48 (95% CI, 1.04 to 2.09) for cancers; the noninferiority of tofacitinib was not shown. The incidences of adjudicated opportunistic infections (including herpes zoster and tuberculosis), all herpes zoster (nonserious and serious), and adjudicated nonmelanoma skin cancer were higher with tofacitinib than with a TNF inhibitor. Efficacy was similar in all three groups, with improvements from month 2 that were sustained through trial completion. In this trial comparing the combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk-enriched population, risks of MACE and cancers were higher with tofacitinib and did not meet noninferiority criteria. Several adverse events were more common with tofacitinib. (Funded by Pfizer; ORAL Surveillance ClinicalTrials.gov number, NCT02092467.).


Transforming growth factor-beta in osteolytic breast cancer bone metastases.
Breast cancers frequently metastasize to the skeleton and cause bone destruction. Tumor cells secrete factors that stimulate osteoclasts. The consequent osteolytic resorption releases active factors from the bone matrix, in particular transforming growth factor-beta (TGF-beta). The released factors then stimulate tumor cell signaling, which causes breast cancer cells to make increased amounts of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), interleukin-11 (IL-11), and vascular endothelial growth factor (VEGF). Therefore, tumor cell-bone cell interactions cause a vicious cycle in which tumor cells stimulate bone cells to cause bone destruction. As a consequence, the local microenvironment is enriched with factors that fuel tumor growth in bone. Transforming growth factor-beta is of particular importance because it increases breast cancer production of PTHrP. Parathyroid hormone-related protein then stimulates osteoblasts to express RANK (receptor activator of nuclear factor kappa B) ligand, which in turns enhances osteoclast formation and activity. Breast cancer osteolytic metastasis can be interrupted at four points in the vicious cycle: by neutralizing PTHrP biologic activity, by blocking the TGF-beta signaling pathway in the tumor cells, by inhibiting PTHrP gene transcription, and by inhibiting bone resorption.


Multiscale analysis of pattern formation via intercellular signalling.
Lateral inhibition, a juxtacrine signalling mechanism by which a cell adopting a particular fate inhibits neighbouring cells from doing likewise, has been shown to be a robust mechanism for the formation of fine-grained spatial patterns (in which adjacent cells in developing tissues diverge to achieve contrasting states of differentiation), provided that there is sufficiently strong feedback. The fine-grained nature of these patterns poses problems for analysis via traditional continuum methods since these require that significant variation takes place only over lengthscales much larger than an individual cell and such systems have therefore been investigated primarily using discrete methods. Here, however, we apply a multiscale method to derive systematically a continuum model from the discrete Delta-Notch signalling model of Collier et al. (J.R. Collier, N.A.M. Monk, P.K. Maini, J.H. Lewis, Pattern formation by lateral inhibition with feedback: a mathematical model of Delta-Notch intercellular signalling, J. Theor. Biol., 183, 1996, 429-446) under particular assumptions on the parameters, which we use to analyse the generation of fine-grained patterns. We show that, on the macroscale, the contact-dependent juxtacrine signalling interaction manifests itself as linear diffusion, motivating the use of reaction-diffusion-based models for such cell-signalling systems. We also analyse the travelling-wave behaviour of our system, obtaining good quantitative agreement with the discrete system.


Neuroendocrine and hormonal perturbations and relations to the serotonergic system in fibromyalgia patients.
The symptomatology of the fibromyalgia syndrome (FMS) often resembles an alteration in central nervous set points at least in three systems. The patients suffer under chronic pain in the region of the locomotor system, presumably reflecting a disturbed central processing of pain. Anxiety and depression often characterizes the clinical picture. Almost all of the hormonal feedback mechanisms controlled by the hypothalamus are altered. Characteristic for FMS patients are the elevated basal values of ACTH, follicle-stimulating hormone (FSH), and cortisol as well as lowered basal values of insulin-like growth factor 1 (IGF-1, somatomedin C), free triiodothyronine (FT3), and oestrogen. In FMS patients, the systemic administration of the relevant releasing hormones of corticotropin-releasing hormone (CRH), growth hormone-releasing hormone (GHRH), thyreotropin-releasing hormone (TRH), and luteinizing hormone-releasing hormone (LHRH) leads to increased secretion of ACTH and prolactin, whereas the degree to which TSH can be stimulated is reduced. The stimulation of the hypophysis with LHRH in female FMS patients during their follicular phase results in a significantly reduced LH response. All in all, the typical alterations in set points of hormonal regulation that are typical for FMS patients can be explained as a primary stress activation of hypothalamic CRH neurons caused by the chronic pain. In addition to the stimulation of pituitary ACTH secretion, CRH activates somatostatin on the hypothalamic level, which in turn inhibits the release of GH and TSH on the hypophyseal level. The lowered oestrogen levels could be accounted for both via an inhibitory effect of the CRH on the hypothalamic release of LHRH or via a direct CRH-mediated inhibition of the FSH-stimulated oestrogen production in the ovary. Serotonin (5HT), precursors like tryptophan (5HTP), drugs which release 5HT or act directly on 5HT receptors stimulate HPA axis, indicating a stimulatory serotonergic influence on HPA axis function. Therefore activation of the HPA axis may reflect an elevated serotonergic tonus in the central nervous system of FMS patients.


