Findings from a pilot randomised trial of a social network self-management intervention in COPD.
Self-Management Support (SMS), refers to the actions taken by individuals to recognise and manage their own health. It is increasingly recognised that individuals with chronic obstructive pulmonary disease (COPD) require additional support with their Self-management. Emerging evidence suggests that the use of a social network intervention can improve health outcomes and increase quality of life. In order to understand the potential benefits of SMS in COPD, the GENIE (Generating Engagement in Network Support) SMS tool was implemented and evaluated in a COPD primary care context. The GENIE intervention is a social networking tool that consists of 3 parts; a concentric circle modelling to map existing social networks; a questions sections to elicit preferences for activities; a map of selected resources is then produced, aligned with the user's interests and suggestions for connections to existing network members and to new resources. A pilot, parallel, single blind, block randomised controlled trial. Patients with COPD ranging from mild-very severe were recruited. Participants provided written consent and were then randomised to either the intervention or usual care. The primary aim was to understand the clinical benefit through the analysis of health status, symptom burden and quality of life. The secondary outcome measure was health utilisation. NHS cost differences were reported between groups using the GENIE intervention over usual care. The GENIE pilot results demonstrate maintenance in health status and clinical symptoms with a decrease in anxiety. An overall increase in quality of life was observed, these findings did not reach significance. A cost reduction was demonstrated in inpatient stay with no difference in primary care costs. Overall a cost reduction in NHS service utilisation was indicated in the intervention group. This pilot study indicated that using a social network intervention can encourage the development of new social connections and extend existing support networks for COPD patients. Increasing network support in this population is of benefit to both patients and NHS providers in terms of cost reductions and enhancing wellbeing. This broadens the understanding of possible new approaches to SMS in community COPD patients, which could now be investigated in a larger population over a longer period. Clinical Trials.gov PRS National Library of Medicine. Protocol ID number: 19175, Clinical Trial ID: NCT02935452.


Epitaxial growth of aligned atomically precise chevron graphene nanoribbons on Cu(111).
Atomically precise chevron graphene nanoribbons (GNRs) have been synthesized on Cu(111) substrates by the surface-assisted coupling of 6,11-dibromo-1,2,3,4-tetraphenyltriphenylene (C42Br2H26) and thermal cyclodehydrogenation of the resulting polymer. The GNRs form on Cu(111) epitaxially along the 〈112〉 crystallographic directions, which was found to be in agreement with the computational results, and at lower temperatures than on Au(111). This work demonstrates that the substrate plays an important role in the on-surface synthesis of GNRs and can result in new assembly modes of GNR structures.


Increasing N abundance in the northwestern Pacific Ocean due to atmospheric nitrogen deposition.
The relative abundance of nitrate (N) over phosphorus (P) has increased over the period since 1980 in the marginal seas bordering the northwestern Pacific Ocean, located downstream of the populated and industrialized Asian continent. The increase in N availability within the study area was mainly driven by increasing N concentrations and was most likely due to deposition of pollutant nitrogen from atmospheric sources. Atmospheric nitrogen deposition had a high temporal correlation with N availability in the study area (r = 0.74 to 0.88), except in selected areas wherein riverine nitrogen load may be of equal importance. The increase in N availability caused by atmospheric deposition and riverine input has switched extensive parts of the study area from being N-limited to P-limited.


Assessment of Mitral Paravalvular Leakage After Mitral Valve Replacement Using Cardiac Computed Tomography: Comparison With Surgical Findings.
The diagnostic performance of cardiac computed tomography (CT) for detection of paravalvular leakage (PVL) after mitral valve replacement has not been investigated in a large population. We aimed to investigate the diagnostic accuracy of CT for diagnosis of mitral PVL using surgical findings as the standard reference and to compare the diagnostic performance of CT with those of transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE). A total of 204 patients with previous mitral valve replacement who underwent cardiac CT were retrospectively included. The presence of mitral PVL was analyzed on CT, TTE, and TEE. In 78 patients who underwent redo-surgery, diagnostic performance for the detection of PVL for CT, TTE, and TEE were compared with surgical findings as the standard reference. The location of mitral PVL on CT and TEE was compared with surgical findings. Mitral PVL was present in 18.1% (37/204) on CT, in 16.2% (32/198) on TTE, and in 42.6% (29/68) on TEE. On the surgical field, PVL was identified in 41.0% (32/78). The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for detection of PVL were 96.9%, 97.8%, 96.9%, 97.8%, and 97.4% for CT; 81.3%, 95.6%, 92.9%, 87.8%, and 89.6% for TTE; and 96.2%, 95.8%, 96.2%, 95.8%, and 96.0% for TEE. CT and TEE identified the correct location of PVL in 75.9% (22/29) and 85.6% (19/23). Cardiac CT may have better diagnostic accuracy compared with TTE for the detection of mitral PVL and may be comparable to TEE for the detection and localization of PVL.


Which dogs with appendicular osteosarcoma benefit most from chemotherapy after surgery? Results from an individual patient data meta-analysis.
Osteosarcoma (OS) is a malignant tumor of mesenchymal origin that produces osteoid. Given that the prognosis can vary considerably between dogs, we aimed to explore whether treatment could be tailored towards patient subgroups, characterized by their predicted risk of mortality. For the current study, a subset of five nonrandomized studies (400 subjects of whom 88 were dead at 5 months follow-up) was used from a previously published 20 study individual patient data meta-analysis. Missing data was dependent on observed variables and was imputed to correct for this dependency. Based on a previously published multivariable prognostic model, the 5-month mortality risk was predicted. Subsequently, in surgically treated dogs, using a logistic regression model with a random intercept for a study indicator, we explored whether chemotherapy effectiveness depended on predicted 5-month mortality risk. After adjustment for potential confounders the main effect of any chemotherapy was 0.48 (odds ratio) (95%CI 0.30; 0.78). Testing for chemotherapy by predicted 5-month mortality risk interaction revealed that the effects of any chemotherapy decreased with increasing predicted risk; interaction OR 3.41 (1.07; 10.84). Results from individually comparing carboplatin, cisplatin, doxorubicin and doxorubicin combination therapy to no chemotherapy, were similar in magnitude and direction. These results indicate that the main treatment effects of chemotherapy do not necessarily apply to all patients.


Application of recent advances in aerosol sampling science towards the development of improved sampling devices: the way ahead.
This paper reviews the framework that underpins the development of a new generation of personal samplers capable of operating at much lower flowrates that those of the current generation and so capable of being used for exposure assessment not only for 'traditional' occupational populations (i.e., industrial workers) but also for people exposed to aerosols in the ambient atmosphere (including children). The opportunity for this new generation of samplers stems from the availability of very light and compact low-flowrate pumps. The development and deployment of such instruments presents: (a) physical challenges in terms of how to collect particle size fractions in a manner which is consistent with the new particle size-selective sampling criteria, and (b) analytical challenges in terms of how to quantitate the much smaller amounts of collected material that need to be analysed. The paper lays out the physical and analytical scenarios, and points the way forward to how such challenges can be overcome. Work is already in progress in several countries to develop prototype instruments for applications like those described.