Mechanisms subserving hormone action in the ovary: role of calcium ions as assessed by steady state calcium exchange in cultured swine granulosa cells.
We have appraised the properties of steady state calcium exchange in cultured swine granulosa cells prelabeled to isotopic equilibrium with 45Ca2+. Subsequent steady state efflux parameters were assessed by nonlinear least-squares curve-fitting to a two-compartment model. The resultant mean rate constants were 0.27 +/- 0.07 min-1 and 0.030 +/- 0.0015 min-1, which correspond to respective half-lives of calcium exchange of 2.6 +/- 0.67 min and 23 +/- 1.1 min (means +/- SD, n = 18 experiments). The estimated sizes of the rapidly and slowly exchangeable calcium compartments in ovarian cells were 1.8 +/- 0.51 and 4.47 +/- 0.15 mumol calcium/mg protein, respectively. Equilibrium exchange of calcium was temperature dependent, and accelerated markedly by putative stimulators of calcium influx, such as maitotoxin, A23187, and BAY K 8644. Conversely, presumptive inhibitors of the calcium-magnesium dependent ATPase, such as trifluoperazine and orthovanadate, significantly diminished the size of the slowly exchangeable pool and its corresponding rate constant. A similar profound reduction in the rate of slow calcium exchange was induced by a phorbol ester and by an inhibitor of intracellular calcium mobilization, dantrolene. Physiological effector hormones also altered equilibrium calcium exchange in swine granulosa cells. Thus, FSH and prostaglandin E2 increased the rapid and slowly exchanging rate constants by factors of approximately 2.2 and 1.6, whereas prostaglandin F2 alpha increased the sizes of the slowly and rapidly exchangeable calcium compartments. In summary, the present work delineates properties of physiological steady state calcium exchange in swine granulosa cells. Physiological effector hormones, such as FSH, prostaglandin E2, and prostaglandin F2 alpha, have distinct effects on steady state calcium exchange in ovarian cells.


Human-aided admixture may fuel ecosystem transformation during biological invasions: theoretical and experimental evidence.
Biological invasions can transform our understanding of how the interplay of historical isolation and contemporary (human-aided) dispersal affects the structure of intraspecific diversity in functional traits, and in turn, how changes in functional traits affect other scales of biological organization such as communities and ecosystems. Because biological invasions frequently involve the admixture of previously isolated lineages as a result of human-aided dispersal, studies of invasive populations can reveal how admixture results in novel genotypes and shifts in functional trait variation within populations. Further, because invasive species can be ecosystem engineers within invaded ecosystems, admixture-induced shifts in the functional traits of invaders can affect the composition of native biodiversity and alter the flow of resources through the system. Thus, invasions represent promising yet under-investigated examples of how the effects of short-term evolutionary changes can cascade across biological scales of diversity. Here, we propose a conceptual framework that admixture between divergent source populations during biological invasions can reorganize the genetic variation underlying key functional traits, leading to shifts in the mean and variance of functional traits within invasive populations. Changes in the mean or variance of key traits can initiate new ecological feedback mechanisms that result in a critical transition from a native ecosystem to a novel invasive ecosystem. We illustrate the application of this framework with reference to a well-studied plant model system in invasion biology and show how a combination of quantitative genetic experiments, functional trait studies, whole ecosystem field studies and modeling can be used to explore the dynamics predicted to trigger these critical transitions.


Dasatinib enhances megakaryocyte differentiation but inhibits platelet formation.
Dasatinib is a novel, potent, ATP-competitive inhibitor of Bcr-Abl, cKIT, and Src family kinases that exhibits efficacy in patients with imatinib-resistant chronic myelogenous leukemia. Dasatinib treatment is associated with mild thrombocytopenia and an increased risk of bleeding, but its biological effect on megakaryocytopoiesis and platelet production is unknown. In this study, we show that dasatinib causes mild thrombocytopenia in mice without altering platelet half-life, suggesting that it inhibits platelet formation. Conversely, the number of megakaryocytes (MKs) in the bone marrow of dasatinib-treated mice was increased and the ploidy of MKs derived from bone marrow progenitor cells in vitro was elevated in the presence of dasatinib. Furthermore, a significant delay in platelet recovery after immune-induced thrombocytopenia was observed in dasatinib-treated mice even though the number of MKs in the bone marrow was increased relative to controls at all time points. Interestingly, the migration of MKs toward a gradient of stromal cell-derived factor 1α (SDF1α) and the formation of proplatelets in vitro were abolished by dasatinib. We propose that dasatinib causes thrombocytopenia as a consequence of ineffective thrombopoiesis, promoting MK differentiation but also impairing MK migration and proplatelet formation.


Longitudinal assessment of oxaliplatin-induced neuropathy.
To characterize the natural history of oxaliplatin-associated neuropathy (ON) and determine whether intraepidermal nerve fiber density (IENFD) is a sensitive measure of neuropathy progression. In addition, we sought to assess the potential of ON as a neuroprotection model and gain insight into the relationship between axon loss and neuropathic symptoms. Eight subjects receiving oxaliplatin for advanced colorectal cancer were prospectively followed prior to starting chemotherapy and at 30, 90, 180, and 360 days (180 days after completing treatment). Electrophysiology, punch biopsies, symptom assessment, and examinations with calculation of a reduced total neuropathy score (rTNS) were performed at each time point. Changes over time were assessed through Poisson regression for IENFD and a mixed effects model for rTNS and electrophysiology measures. The distal leg IENFD, rTNS, peroneal, and sural amplitudes were all significantly reduced over time, while conduction velocity (peroneal and sural) and distal thigh IENFD were not. Measures of axon loss continued to worsen following discontinuation of oxaliplatin. Five of 8 subjects reported prominent symptoms associated with oxaliplatin administration. This study demonstrates that oxaliplatin is associated with mild, sensory, and motor axon loss that may not be reversible. Axonal loss was detected by electrophysiology, rTNS, and distal leg IENFD. Several subjects reported prominent sensory symptoms that were not associated with axon loss, and that may or may not represent neuropathy. ON is an attractive paradigm for neuroprotection studies and the distal leg IENFD is an objective measure that requires minimal subject participation or study site expertise.


PTGS2 gene polymorphism -765G>C is associated with coronary artery disease: a meta-analysis.
Previous studies focusing on the association of PTGS2 polymorphism -765G>C with coronary artery disease (CAD) have failed to reach the same conclusion. In the present study, we performed a meta-analysis to systematically summarize the possible association between PTGS2 polymorphism -765G>C and the risk of CAD. We conducted a search of case-control studies on the associations of PTGS2 with susceptibility to CAD in PubMed, EMBASE, and Chinese National Knowledge Infrastructure databases. Data from eligible studies were extracted for meta-analysis. CAD risk associated with PTGS2 -765G>C was estimated by pooled odds ratios (ORs) and 95% confidence intervals (95%CI) with the RevMan 5.2 software. Eleven independent case-control studies on PTGS2 -765G>C were included in our meta-analysis. Our results showed that PTGS2 -765G>C was associated with a decreased risk of CAD (OR = 0.66, 95%CI = 0.56-0.79; P < 0.001). This meta-analysis suggests that PTGS2 -765G>C is associated with a decreased risk of CAD.


Enhanced near-infrared photoresponse of organic phototransistors based on single-component donor-acceptor conjugated polymer nanowires.
Single-component near-infrared phototransistors based on ambipolar organic semiconductor nanowires have been investigated and compared with their corresponding thin-film counterparts. The nanowire organic phototransistors (NW-OPTs) showed photocurrent/dark-current ratios and photoresponsivities as high as 1.3 × 10(4) and 440 mA W(-1) for the p-type channel, and 3.3 × 10(4) and 70 mA W(-1) for the n-type channel, respectively, upon near-infrared illumination with an intensity of 47.1 mW cm(-2). These were much higher values compared to their thin-film counterparts. The enhancement of the near-infrared photoresponse could be attributed to the larger trap density originating from the semiconductor/insulator interface and the semiconductor/air interface. The performance of NW-OPTs was demonstrated to open up new possibilities to improve the near-infrared photoresponse of single-component devices.


Predictable morphometric parameters for rupture of intracranial aneurysms - a series of 142 operated aneurysms.
Intracranial aneurysm rupture is followed by high mortality and morbidity. In order to understand the aneurysm's natural course, it is necessary to recognize the predisposing factors for the rupture. Analysis included 142 operated aneurysms (94 hemorrhaging and 48 unruptured) in the period from 2008 to 2010. The ratio between the width of the aneurysm neck and diameter of the carrying blood vessel - artery in ruptured aneurysms (OR) was 1.58 ± 0.61, and in unruptured aneurysms 1.14 ± 0.52 (p < 0.01). Aspect ratio of ruptured aneurysm was 1.89 ± 0.59, and in unruptured 1:33 ± 0.17. The angle of inclination of ruptured aneurysms was 139.22 ± 21.53, while in unruptured aneurysms it was 101.73 ± 21.26. Based on the results of our research, a predictive model of morphometric characteristics of the vessel bearing the aneurysm to rupture can be identified: an irregular shape of the aneurysm, AR > 1.6, OR > 1.5 and inclination angle > 135 deg.