Energy loss mechanisms of superconductors used in alternating-current power transmission systems.
The intrinsic hysteretic loss of superconductors carrying alternating current has been derived from simple models and verified experimentally. In practical cable designs the losses are increased by surface roughness, conductor configuration, and added metallic components. When possible applications by electric utility companies are being considered, such losses are only one of many factors that must be adjusted in an optimization that produces the lowest cost(including both capital and operating expenses) during the lifetime of the system.


Positive selection of deleterious alleles through interaction with a sex-ratio suppressor gene in African Buffalo: a plausible new mechanism for a high frequency anomaly.
Although generally rare, deleterious alleles can become common through genetic drift, hitchhiking or reductions in selective constraints. Here we present a possible new mechanism that explains the attainment of high frequencies of deleterious alleles in the African buffalo (Syncerus caffer) population of Kruger National Park, through positive selection of these alleles that is ultimately driven by a sex-ratio suppressor. We have previously shown that one in four Kruger buffalo has a Y-chromosome profile that, despite being associated with low body condition, appears to impart a relative reproductive advantage, and which is stably maintained through a sex-ratio suppressor. Apparently, this sex-ratio suppressor prevents fertility reduction that generally accompanies sex-ratio distortion. We hypothesize that this body-condition-associated reproductive advantage increases the fitness of alleles that negatively affect male body condition, causing genome-wide positive selection of these alleles. To investigate this we genotyped 459 buffalo using 17 autosomal microsatellites. By correlating heterozygosity with body condition (heterozygosity-fitness correlations), we found that most microsatellites were associated with one of two gene types: one with elevated frequencies of deleterious alleles that have a negative effect on body condition, irrespective of sex; the other with elevated frequencies of sexually antagonistic alleles that are negative for male body condition but positive for female body condition. Positive selection and a direct association with a Y-chromosomal sex-ratio suppressor are indicated, respectively, by allele clines and by relatively high numbers of homozygous deleterious alleles among sex-ratio suppressor carriers. This study, which employs novel statistical techniques to analyse heterozygosity-fitness correlations, is the first to demonstrate the abundance of sexually-antagonistic genes in a natural mammal population. It also has important implications for our understanding not only of the evolutionary and ecological dynamics of sex-ratio distorters and suppressors, but also of the functioning of deleterious and sexually-antagonistic alleles, and their impact on population viability.


Effects of Sublethal Doses of Herbicides on the Competitive Interactions Between 2 Nontarget Plants, Centaurea cyanus L. and Silene noctiflora L.
Plant competitive interactions influence the effect of herbicides, and the effect of competitive interactions on plant responses may be important to include in the ecological risk assessment of herbicides. In the present study the effect of competitive interactions and sublethal doses of 2 herbicides on plant species was investigated in competition experiments and fitted to empirical competition models. Two nontarget species commonly found in agroecosystems (Centaurea cyanus L. and Silene noctiflora L.) and 2 herbicides (glyphosate and metsulfuron methyl) were used in separate experiments. Plants were sprayed at the 6- to 8-leaf stage. Effects of herbicide treatments and plant density were modeled by generalization of a discrete hyperbolic competition model. The 10% effective dose (ED10) was calculated for C. cyanus. All experiments showed that as density increased, plants were negatively affected. Furthermore, in all cases, C. cyanus remained a better competitor than S. noctiflora. Nevertheless, the density of S. noctiflora (competitor) was an influential element in determining the ED10 of C. cyanus measured at the mature stage. With herbicide exposure, the competitive interactions were further altered; C. cyanus was less affected by glyphosate when S. noctiflora increased to high density. In contrast, at the young stage, conspecific density was important in determining the sensitivity of C. cyanus to metsulfuron methyl, whereas the density of the competitor S. noctiflora had a limited influence. Overall, the results demonstrate the importance of integrating the effect of herbicide and species interactions measured at the reproductive stage into the ecological risk assessments of pesticides. Environ Toxicol Chem 2019;38:2053-2064. © 2019 SETAC.


Rice bran constituents: immunomodulatory and therapeutic activities.
Rice bran, one of the most abundant and valuable byproducts produced during the rice milling process, is of steadily growing interest in recent years due to its potential health benefits. Evidence is rapidly accumulating for the beneficial effects of nutraceuticals. However, the potential benefits of rice bran are found in several of its bioactive ingredients including oils, polysaccharides, proteins, and micronutrients. In addition, a significant advantage of rice bran is that it contains more than 100 antioxidants and several categories of bioactive phytonutrients, such as polyphenols, phytosterols, tocotrienols, γ-oryzanol, B vitamins, minerals, and trace minerals. As an immunomodulator, rice bran has beneficial constituents such as polysaccharides, proteins, and oils. Numerous studies also reported that potent antioxidants in rice bran included immune system enhancing compounds, such as phytosterols, polysaccharides, minerals and trace minerals including magnesium, selenium, zinc, vitamin E, omega-3 fatty acids and several other phytonutrients. We believe that this review will be a valuable resource for more studies on rice barn as a dietary source.


Plant-produced idiotype vaccines for the treatment of non-Hodgkin's lymphoma: safety and immunogenicity in a phase I clinical study.
Plant-made vaccines have been the subject of intense interest because they can be produced economically in large scale without the use of animal-derived components. Plant-made therapeutic vaccines against challenging chronic diseases, such as cancer, have received little research attention, and no previous human clinical trials have been conducted in this vaccine category. We document the feasibility of using a plant viral expression system to produce personalized (patient-specific) recombinant idiotype vaccines against follicular B cell lymphoma and the results of administering these vaccines to lymphoma patients in a phase I safety and immunogenicity clinical trial. The system allowed rapid production and recovery of idiotypic single-chain antibodies (scFv) derived from each patient's tumor and immunization of patients with their own individual therapeutic antigen. Both low and high doses of vaccines, administered alone or co-administered with the adjuvant GM-CSF, were well tolerated with no serious adverse events. A majority (>70%) of the patients developed cellular or humoral immune responses, and 47% of the patients developed antigen-specific responses. Because 15 of 16 vaccines were glycosylated in plants, this study also shows that variation in patterns of antigen glycosylation do not impair the immunogenicity or affect the safety of the vaccines. Collectively, these findings support the conclusion that plant-produced idiotype vaccines are feasible to produce, safe to administer, and a viable option for idiotype-specific immune therapy in follicular lymphoma patients.