Glucose consumption and rate constants for 18F-fluorodeoxyglucose in human gliomas.
To investigate the value of direct measurement of the rate constants by performing 18F-labeled fluorodeoxyglucose (FDG) studies of glucose consumption in human gliomas in vivo, a kinetic method with 3- and 4-parameter rate constant models for FDG uptake was used to analyze data from dynamic scans obtained by positron emission tomography after injection of FDG into 14 patients with glioma. The results were compared with those obtained by the autoradiographic method using 3- and 4-parameter rate constant models. There were no significant differences in the glucose consumption calculated by the four different methods both in the gliomas and in the contralateral intact cortex. It was found that the rate constant k4* could be neglected in calculation of glucose consumption in gliomas as well as in the contralateral intact cortex. The rate constant k3*, an index of hexokinase function, was higher in malignant gliomas than in benign gliomas and was close to that in the contralateral cortex. This study indicates that the 3-parameter autoradiographic method, which is the most common one used in clinical practice, is reliable for the calculation of glucose consumption in human gliomas. Furthermore, direct measurement of the regional rate constants for FDG by the kinetic method was found to be useful for evaluation of the biochemical and physiological characteristics of human gliomas in vivo.


Antenatal Management of Bronchopulmonary Sequestration by Intrafetal Vascular Laser Ablation under Ultrasound Control: Narrative Review of the Literature and Report of Three Cases.
The objective of this study is to assess the effectiveness and safety of intrafetal vascular laser ablation (VLA) for fetuses with bronchopulmonary sequestration (BPS) with hydrops. First, we present 3 cases of fetuses with BPS and hydrops treated by VLA. Second, we aimed to conduct a narrative review to identify all reported cases of fetuses with BPS treated by intrafetal VLA. The review of the literature identified 41 fetuses treated by VLA for BPS with hydrops. The median gestational age of the VLA was 27+0 weeks' gestation [25+0-31+0] with an associated procedure at the same time in 43% of the cases (pleuroamniotic shunt, thoracentesis, and amniodrainage). A second procedure was required in 25% of cases for residual flow in the feeding vessel. No stillbirth or neonatal death was reported. The complications reported were a fetal thoracic hematoma complicated by fetal anemia and 4 preterm deliveries with a rate of 9%. VLA of the feeding vessel can be an effective treatment but is not without complications. In cases demonstrating cardiac output failure, intrafetal VLA should be considered as a treatment for BPS.


Regulation of postembryonic G(1) cell cycle progression in Caenorhabditis elegans by a cyclin D/CDK-like complex.
In many organisms, initiation and progression through the G(1) phase of the cell cycle requires the activity of G(1)-specific cyclins (cyclin D and cyclin E) and their associated cyclin-dependent kinases (CDK2, CDK4, CDK6). We show here that the Caenorhabditis elegans genes cyd-1 and cdk-4, encoding proteins similar to cyclin D and its cognate cyclin-dependent kinases, respectively, are necessary for proper division of postembryonic blast cells. Animals deficient for cyd-1 and/or cdk-4 activity have behavioral and developmental defects that result from the inability of the postembryonic blast cells to escape G(1) cell cycle arrest. Moreover, ectopic expression of cyd-1 and cdk-4 in transgenic animals is sufficient to activate a S-phase reporter gene. We observe no embryonic defects associated with depletion of either of these two gene products, suggesting that their essential functions are restricted to postembryonic development. We propose that the cyd-1 and cdk-4 gene products are an integral part of the developmental control of larval cell proliferation through the regulation of G(1) progression.


Coupled global and targeted proteomics of human embryonic stem cells during induced differentiation.
Elucidating the complex combinations of growth factors and signaling molecules that maintain pluripotency or, alternatively, promote the controlled differentiation of human embryonic stem cells (hESCs) has important implications for the fundamental understanding of human development, devising cell replacement therapies, and cancer cell biology. hESCs are commonly grown on irradiated mouse embryonic fibroblasts (MEFs) or in conditioned medium from MEFs. These culture conditions interfere with many experimental conclusions and limit the ability to perform conclusive proteomics studies. The current investigation avoided the use of MEFs or MEF-conditioned medium for hESC culture, allowing global proteomics analysis without these confounding conditions, and elucidated neural cell-specific signaling pathways involved in noggin-induced hESC differentiation. Based on these analyses, we propose the following early markers of hESC neural differentiation: collapsin response mediator proteins 2 and 4 and the nuclear autoantigenic sperm protein as a marker of pluripotent hESCs. We then developed a directed mass spectrometry assay using multiple reaction monitoring (MRM) to identify and quantify these markers and in addition the epidermal ectoderm marker cytokeratin-8. Analysis of global proteomics, quantitative RT-PCR, and MRM data led to testing the isoform interference hypothesis where redundant peptides dilute quantification measurements of homologous proteins. These results show that targeted MRM analysis on non-redundant peptides provides more exact quantification of homologous proteins. This study describes the facile transition from discovery proteomics to targeted MRM analysis and allowed us to identify and verify several potential biomarkers for hESCs during noggin-induced neural and BMP4-induced epidermal ectoderm differentiation.


Gestational Hypothyroxinemia Affects Its Offspring With a Reduced Suppressive Capacity Impairing the Outcome of the Experimental Autoimmune Encephalomyelitis.
Hypothyroxinemia (Hpx) is a thyroid hormone deficiency (THD) condition highly frequent during pregnancy, which although asymptomatic for the mother, it can impair the cognitive function of the offspring. Previous studies have shown that maternal hypothyroidism increases the severity of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model for multiple sclerosis (MS). Here, we analyzed the immune response after EAE induction in the adult offspring gestated in Hpx. Mice gestated in Hpx showed an early appearance of EAE symptoms and the increase of all parameters of the disease such as: the pathological score, spinal cord demyelination, and immune cell infiltration in comparison to the adult offspring gestated in euthyroidism. Isolated CD4+CD25+ T cells from spleen of the offspring gestated in Hpx that suffer EAE showed reduced capacity to suppress proliferation of effector T cells (TEff) after being stimulated with anti-CD3 and anti-CD28 antibodies. Moreover, adoptive transfer experiments of CD4+CD25+ T cells from the offspring gestated in Hpx suffering EAE to mice that were induced with EAE showed that the receptor mice suffer more intense EAE pathological score. Even though, no significant differences were detected in the frequency of Treg cells and IL-10 content in the blood, spleen, and brain between mice gestated in Hpx or euthyroidism, T cells CD4+CD25+ from spleen have reduced capacity to differentiate in vitro to Treg and to produce IL-10. Thus, our data support the notion that maternal Hpx can imprint the immune response of the offspring suffering EAE probably due to a reduced capacity to trigger suppression. Such "imprints" on the immune system could contribute to explaining as to why adult offspring gestated in Hpx suffer earlier and more intense EAE.


[Elective induction of labor using oral PGE2].
100 inductions of labour were attempted in 98 patients by administration of tablets of Prostaglandin E2. 12 inductions were dropped from the study to achieve an homogeneous population of 88 patients filling the criteria of elective induction of labour at term. All these inductions were attempted under electronic monitoring and according to a fixed dosage schedule. Low amniotomy was performed only in presence of advancing labour. Oral prostaglandin E2 successfully induced labour in 92%. The digestive side-effects were the most frequently encountered (34%). 5 cases of uterine hyperstimulation were recorded without fetal repercussion at birth. The procedure was considered safe for the fetus and the newborn as demonstrated by monitoring and clinical evaluation (Apgar score).


NMR study of xenotropic murine leukemia virus-related virus protease in a complex with amprenavir.
Xenotropic murine leukemia virus-related virus (XMRV) is a virus created through recombination of two murine leukemia proviruses under artificial conditions during the passage of human prostate cancer cells in athymic nude mice. The homodimeric protease (PR) of XMRV plays a critical role in the production of functional viral proteins and is a prerequisite for viral replication. We synthesized XMRV PR using the wheat germ cell-free expression system and carried out structural analysis of XMRV PR in a complex with an inhibitor, amprenavir (APV), by means of NMR. Five different combinatorially (15)N-labeled samples were prepared and backbone resonance assignments were made by applying Otting's method, with which the amino acid types of the [(1)H, (15)N] HSQC resonances were automatically identified using the five samples (Wu et al., 2006) [14]. A titration experiment involving APV revealed that one APV molecule binds to one XMRV PR dimer. For many residues, two distinct resonances were observed, which is thought to be due to the structural heterogeneity between the two protomers in the APV:XMRV PR=1:2 complex. PR residues at the interface with APV have been identified on the basis of chemical shift perturbation and identification of the intermolecular NOEs by means of filtered NOE experiments. Interestingly, chemical shift heterogeneity between the two protomers of XMRV PR has been observed not only at the interface with APV but also in regions apart from the interface. This indicates that the structural heterogeneity induced by the asymmetry of the binding of APV to the XMRV PR dimer is transmitted to distant regions. This is in contrast to the case of the APV:HIV-1 PR complex, in which the structural heterogeneity is only localized at the interface. Long-range transmission of the structural change identified for the XMRV PR complex might be utilized for the discovery of a new type of drug.


Pancreatic lipase and its related proteins: where are we now?
Obesity is a disease of epidemic proportions, with a worrisome upward trend. The high consumption of lipids, a major energy source, leads to obesity because of their high calorific value. Pancreatic lipase (PTL), produced by pancreatic acinar cells, hydrolyzes 50-70% of triacylglycerol (TAG) from food. PTL-related protein 1 (PLRP1) and 2 (PLRP2) are also produced by these cells. In vertebrates, PLRP1 has relatively less lipolytic activity, whereas PLRP2 has an essential role in lipid digestion, especially in infants. In this review, we summarize the structure and function of PTL, PLRP1, and PLRP2, and the metabolic fate of PTL inhibitors. We also discuss the current status of clinical trials on orlistat and its combinations for obesity treatment.