American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part I--evidence assessment.
Opioid abuse has continued to increase at an alarming rate since the 1990 s. As documented by different medical specialties, medical boards, advocacy groups, and the Drug Enforcement Administration, available evidence suggests a wide variance in chronic opioid therapy of 90 days or longer in chronic non-cancer pain. Part 1 describes evidence assessment. The objectives of opioid guidelines as issued by the American Society of Interventional Pain Physicians (ASIPP) are to provide guidance for the use of opioids for the treatment of chronic non-cancer pain, to produce consistency in the application of an opioid philosophy among the many diverse groups involved, to improve the treatment of chronic non-cancer pain, and to reduce the incidence of abuse and drug diversion. The focus of these guidelines is to curtail the abuse of opioids without jeopardizing non-cancer pain management with opioids. 1) There is good evidence that non-medical use of opioids is extensive; one-third of chronic pain patients may not use prescribed opioids as prescribed or may abuse them, and illicit drug use is significantly higher in these patients. 2) There is good evidence that opioid prescriptions are increasing rapidly, as the majority of prescriptions are from non-pain physicians, many patients are on long-acting opioids, and many patients are provided with combinations of long-acting and short-acting opioids. 3) There is good evidence that the increased supply of opioids, use of high dose opioids, doctor shoppers, and patients with multiple comorbid factors contribute to the majority of the fatalities. 4) There is fair evidence that long-acting opioids and a combination of long-acting and short-acting opioids contribute to increasing fatalities and that even low-doses of 40 mg or 50 mg of daily morphine equivalent doses may be responsible for emergency room admissions with overdoses and deaths. 5) There is good evidence that approximately 60% of fatalities originate from opioids prescribed within the guidelines, with approximately 40% of fatalities occurring in 10% of drug abusers. 6) The short-term effectiveness of opioids is fair, whereas the long-term effectiveness of opioids is limited due to a lack of long-term (> 3 months) high quality studies, with fair evidence with no significant difference between long-acting and short-acting opioids. 7) Among the individual drugs, most opioids have fair evidence for short-term and limited evidence for long-term due to a lack of quality studies. 8) The evidence for the effectiveness and safety of chronic opioid therapy in the elderly for chronic non-cancer pain is fair for short-term and limited for long-term due to lack of high quality studies; limited in children and adolescents and patients with comorbid psychological disorders due to lack of quality studies; and the evidence is poor in pregnant women. 9) There is limited evidence for reliability and accuracy of screening tests for opioid abuse due to lack of high quality studies. 10) There is fair evidence to support the identification of patients who are non-compliant or abusing prescription drugs or illicit drugs through urine drug testing and prescription drug monitoring programs, both of which can reduce prescription drug abuse or doctor shopping. The guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a "standard of care."


Venom collection and analysis in the pseudoscorpion Chelifer cancroides (Pseudoscorpiones: Cheliferidae).
Pseudoscorpions are very small arthropods with almost worldwide distribution. They possess a unique venom delivery system in the chelal hands of their pedipalps that has evolved independently from that of scorpions and spiders. Studies on the venom composition of pseudoscorpions are very rare. Recently, the potential venom composition of the pseudoscorpion Synsphyronus apimelus Harvey, 1987 (Pseudoscorpiones: Garypidae) has been studied by transcriptome analysis. However, a proteome analysis of venom to identify the genuine venom compounds of pseudoscorpions has not yet been performed. In our study, we have developed a non-invasive approach for extracting minute amounts of venom, which for the first time allowed collecting pure venom samples of pseudoscorpions with minimal contaminations and high reproducibility. These experiments first required a morphological investigation of the venom delivery system with a focus on the role of the lamina defensor in the release of venom. Likely, the venom delivery system of pseudoscorpions has a mechanism that prevents the release of venom if the prey is not successfully penetrated by a venom tooth. Electrical stimulation of a gland-containing chelal hand in combination with a mechanical stimulation of the lamina defensor at the base of the venom tooth resulted in an average of 5 nl of collected venom. The utility of the method was then validated by repeated venom extractions and subsequent analysis of the venom composition using MALDI-TOF mass fingerprinting. Subsequent proteomics analysis in combination with transcriptome analyses of chelal hand tissue has identified the first genuine venom compounds of pseudoscorpions with putative antimicrobial peptides. For our experiments, we used the house pseudoscorpion Chelifer cancroides (Linnaeus, 1758) (Pseudoscorpiones: Cheliferidae).


Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung.
Mice with a functional human immune system have the potential to allow in vivo studies of human infectious diseases and to enable vaccine testing. To this end, mice need to fully support the development of human immune cells, allow infection with human pathogens, and be capable of mounting effective human immune responses. A major limitation of humanized mice is the poor development and function of human myeloid cells and the absence of human immune responses at mucosal surfaces, such as the lung. To overcome this, we generated human IL-3/GM-CSF knock-in (hIL-3/GM-CSF KI) mice. These mice faithfully expressed human GM-CSF and IL-3 and developed pulmonary alveolar proteinosis because of elimination of mouse GM-CSF. We demonstrate that hIL-3/GM-CSF KI mice engrafted with human CD34(+) hematopoietic cells had improved human myeloid cell reconstitution in the lung. In particular, hIL-3/GM-CSF KI mice supported the development of human alveolar macrophages that partially rescued the pulmonary alveolar proteinosis syndrome. Moreover, human alveolar macrophages mounted correlates of a human innate immune response against influenza virus. The hIL-3/GM-CSF KI mice represent a unique mouse model that permits the study of human mucosal immune responses to lung pathogens.


Protocolized versus non-protocolized weaning for reducing the duration of mechanical ventilation in critically ill adult patients.
This is an update of a review last published in Issue 5, 2010, of The Cochrane Library. Reducing weaning time is desirable in minimizing potential complications from mechanical ventilation. Standardized weaning protocols are purported to reduce time spent on mechanical ventilation. However, evidence supporting their use in clinical practice is inconsistent. The first objective of this review was to compare the total duration of mechanical ventilation of critically ill adults who were weaned using protocols versus usual (non-protocolized) practice.The second objective was to ascertain differences between protocolized and non-protocolized weaning in outcomes measuring weaning duration, harm (adverse events) and resource use (intensive care unit (ICU) and hospital length of stay, cost).The third objective was to explore, using subgroup analyses, variations in outcomes by type of ICU, type of protocol and approach to delivering the protocol (professional-led or computer-driven). We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2014), MEDLINE (1950 to January 2014), EMBASE (1988 to January 2014), CINAHL (1937 to January 2014), LILACS (1982 to January 2014), ISI Web of Science and ISI Conference Proceedings (1970 to February 2014), and reference lists of articles. We did not apply language restrictions. The original search was performed in January 2010 and updated in January 2014. We included randomized controlled trials (RCTs) and quasi-RCTs of protocolized weaning versus non-protocolized weaning from mechanical ventilation in critically ill adults. Two authors independently assessed trial quality and extracted data. We performed a priori subgroup and sensitivity analyses. We contacted study authors for additional information. We included 17 trials (with 2434 patients) in this updated review. The original review included 11 trials. The total geometric mean duration of mechanical ventilation in the protocolized weaning group was on average reduced by 26% compared with the usual care group (N = 14 trials, 95% confidence interval (CI) 13% to 37%, P = 0.0002). Reductions were most likely to occur in medical, surgical and mixed ICUs, but not in neurosurgical ICUs. Weaning duration was reduced by 70% (N = 8 trials, 95% CI 27% to 88%, P = 0.009); and ICU length of stay by 11% (N = 9 trials, 95% CI 3% to 19%, P = 0.01). There was significant heterogeneity among studies for total duration of mechanical ventilation (I(2) = 67%, P < 0.0001) and weaning duration (I(2) = 97%, P < 0.00001), which could not be explained by subgroup analyses based on type of unit or type of approach. There is evidence of reduced duration of mechanical ventilation, weaning duration and ICU length of stay with use of standardized weaning protocols. Reductions are most likely to occur in medical, surgical and mixed ICUs, but not in neurosurgical ICUs. However, significant heterogeneity among studies indicates caution in generalizing results. Some study authors suggest that organizational context may influence outcomes, however these factors were not considered in all included studies and could not be evaluated. Future trials should consider an evaluation of the process of intervention delivery to distinguish between intervention and implementation effects. There is an important need for further development and research in the neurosurgical population.