Human adult CD34- progenitor cells functionally express the chemokine receptors CCR1, CCR4, CCR7, CXCR5, and CCR10 but not CXCR4.
The homing and tissue-specific recruitment of bone marrow-derived progenitor cells is a major issue in stem cell research and therapy. Chemokine biology plays a central role in the homing and trafficking of leukocytes. Here we show functional expression of the chemokine receptors CCR1, CCR4, CCR7, CCR10, and CXCR5 on primary isolates of CD34- mesenchymal progenitor cells as well as immortalized mesenchymal stem cell (MSC) lines. Although mRNA expression of CXCR4 was detected in both primary cells and immortalized clones, the receptor was not expressed on the cell surface. On the basis of this expression profile, the MSC could potentially home to secondary lymphatic organs (CCR7, CXCR5), skin (CCR4, CCR10), small intestine (CCR10), and salivary glands (CCR10). To study tissue-specific homing, murine CD34- MSC lines showing concordant chemokine receptor expression were either transiently labeled with CMFDA, or were stably transfected with green fluorescent protein (GFP) expression plasmids. The MSC were then injected into syngeneic healthy mice, and the distribution of the cells determined. The injected cells efficiently homed to spleen, thymus, and lymph nodes. In addition, cells were found in the mucosa of the small intestine, skin, and salivary gland. No significant recruitment to bone marrow, liver, or kidney was seen. Chemokine biology may play an important role in the homeostasis and potentially tissue recruitment of early adult progenitor cells.


Do Attitudes Towards Immigrants Matter? The Subjective Wellbeing of Immigrants in England and Wales and Their Exposure to Non-migrants.
The wellbeing of immigrants is affected by those around them and the context in which they live. Yet we still know relatively little about the impact that attitudes towards immigrants (ATI) have on immigrants' life satisfaction, nor do we know the routes by which it manifests. By matching individual data from the UK Understanding Society study to area-level data on ATI for England and Wales from the 2018 European Values Study, I examine whether subnational ATI are associated with immigrants' life satisfaction. If so, I aim to determine the geographical level at which it is prominent and identify the channels through which this association operates. By exploiting the different geographical scales at which ATI are aggregated, I show within-country variation in ATI. Controlling for contextual- and individual-level characteristics, I find that immigrants' wellbeing is sensitive to exposure to the negative ATI of non-migrants at the regional level but not at the municipal level. Theoretically identified channels (local social cohesion and ethnic composition) are not drivers of this association, but it is moderated by (interethnic) friendships. Further, I show that ATI are a measure of environment rather than a function of intergroup contact or exposure and that the entire composition of the ATI in an area is more important than the most negative attitudes. I discuss the implications of these findings.


Direct-to-consumer drug advertisements on network television: an exploration of quantity, frequency, and placement.
Prescription and over-the-counter (OTC) drug advertisements that appear on television are among the most common forms of health communication reaching the U.S. public, but no studies to date have explored the quantity, frequency, or placement of these ads on television. We explored these questions by recording all programs and advertisements that appeared on network television in a southeastern city during a selected week in the summer of 2001 and coding each prescription and OTC drug ad for its frequency, length, and placement by time of day and television program genre. A total of 18,906 ads appeared in the 504-hour sample, including 907 OTC drug ads (4.8%) and 428 prescription (Rx) drug ads (2.3%), which together occupied about 8% of all commercial airtime. Although OTC drug ads were more common, Rx drug ads on average were significantly longer. Direct-to-consumer drug ads appeared most frequently during news programs and soap operas and during the middle-afternoon and early-evening hours. Overall, we found that direct-to-consumer drug advertisements occupy a large percentage of network television commercial advertising and, based on time and program placement, many ads may be targeted specifically at women and older viewers. Our findings suggest that Americans who watch average amounts of television may be exposed to more than 30 hours of direct-to-consumer drug advertisements each year, far surpassing their exposure to other forms of health communication.


Cyclin-dependent kinase E1 (CDKE1) provides a cellular switch in plants between growth and stress responses.
Plants must deal effectively with unfavorable growth conditions that necessitate a coordinated response to integrate cellular signals with mitochondrial retrograde signals. A genetic screen was carried out to identify regulators of alternative oxidase (rao mutants), using AOX1a expression as a model system to study retrograde signaling in plants. Two independent rao1 mutant alleles identified CDKE1 as a central nuclear component integrating mitochondrial retrograde signals with energy signals under stress. CDKE1 is also necessary for responses to general cellular stresses, such as H(2)O(2) and cold that act, at least in part, via anterograde pathways, and integrates signals from central energy/stress sensing kinase signal transduction pathways within the nucleus. Together, these results place CDKE1 as a central kinase integrating diverse cellular signals and shed light on a mechanism by which plants can effectively switch between growth and stress responses.