Pregnancy-associated outcomes in women who spent some of their childhood looked after by local authorities: findings from the UK Millennium Cohort Study.
There has been very little description of the health and social outcomes at pregnancy and early motherhood of girls who were previously looked after by local authorities. The objectives of this study were to compare the sociodemographic and health profiles of mothers who had spent time in a children's home or with foster parents as a child to mothers who had not. In particular, to examine associations between being looked after and the likelihood of smoking during pregnancy, birth weight, the presence of symptoms of maternal depression and the initiation of breastfeeding. A retrospective cross-sectional study using the baseline questionnaire of the Millennium Cohort Study. The UK. A nationally representative study of 18,492 mothers of babies born in the UK during 2000-2002. A history of spending time in a children's home or with foster parents. (1) Smoking during pregnancy; (2) low birth weight; (3) symptoms of maternal depression and (4) initiation of breastfeeding. In univariable analyses, women who had been looked after by local authorities were significantly less likely to be of a higher social class, live in a high-income household or have achieved a high level of education. They were more likely to have a low-birthweight baby and be a single parent. In multivariable analyses, women who had been looked after by local authorities were more likely to smoke during pregnancy (adjusted OR 3.0 95% CI 2.14 to 4.3) and were more likely to have symptoms of depression (adjusted OR 1.98 95% CI 1.4 to 2.7) compared with women who had not been looked after. Our results suggest that these women carry social disadvantage into motherhood, with the potential of continuing the cycle of deprivation. There is a case for increasing our attention on this group, which can be readily accessed by maternity and early years' services.


Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4-1.1/Kvbeta1.1 and Kv1.4-1.1/Kvbeta1.2.
Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by constant muscle rippling movements (myokymia) and episodic attacks of ataxia. Several heterozygous point mutations have been found in the coding sequence of the voltage-gated potassium channel gene KCNA1 (hKv1.1), which alter the delayed-rectifier function of the channel. Shaker-like channels of different cell types may be formed by unique hetero-oligomeric complexes comprising Kv1.1, Kv1.4 and Kvbeta1.x subunits. Here we show that the human Kvbeta1.1 and Kvbeta1.2 subunits modulated the functional properties of tandemly linked Kv1.4-1.1 wild-type channels expressed in Xenopus laevis oocytes by (i) increasing the rate and amount of N-type inactivation, (ii) slowing the recovery rate from inactivation, (iii) accelerating the cumulative inactivation of the channel and (iv) negatively shifting the voltage dependence of inactivation. To date, the role of the human Kv1.4-1.1, Kv1.4-1.1/Kvbeta1.1 and Kv1.4-1.1/Kvbeta1.2 channels in the aetiopathogenesis of EA1 has not been investigated. Here we also show that the EA1 mutations E325D, V404I and V408A, which line the ion-conducting pore, and I177N, which resides within the S1 segment, alter the fast inactivation and repriming properties of the channels by decreasing both the rate and degree of N-type inactivation and by accelerating the recovery from fast inactivation. Furthermore, the E325D, V404I and I177N mutations shifted the voltage dependence of the steady-state inactivation to more positive potentials. The results demonstrate that the human Kvbeta1.1 and Kvbeta1.2 subunits regulate the proportion of wild-type Kv1.4-1.1 channels that are available to open. Furthermore, EA1 mutations alter heteromeric channel availability which probably modifies the integration properties and firing patterns of neurones controlling cognitive processes and body movements.


Palladium-catalyzed cross-coupling reaction of triorganoindium reagents with propargylic esters.
[reaction: see text] Triorganoindium reagents (R(3)In) react with propargylic esters under palladium catalysis via an S(N)2' rearrangement to afford allenes in good yields and with high regioselectivity. The reaction proceeds smoothly at room temperature with a variety of R(3)In (aryl, alkenyl, alkynyl, and methyl). When chiral, nonracemic propargylic esters are employed, the reaction takes place with high anti-stereoselectivity providing allenes with high enantiomeric excess.


Benign vs malignant soft tissue neoplasms: limitations of magnetic resonance imaging.
Various features have been described in the literature to differentiate benign from malignant lesions. The aim of the present study was to study the accuracy of each of these features and that of magnetic resonance imaging (MRI) in diagnosing malignant lesions. Fifty-five consecutive patients presenting with neoplastic (both benign and malignant) lesions diagnosed clinically and on ultrasound were studied and their MRI features were compared with the findings on surgical exploration and histopathologic examination. There were 32 (58%) benign and 23 (42%) malignant masses. Malignant masses were more common in patients older than 20 years (83%), and these had symptoms of less than 6 months duration (75%), as against benign lesions. The swelling was painful in 8 malignant masses and these were more common in the upper limbs (61%). Various features of malignant lesions were size more than 5 cm in 83%, change in signal intensity from homogenous on T1-weighted images to heterogenous on T2-weighted images in 74%, irregular margins in 74%, and heterogenous contrast enhancement in 91%. The accuracy of these features was 76%, 58%, 78%, and 60%, respectively. Most benign and malignant lesions were intramuscular in location. A significant number (38%) of benign lesions were located in the intermuscular facial plane. Definitive diagnosis was made in 42% of the lesions. MRI is an excellent modality for evaluating soft tissue neoplasms; however, prediction of a specific diagnosis and differentiation of malignant and benign lesions is not always possible.


Physically demanding workloads and the risks of musculoskeletal disorders in homecare workers in the USA.
Although musculoskeletal disorders (MSDs) are prevalent among homecare workers, little is known about the MSD risk factors. This study investigated whether physically demanding workloads among homecare workers are related to MSDs, especially in neck, shoulder and back pain. Data were taken from two waves of a random sample (June to December 2003 and December 2003 to February 2004). The sample included 1643 homecare workers at Wave 1 and 1198 homecare workers at Wave 2, respectively. A basic telephone interview and 30 minutes computer-assisted interview were performed for homecare workers in Wave 1 and Wave 2. The prevalence of neck, shoulder and back MSDs was assessed at Wave 1 and Wave 2 using the Nordic questionnaire of musculoskeletal symptoms. The incidence of MSDs at 6 months was estimated at Wave 2 using only those who were in the asymptomatic reference group at Wave 1 as the denominator. At Wave 1, back MSDs were the most prevalent (10.2%), followed by neck (9.6%) and shoulder (7.1%) MSDs. After 6 months, the incidence of neck MSDs was the highest (7.0%), followed by back (6.4%) and shoulder (4.8%) MSDs. Physical demands of work were assessed using items developed from focus groups of workers. When compared with asymptomatic workers, those with MSDs showed a dose-response effect for physical job demands. After controlling for age, psychosocial demands and social support on-the-job, physical demands among homecare workers were significantly associated with an excessive odds of neck, shoulder and back MSDs incident at 6 months (odds ratios of 1.14-1.17 for each unit increase on a physical demand scale). Our study shows that the physical demands of work are a significant risk factor for MSDs among homecare workers. Considering the high physical demands among homecare workers, the finding in this study clearly indicates that practical intervention strategies should be implemented to protect homecare workers from exposure to MSD risk factors.


Mortality after acute renal failure: models for prognostic stratification and risk adjustment.
To adjust adequately for comorbidity and severity of illness in quality improvement efforts and prospective clinical trials, predictors of death after acute renal failure (ARF) must be accurately identified. Most epidemiological studies of ARF in the critically ill have been based at single centers, or have examined exposures at single time points using discrete outcomes (e.g., in-hospital mortality). We analyzed data from the Program to Improve Care in Acute Renal Disease (PICARD), a multi-center observational study of ARF. We determined correlates of mortality in 618 patients with ARF in intensive care units using three distinct analytic approaches. The predictive power of models using information obtained on the day of ARF diagnosis was extremely low. At the time of consultation, advanced age, oliguria, hepatic failure, respiratory failure, sepsis, and thrombocytopenia were associated with mortality. Upon initiation of dialysis for ARF, advanced age, hepatic failure, respiratory failure, sepsis, and thrombocytopenia were associated with mortality; higher blood urea nitrogen and lower serum creatinine were also associated with mortality in logistic regression models. Models incorporating time-varying covariates enhanced predictive power by reducing misclassification and incorporating day-to-day changes in extra-renal organ system failure and the provision of dialysis during the course of ARF. Using data from the PICARD multi-center cohort study of ARF in critically ill patients, we developed several predictive models for prognostic stratification and risk-adjustment. By incorporating exposures over time, the discriminatory power of predictive models in ARF can be significantly improved.


Diffusion tensor imaging at 3 hours after traumatic spinal cord injury predicts long-term locomotor recovery.
Accurate diagnosis of spinal cord injury (SCI) severity must be achieved before highly aggressive experimental therapies can be tested responsibly in the early phases after trauma. These studies demonstrate for the first time that axial diffusivity (lambda||), derived from diffusion tensor imaging (DTI) within 3 h after SCI, accurately predicts long-term locomotor behavioral recovery in mice. Female C57BL/6 mice underwent sham laminectomy or graded contusive spinal cord injuries at the T9 vertebral level (5 groups, n = 8 for each group). In-vivo DTI examinations were performed immediately after SCI. Longitudinal measurements of hindlimb locomotor recovery were obtained using the Basso mouse scale (BMS). Injured and spared regions of ventrolateral white matter (VLWM) were reliably separated in the hyperacute phase by threshold segmentation. Measurements of lambda|| were compared with histology in the hyperacute phase and 14 days after injury. The spared normal VLWM determined by hyperacute lambda|| and 14-day histology correlated well (r = 0.95). A strong correlation between hindlimb locomotor function recovery and lambda||-determined spared normal VLWM was also observed. The odds of significant locomotor recovery increased by 18% with each 1% increase in normal VLWM measured in the hyperacute phase (odds ratio = 1.18, p = 0.037). The capability of measuring subclinical changes in spinal cord physiology and murine genetic advantages offer an early window into the basic mechanisms of SCI that was not previously possible. Although significant obstacles must still be overcome to derive similar data in human patients, the path to clinical translation is foreseeable and achievable.


Systolic Blood Pressure Control Among Individuals With Type 2 Diabetes: A Comparative Effectiveness Analysis of Three Interventions.
The relative effectiveness of 3 approaches to blood pressure control-(i) an intensive lifestyle intervention (ILI) focused on weight loss, (ii) frequent goal-based monitoring of blood pressure with pharmacological management, and (iii) education and support-has not been established among overweight and obese adults with type 2 diabetes who are appropriate for each intervention. Participants from the Action for Health in Diabetes (Look AHEAD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) cohorts who met criteria for both clinical trials were identified. The proportions of these individuals with systolic blood pressure (SBP) <140 mm Hg from annual standardized assessments over time were compared with generalized estimating equations. Across 4 years among 480 Look AHEAD and 1,129 ACCORD participants with baseline SBPs between 130 and 159 mm Hg, ILI (OR = 1.46; 95% CI = [1.18-1.81]) and frequent goal-based monitoring with pharmacotherapy (OR = 1.51; 95% CI = [1.16-1.97]) yielded higher rates of blood pressure control compared to education and support. The intensive behavioral-based intervention may have been more effective among individuals with body mass index >30 kg/m2, while frequent goal-based monitoring with medication management may be more effective among individuals with lower body mass index (interaction P = 0.047). Among overweight and obese adults with type 2 diabetes, both ILI and frequent goal-based monitoring with pharmacological management can be successful strategies for blood pressure control. clinicaltrials.gov identifiers NCT00017953 (Look AHEAD) and NCT00000620 (ACCORD).


Prevalence of Low Back Pain in Health Care Workers and Comparison with Other Occupational Categories in Iran: A Systematic Review.
There are few research studies evaluating the significance of low back pain (LBP) in Iran, even though the majority of locally published surveys are written in the Persian language. In the present review study, we aimed at appraising published articles related to the burden of LBP and its divergence among different jobs. A comprehensive search was conducted in all accessible national and international electronic databases from 1948 to mid-2012. The international electronic databases were MEDLINE (PubMed), Web of Sciences, Google Scholar, Scopus, CINAHL, and the Iranian equivalents were SID, IRANDOC, IranMedex, and Magiran. The main search terms were musculoskeletal disorders, musculoskeletal symptoms, low back pain, back pain, and Iran. All keywords were searched electronically by three Boolean operators. The inclusion criteria were age ≥10 years, study focus on LBP prevalence, inclusion of both genders, and no limitation to the study design. A dedicated STROBE questionnaire was developed as a critical appraisal tool and the quality of the identified literature was examined according to the 5-point Linker scale. Articles scoring ≥3 on the Linker scale were appraised. Each literature was screened by four reviewers independently and possible disagreements were streamlined in a joint review meeting. The extracted data were entered into a dedicated table using Microsoft Office Excel program. Data were analyzed for homogeneity using the STATA software (version 11). Of the 51 articles that were included in the present review study, 35 articles reported 1-year LBP with Nordic questionnaire and 3 articles reported point prevalence of LBP. The calculated global prevalence of 1-year LBP in workers was 25% and LBP was the most prevalent issue among health care workers. There was no association between the prevalence of LBP and job classification among workers. LBP is the most common issue among health care workers. It is recommended that future research should focus on this job category for investigating LBP prevalence. This allows parameters that increase the frequency of LBP to be assessed and subsequently permits the reduction or elimination of such factors.