Response definition criteria for ELISPOT assays revisited.
No consensus has been reached on how to determine if an immune response has been detected based on raw data from an ELISPOT assay. The goal of this paper is to enable investigators to understand and readily implement currently available methods for response determination. We describe empirical and statistical approaches, identifying the strengths and limitations of each approach to allow readers to rationally select and apply a scientifically sound method appropriate to their specific laboratory setting. Five representative approaches were applied to data sets from the CIMT Immunoguiding Program and the response detection and false positive rates were compared. Simulation studies were also performed to compare empirical and statistical approaches. Based on these, we recommend the use of a non-parametric statistical test. Further, we recommend that six medium control wells or four wells each for both medium control and experimental conditions be performed to increase the sensitivity in detecting a response, that replicates with large variation in spot counts be filtered out, and that positive responses arising from experimental spot counts below the estimated limit of detection be interpreted with caution. Moreover, a web-based user interface was developed to allow easy access to the recommended statistical methods. This interface allows the user to upload data from an ELISPOT assay and obtain an output file of the binary responses.


Non-specific gastrointestinal features: Could it be Fabry disease?
Non-specific gastrointestinal symptoms, including pain, diarrhoea, nausea, and vomiting, can be the first symptoms of Fabry disease. They may suggest more common disorders, e.g. irritable bowel syndrome or inflammatory bowel disease. The confounding clinical presentation and rarity of Fabry disease often cause long diagnostic delays and multiple misdiagnoses. Therefore, specialists involved in the clinical evaluation of non-specific upper and lower gastrointestinal symptoms should recognize Fabry disease as a possible cause of the symptoms, and should consider Fabry disease as a possible differential diagnosis. When symptoms or family history suggest Fabry disease, in men, low alpha-galactosidase A enzyme levels, and in women, specific Fabry mutations confirm the diagnosis. In addition to symptomatic treatments, disease-specific enzyme replacement therapy with recombinant human alpha-galactosidase A enzyme or chaperone therapy (migalastat) in patients with amenable mutations can improve the disease, including gastrointestinal symptoms, and should be initiated as early as possible after Fabry disease has been confirmed; starting enzyme replacement therapy at as young an age as possible after diagnosis improves long-term clinical outcomes. Improved diagnostic tools, such as a modified gastrointestinal symptom rating scale, may facilitate diagnosing Fabry disease in patients with gastrointestinal symptoms of unknown cause and thus assure timely initiation of disease-specific treatment.


Diabetes and cancer: Associations, mechanisms, and implications for medical practice.
Both diabetes mellitus and cancer are prevalent diseases worldwide. It is evident that there is a substantial increase in cancer incidence in diabetic patients. Epidemiologic studies have indicated that diabetic patients are at significantly higher risk of common cancers including pancreatic, liver, breast, colorectal, urinary tract, gastric and female reproductive cancers. Mortality due to cancer is moderately increased among patients with diabetes compared with those without. There is increasing evidence that some cancers are associated with diabetes, but the underlying mechanisms of this potential association have not been fully elucidated. Insulin is a potent growth factor that promotes cell proliferation and carcinogenesis directly and/or through insulin-like growth factor 1 (IGF-1). Hyperinsulinemia leads to an increase in the bioactivity of IGF-1 by inhibiting IGF binding protein-1. Hyperglycemia serves as a subordinate plausible explanation of carcinogenesis. High glucose may exert direct and indirect effects upon cancer cells to promote proliferation. Also chronic inflammation is considered as a hallmark of carcinogenesis. The multiple drugs involved in the treatment of diabetes seem to modify the risk of cancer. Screening to detect cancer at an early stage and appropriate treatment of diabetic patients with cancer are important to improve their prognosis. This paper summarizes the associations between diabetes and common cancers, interprets possible mechanisms involved, and addresses implications for medical practice.


In situ cellular hitchhiking of nanoparticles for drug delivery.
Since the inception of the concept of "magic bullet", nanoparticles have evolved to be one of the most effective carriers in drug delivery. Nanoparticles improve the therapeutic efficacy of drugs offering benefits to treating various diseases. Unlike free drugs which freely diffuse and distribute through the body, nanoparticles protect the body from the drug by reducing non-specific interactions while also improving the drug's pharmacokinetics. Despite acquiring some FDA approvals, further clinical application of nanoparticles is majorly hindered by its limited ability to overcome biological barriers resulting in uncontrolled biodistribution and high clearance. The use of cell-inspired systems has emerged as a promising approach to overcome this challenge as cells are biocompatible and have improved access to tissues and organs. One of such is the hitchhiking of nanoparticles to circulating cells such that they are recognized as 'self' components evading clearance and resulting in site-specific drug delivery. In this review, we discuss the concept of nanoparticle cellular hitchhiking, highlighting its advantages, the principles governing the process and the challenges currently limiting its clinical translation. We also discuss in situ hitchhiking as a tool for overcoming these challenges and the considerations to be taken to guide research efforts in advancing this promising technology.