Lipocalin-2 is increased in progressive multiple sclerosis and inhibits remyelination.
We aimed to examine the regulation of lipocalin-2 (LCN2) in multiple sclerosis (MS) and its potential functional relevance with regard to myelination and neurodegeneration. We determined LCN2 levels in 3 different studies: (1) in CSF and plasma from a case-control study comparing patients with MS (n = 147) with controls (n = 50) and patients with relapsing-remitting MS (n = 75) with patients with progressive MS (n = 72); (2) in CSF and brain tissue microdialysates from a case series of 7 patients with progressive MS; and (3) in CSF at baseline and 60 weeks after natalizumab treatment in a cohort study of 17 patients with progressive MS. Correlation to neurofilament light, a marker of neuroaxonal injury, was tested. The effect of LCN2 on myelination and neurodegeneration was studied in a rat in vitro neuroglial cell coculture model. Intrathecal production of LCN2 was increased predominantly in patients with progressive MS (p < 0.005 vs relapsing-remitting MS) and displayed a positive correlation to neurofilament light (p = 0.005). Levels of LCN2 in brain microdialysates were severalfold higher than in the CSF, suggesting local production in progressive MS. Treatment with natalizumab in progressive MS reduced LCN2 levels an average of 13% (p < 0.0001). LCN2 was found to inhibit remyelination in a dose-dependent manner in vitro. LCN2 production is predominantly increased in progressive MS. Although this moderate increase does not support the use of LCN2 as a biomarker, the correlation to neurofilament light and the inhibitory effect on remyelination suggest that LCN2 might contribute to neurodegeneration through myelination-dependent pathways.


Total cardiovascular disease burden: comparing intensive with moderate statin therapy insights from the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial.
This post-hoc analysis of the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial was designed to assess the comparative treatment efficacy of high-dose atorvastatin and usual-dose simvastatin for the prevention of events subsequent to the first event, using the Wei, Lin, and Weissfeld method. Time-to-first-event analysis of data is frequently utilized to provide efficacy outcome information in coronary heart disease prevention trials. However, during the course of such long-term trials, a large number of events occur subsequent to the first event, the analysis of which will be precluded by this approach. The Wei, Lin, and Weissfeld method allows the analysis of repeated occurrence of events of the same type or of entirely different natures. It regards the recurrence times as multivariate event (failure) times, and models the marginal (individual) distribution for each event with the Cox proportional hazards model. In the IDEAL trial, compared with patients taking simvastatin 20 to 40 mg daily, patients receiving atorvastatin 80 mg daily had their relative risk of a first cardiovascular event reduced by 17% (p < 0.0001), of a second by 24% (p < 0.0001), of a third by 19% (p = 0.035), of a fourth by 24% (p = 0.058), and of a fifth by 28% (p = 0.117). Our results indicate that intensive statin therapy continues to be more effective than standard statin therapy, even beyond the first event, and suggest that clinicians should not hesitate to prescribe high-dose statin therapy for patients experiencing multiple recurrent cardiovascular events.


Mitochondrial encephalomyopathies.
Mitochondrial diseases are uniquely interesting from a genetic point of view because mitochondria contain their own DNA (mtDNA) and are capable of synthesizing a small but vital set of proteins, all of which are components of respiratory chain complexes. Numerous mutations in mtDNA have been described in the past 5 years, and, it is, therefore, important for the clinician to keep in mind both some characteristic clinical presentations and, more importantly, some basic principles of "mitochondrial genetics," including heteroplasmy, the threshold effect, mitotic segregation, and maternal inheritance. The vast majority of mitochondrial proteins are encoded by nuclear DNA (nDNA) and have to be imported from the cytoplasm into mitochondria through a complex translocation machinery, which is also under the control of the nuclear genome. In addition, nDNA encodes several factors that control mtDNA replication, transcription, and translocation. Mitochondrial diseases due to mutations in nDNA are transmitted as mendelian traits and fall into three categories: (1) alterations of mitochondrial proteins; (2) alterations of mitochondrial protein importation; and (3) alterations of intergenomic communication. The first group of disorders can be further classified on the basis of the biochemical area affected, including defects of transport, defects of substrate utilization, defects of the Krebs cycle, defects of oxidation/phosphorylation coupling, and defects of the respiratory chain. The second group includes only few well-documented disorders but will certainly expand in the near future. The third group includes two conditions, an autosomal dominant form of progressive external ophthalmoplegia associated with multiple mtDNA deletions, and a quantitative defect of mtDNA (mtDNA depletion) causing severe infantile myopathy or hepatopathy.


Population pharmacokinetics of landiolol hydrochloride in healthy subjects.
Landiolol hydrochloride is a newly developed cardioselective, ultra short-acting beta(1)-adrenergic receptor blocking agent used for perioperative arrhythmia control. The objective of this study was to characterize the population pharmacokinetics of landiolol hydrochloride in healthy male subjects. A total of 420 blood concentration data points collected from 47 healthy male subjects were used for the population pharmacokinetic analysis. NONMEM was used for population pharmacokinetic analysis. In addition, the final pharmacokinetic model was evaluated using a bootstrap method and a leave-one-out cross validation method. The concentration time course of landiolol hydrochloride was best described by a two-compartment model with lag time. The final parameters were total body clearance (CL: 36.6 mL/min/kg), distribution volume of the central compartment (V1: 101 mL/kg), inter-compartmental clearance (16.1 mL/min/kg), distribution volume of the peripheral compartment (55.6 mL/kg), and lag time (0.82 min). The inter-individual variability in the CL and V1 were 21.8% and 46.3%, respectively. The residual variability was 22.1%. Model evaluation by the two different methods indicated that the final model was robust and parameter estimates were reasonable. The population pharmacokinetic model for landiolol hydrochloride in healthy subjects was developed and was shown to be appropriate by both bootstrap and leave-one-out cross validation methods.


Birth Territory: a theory for midwifery practice.
The theory of Birth Territory describes, explains and predicts the relationships between the environment of the individual birth room, issues of power and control, and the way the woman experiences labour physiologically and emotionally. The theory was synthesised inductively from empirical data generated by the authors in their roles as midwives and researchers. It takes a critical post-structural feminist perspective and expands on some of the ideas of Michel Foucault. Theory synthesis was also informed by current research about the embodied self and the authors' scholarship in the fields of midwifery, human biology, sociology and psychology. In order to demonstrate the significance of the theory, it is applied to two clinical stories that both occur in hospital but are otherwise different. This analysis supports the central proposition that when midwives use 'midwifery guardianship' to create and maintain the ideal Birth Territory then the woman is most likely to give birth naturally, be satisfied with the experience and adapt with ease in the post-birth period. These benefits together with the reduction in medical interventions also benefit the baby. In addition, a positive Birth Territory is posited to have a broader impact on the woman's partner, family and society in general.


Methodologies to generate, extract, purify and fractionate yeast ECM for analytical use in proteomics and glycomics.
In a multicellular organism, the extracellular matrix (ECM) provides a cell-supporting scaffold and helps maintaining the biophysical integrity of tissues and organs. At the same time it plays crucial roles in cellular communication and signalling, with implications in spatial organisation, motility and differentiation. Similarly, the presence of an ECM-like extracellular polymeric substance is known to support and protect bacterial and fungal multicellular aggregates, such as biofilms or colonies. However, the roles and composition of this microbial ECM are still poorly understood. This work presents a protocol to produce S. cerevisiae and C. albicans ECM in an equally highly reproducible manner. Additionally, methodologies for the extraction and fractionation into protein and glycosidic analytical pure fractions were improved. These were subjected to analytical procedures, respectively SDS-PAGE, 2-DE, MALDI-TOF-MS and LC-MS/MS, and DAE and FPLC. Additional chemical methods were also used to test for uronic acids and sulphation. The methodologies hereby presented were equally efficiently applied to extract high amounts of ECM material from S. cerevisiae and C. albicans mats, therefore showing their robustness and reproducibility for yECM molecular and structural characterization. yECM from S. cerevisiae and C. albicans displayed a different proteome and glycoside fractions. S. cerevisiae yECM presented two well-defined polysaccharides with different mass/charge, and C. albicans ECM presented a single different one. The chemical methods further suggested the presence of uronic acids, and chemical modification, possibly through sulphate substitution. All taken, the procedures herein described present the first sensible and concise approach to the molecular and chemical characterisation of the yeast ECM, opening the way to the in-depth study of the microbe multicellular aggregates structure and life-style.


Prevalence of Helicobacter pylori infection among sewage workers.
An increased risk for gastric cancer among sewage workers has been described in several studies. During the last decade the bacterium Helicobacter pylori has emerged as one important risk factor for gastric cancer and is now considered a class I carcinogen by the International Agency for Research on Cancer. The route of transmission for this bacterium remains unclear, but fecal-oral transmission has been proposed. If true, this might entail a yet undescribed risk for sewage workers. The prevalence of immunoglobulin G (IgG) antibodies against H pylori was studied with a cross-sectional study design in a group of 289 municipal workers. Samples of serum from 151 sewage workers at 11 sewage plants in Sweden and of serum from 138 referents were analyzed. The referents were group matched for age and socioeconomic status. The prevalence of IgG antibodies against H pylori among sewage workers did not differ from that of the referents. The adjusted odds ratio (adjOR) was calculated from a logistic model with age and residence as confounding variables (adjOR 0.90, 95% confidence interval 0.53-1.5). The previously described increase in the prevalence of IgG antibodies against H pylori with increasing age was observed. Geographic differences were also observed in the prevalence of H pylori in Sweden. The exposures in sewage work in Sweden do not cause an increased risk of infection with H pylori.


Predicting Trajectories of Functional Decline in 60- to 70-Year-Old People.
Early identification of people at risk of functional decline is essential for delivering targeted preventive interventions. The aim of this study is to identify and predict trajectories of functional decline over 9 years in males and females aged 60-70 years. We included 403 community-dwelling participants from the InCHIANTI study and 395 from the LASA study aged 60-70 years at baseline, of whom the majority reported no functional decline at baseline (median 0, interquartile range 0-1). Participants were included if they reported data on ≥2 measurements of functional ability during a 9-year follow-up. Functional ability was scored with 6 self-reported items on activities of daily living. We performed latent class growth analysis to identify trajectories of functional decline and applied multinomial regression models to develop prediction models of identified trajectories. Analyses were stratified for sex. Three distinct trajectories were identified: no/little decline (219 males, 241 females), intermediate decline (114 males, 158 females), and severe decline (36 males, 30 females). Higher gait speed showed decreased risk of functional limitations in males (intermediate limitations, odds ratio [OR] 0.74, 95% CI 0.57-0.97; severe limitations, OR 0.42, 95% CI 0.26-0.66). The final model in males further included the predictors fear of falling and alcohol intake (no/little decline, area under the receiver operating curve [AUC] 0.68, 95% CI 0.62-0.73; intermediate decline, AUC 0.63, 95% CI 0.56-0.69; severe decline, AUC 0.79, 95% CI 0.71-0.87). In females, higher gait speed showed a decreased risk of intermediate limitations (OR 0.51, 95% CI 0.38-0.68) and severe limitations (OR 0.18, 95% CI 0.07-0.44). Other predictors in females were age, living alone, economic satisfaction, balance, physical activity, BMI, and cardiovascular disease (no/little decline, AUC 0.80, 95% CI 0.75-0.85; intermediate decline, AUC 0.74, 95% CI 0.69-0.79; severe decline, AUC 0.95, 95% CI 0.91-0.99). Already in people aged 60-70 years, 3 distinct trajectories of functional decline were identified in these cohorts over a 9-year follow-up. Predictors of trajectories differed between males and females, except for gait speed. Identification of people at risk is the basis for targeting interventions.


Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment.
Tumor endothelial cells (TECs) perform tumor angiogenesis, which is essential for tumor growth and metastasis. Tumor cells produce large amounts of lactic acid from glycolysis; however, the mechanism underlying the survival of TECs to enable tumor angiogenesis under high lactic acid conditions in tumors remains poorly understood. The metabolomes of TECs and normal endothelial cells (NECs) were analyzed by capillary electrophoresis time-of-flight mass spectrometry. The expressions of pH regulators in TECs and NECs were determined by quantitative reverse transcription-PCR. Cell proliferation was measured by the MTS assay. Western blotting and ELISA were used to validate monocarboxylate transporter 1 and carbonic anhydrase 2 (CAII) protein expression within the cells, respectively. Human tumor xenograft models were used to access the effect of CA inhibition on tumor angiogenesis. Immunohistochemical staining was used to observe CAII expression, quantify tumor microvasculature, microvessel pericyte coverage, and hypoxia. The present study shows that, unlike NECs, TECs proliferate in lactic acidic. TECs showed an upregulated CAII expression both in vitro and in vivo. CAII knockdown decreased TEC survival under lactic acidosis and nutrient-replete conditions. Vascular endothelial growth factor A and vascular endothelial growth factor receptor signaling induced CAII expression in NECs. CAII inhibition with acetazolamide minimally reduced tumor angiogenesis in vivo. However, matured blood vessel number increased after acetazolamide treatment, similar to bevacizumab treatment. Additionally, acetazolamide-treated mice showed decreased lung metastasis. These findings suggest that due to their effect on blood vessel maturity, pH regulators like CAII are promising targets of antiangiogenic therapy. Video Abstract.