[Locally Advanced Gastric Cancer Responding to Neoadjuvant Chemotherapy with Ramucirumab plus Paclitaxel-Case Report].
Neoadjuvant chemotherapy(NAC)is a promising approach for the improvement of gastric cancer treatment outcome. S-1 plus cisplatin(SP)or S-1 plus oxaliplatin (SOX)is generallythe first choice of NAC regimen. We experienced that NAC with ramucirumab(RAM)plus paclitaxel(PTX)was effective in locallyadvanced gastric cancer, but that with SOX was ineffective. A 68-year-old man developed locallyadvanced gastric cancer and received NAC with SOX, which was stopped because of tumor enlargement. The patient was then given NAC with RAM plus PTX, which was effective and enabled radical excision. Anti-angiogenic agents maycause wound healing complications, which mayincrease the risk of leakage. However, he was discharged without postoperative complications. Therefore, RAM plus PTX can be a promising NAC regimen for locallyadvanced gastric cancer.


Fundus autofluorescence and optical coherence tomography findings in glutathione synthetase deficiency.
We report the autofluorescence pattern and optical coherence tomography (OCT) characteristics in a 6-year-old boy with glutathione synthetase deficiency. The patient underwent complete ophthalmological examination, including full-field electroretinography, visual evoked potentials, fundus autofluorescence, and OCT imaging. Electrophysiological studies showed time-delay and subnormal responses. Fundus autofluorescence imaging revealed increased parafoveal autofluorescence compared to normal, and OCT showed alteration of photoreceptor and retinal pigment epithelium layers in the parafoveal region.


Repetitive health examinations as an intervention measure.
A cohort of 107 men aged 51-53 years with borderline levels of blood pressure, serum cholesterol, or glucose tolerance was recruited from a general population in central Zagreb, Yugoslavia, and randomized into two groups; one was treated with drugs and the other observed in a similar fashion but not treated. Ninety-five men appeared regularly for the check-ups over a 2-year period. Levels of systolic blood pressure, cholesterol, and glucose showed a substantial decrease over a period of 2 years in both treated and control groups. The possible effect of repeated check-ups and their implications are discussed.


Why to smoke? Why not to smoke? Major reasons for children's decisions on whether or not to smoke.
This study, aimed at the primary prevention of smoking behaviour in children and adolescents, attempts to find the main factors that distinguish smokers and non-smokers in the period of their first experimentation with cigarettes. There are only a few studies dealing with investigations into current motivations of teenagers as to whether or not to smoke. The programme entitled "Normal is not to smoke", using evaluation questionnaires given to children in the 3rd and 5th classes, also contains--among many other things--specifics on reasons children have for making the decision whether to become a smoker or non-smoker. The results are reported in this paper. Responses concerning potential inclination to smoking that were collected from children on the basis of questionnaires were categorized into the following groups: image, the influence of a role model, the effects of smoking, curiosity. Reasons for non-smoking were categorized into the following groups: health, aesthetic, economic, restrictive, other aspects. Children were also asked to describe smokers by using three pairs of opposite characteristics: education, success, wealth. The frequencies of answers were analysed for the whole set, for boys and girls and for children with different smoking behaviour; the differences were evaluated using the statistical programme EPI INFO, version 6. A total of 1153 children in the 3rd class and 799 children in the 5th class completed the questionnaire. Motivations for smoking were given by nearly 17% of children in the 3rd class and by nearly 27% of the same cohort in the 5th class. Aspects such as image (41.9% vs. 46.2%) were mentioned most frequently, by boys more frequently than by girls (OR 1.77; 95% CI 0.93-3.36; p = 0.06), by children from smokers' families more frequently than by children from non-smokers' families (OR 1.33; 95% CI 0.69-2.57; p = 0.3) and more frequently by children with repeated attempts to smoke (OR 3.93; 95% CI 2.32-6.65) or children who had only had a single smoking attempt (OR 3.18; 95% CI 1.52-6.75). Also the role of models (parents, relatives, friends) was often mentioned (12.9% in the 3rd class and 10.2% in the 5th class). Potential beneficial effects of smoking were expressed by 13% of children in the 3rd class and by 55% of children in the 5th class (p < 0.0001). About 40% of children considered smoking as effective coping with stress and about 20% of them declared smoking for mood improvement. Beneficial effects of smoking significantly more often described children with repeated smoking attempts (OR 2.91; 95% CI 1.73-4.89; p < 0.001). Children often linked smoking to the less educated and less successful social groups but also to the rich. In both investigations, health aspects were the most common reasons for choosing not to smoke (69.2% vs. 73.3%), being more frequently presented by girls and non-smokers. A significant shift in the negative aesthetic perception of smoking (14.1% in the 3rd class vs. 40.2% in the 5th class) and economic disadvantages of smoking (3.9% vs. 24.8%) was observed in the given period of time. Restrictive reasons were given only rarely by pupils in the 3rd class (0.7%), unlike pupils in the 5th class who feared the reaction of their parents (24.8%). Our study provides an overview of current motivations in children aged 9 and 11 years that are crucial for their future smoking/nonsmoking behaviour. The results of the study are important for developing a strategy for the primary prevention of smoking in school programmes and for introducing a general social approach to address the problem of the decreasing age of smoking initiation.