Parent-mediated communication interventions for improving the communication skills of preschool children with non-progressive motor disorders.
Children with motor disorders can have difficulties in producing accurate and consistent movements for speech, gesture or facial expression (or a combination of these), making their communication difficult to understand. Parents may be offered training to help recognise and interpret their child's signals and to stimulate their children's development of new communication skills. To assess the effectiveness of parent-mediated communication interventions, compared to no intervention, treatment as usual or clinician-mediated interventions, for improving the communication skills of preschool children up to five years of age who have non-progressive motor disorders. We searched CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, 12 other databases and three trials registers in July 2017. We also searched the reference lists of relevant papers and reviews, and contacted experts working in the field to find unpublished studies. We included studies that used randomised or quasi-randomised designs; compared a parent-mediated communication intervention with no treatment, treatment as usual or clinician-mediated therapy; and included children with non-progressive motor disorders up to five years of age. We used the standard methodological procedures expected by Cochrane. This review included two randomised controlled trials involving 38 children (20 boys, 18 girls), aged 15 to 96 months, and their mothers. All children had developmental disabilities; 10 had motor disorders, but it was unclear if these motor disorders affected their gestural, vocal or verbal communication. Mothers attended eight group training sessions over 11 to 12 weeks and received two or three home visits. Outcomes were assessed immediately after training. We found no report of longer-term follow-up. One study took place at an intervention centre in Canada and the other in South Korea.Both studies recruited small numbers of participants from single centres. Since it is not possible to blind participants attending or therapists providing training to group allocation, we considered both studies to be at high risk of performance bias. We also rated one study at high risk of attrition bias, and both studies at low risk of reporting bias.There was very low-quality evidence for all outcomes assessed. There was no evidence of an effect of training for children's initiation of conversation or engagement in joint attention during interaction with their mothers. Mothers who received training became more responsive to their children's communication, but there were no differences in the extent to which they controlled conversation by directing their children. Missing data meant that we were unable to evaluate the effects of training on children's frequency of communication, frequency of spoken language in conversation, speech production, or receptive or expressive language development. There were no effects on maternal stress. We found no reports of the effects of parent training on children's use of individual communication skills, such as asking questions or providing information, on their generic participation or adverse outcomes. Neither did we find reports of mothers' satisfaction with treatment, its acceptability or their compliance with it. There is only limited, very low quality evidence that parent-mediated communication interventions may be associated with improvements in interaction between mothers and their preschool children who have motor disorders. The indirectness of the study samples and high risk of bias in the included the studies significantly limits our confidence in the evidence, as do issues with study design and lack of detail in results. It is not clear if training has been tested with children whose motor disorders limit the consistency and accuracy of movements underpinning spoken or gestural communication. Some speech and language therapists currently provide communication training for parents. Further research, with larger numbers of children whose movement disorders affect their speech and gestures, coupled with detailed reporting of children's baseline skills, is needed to test whether communication training for parents can help them to promote the communication development of their young children with movement disorders.


Sustained High-dose Thiamine Supplementation in High-risk Cardiac Patients Undergoing Cardiopulmonary Bypass: A Pilot Feasibility Study (The APPLY trial).
To test the feasibility and investigate possible cardiovascular effects of a sustained high-dose intravenous thiamine protocol in patients undergoing combined valvular and coronary artery bypass graft surgery. Randomized, placebo-controlled, pilot feasibility trial. Cardiac surgery department of a tertiary hospital. Forty patients undergoing combined valvular and coronary artery bypass surgery. Intravenous thiamine (600 mg on the day of surgery, and 400 mg/day on postoperative days 1, 2, and 3) or placebo. The primary feasibility endpoints were recruitment rate and protocol compliance. Secondary endpoints included markers of possible biological and physiological effects. The mean recruitment rate was 8 patients per month and protocol compliance was 97.5%. There were no differences in median peak postoperative lactate (2.7 mmol/L [interquartile range [IQR] 1.4-4.6] for thiamine v 2.5 mmol/L [IQR 1.4-3.6] for placebo; p = 0.53), median peak postoperative creatinine (104 µmol/L [IQR 92.5-129] for thiamine v 99 µmol/L [IQR 86.5-109.5] for placebo; p = 0.53), median nadir postoperative cardiac index (1.8 L/min/m2 [IQR 1.5-2.1] for thiamine v 2.2 L/min/m2 [IQR 1.5-2.5] for placebo; p = 0.25), or the number of patients on vasopressor/inotropic agents (thiamine, 12 [63%]; placebo, 12 [60%]; p = 0.80), or in the total inotrope/vasopressor dose 0.14 µg/kg for thiamine v 0.12 µg/kg for placebo; p = 0.88). A double-blind trial of sustained high-dose intravenous thiamine supplementation in higher-risk cardiac surgery patients was feasible and appeared to be safe. However, such treatment did not demonstrate evidence of biological or physiological effects.


Treatment of status epilepticus in adults.
Status epilepticus is a medical emergency requiring immediate treatment. General treatment is aimed at restoring physiologic homeostasis, and drug therapy is aimed at arresting the convulsive activity and preventing its recurrence. Concurrent administration of diazepam and either phenytoin or phenobarbital will be effective in most cases. After the status epilepticus has been treated the underlying cause should be investigated and, if possible, treated.


Regulation of Poly(A) Tail and Translation during the Somatic Cell Cycle.
Poly(A) tails are critical for mRNA stability and translation. However, recent studies have challenged this view, showing that poly(A) tail length and translation efficiency are decoupled in non-embryonic cells. Using TAIL-seq and ribosome profiling, we investigate poly(A) tail dynamics and translational control in the somatic cell cycle. We find dramatic changes in poly(A) tail lengths of cell-cycle regulatory genes like CDK1, TOP2A, and FBXO5, explaining their translational repression in M phase. We also find that poly(A) tail length is coupled to translation when the poly(A) tail is <20 nucleotides. However, as most genes have >20 nucleotide poly(A) tails, their translation is regulated mainly via poly(A) tail length-independent mechanisms during the cell cycle. Specifically, we find that terminal oligopyrimidine (TOP) tract-containing transcripts escape global translational suppression in M phase and are actively translated. Our quantitative and comprehensive data provide a revised view of translational control in the somatic cell cycle.


Importance of quality of life in patients with non-small-cell lung cancer.
The therapeutic options for patients with advanced non-small-cell lung cancer (NSCLC) are palliative. Therefore, the quality of life in oncology is considered as an endpoint in clinical trials, and several scales have been accepted for its measurement in parallel with other clinical determinations. However, its use in clinical practice is hindered by various obstacles that need to be overcome. In this article we examine the concept of the quality of life in patients with NSCLC, as well as giving an evaluation and interpretation of the results of various clinical trials. We describe the new technological methods used in daily clinical practice to measure the quality of life.


Involvement of replicative polymerases, Tel1p, Mec1p, Cdc13p, and the Ku complex in telomere-telomere recombination.
Telomere maintenance is required for chromosome stability, and telomeres are typically replicated by the action of the reverse transcriptase telomerase. In both tumor and yeast cells that lack telomerase, telomeres are maintained by an alternative recombination mechanism. Genetic studies have led to the identification of DNA polymerases, cell cycle checkpoint proteins, and telomere binding proteins involved in the telomerase pathway. However, how these proteins affect telomere-telomere recombination has not been identified to date. Using an assay to trace the in vivo recombinational products throughout the course of survivor development, we show here that three major replicative polymerases, alpha, delta, and epsilon, play roles in telomere-telomere recombination and that each causes different effects and phenotypes when they as well as the telomerase are defective. Polymerase delta appears to be the main activity for telomere extension, since neither type I nor type II survivors arising via telomere-telomere recombination were seen in its absence. The frequency of type I versus type II is altered in the polymerase alpha and epsilon mutants relative to the wild type. Each prefers to develop a particular type of survivor. Moreover, type II recombination is mediated by the cell cycle checkpoint proteins Tel1 and Mec1, and telomere-telomere recombination is regulated by telomere binding protein Cdc13 and the Ku complex. Together, our results suggest that coordination between DNA replication machinery, DNA damage signaling, DNA recombination machinery, and the telomere protein-DNA complex allows telomere recombination to repair telomeric ends in the absence of telomerase.


CPNCoverageAnalysis: An R package for parameter estimation in conceptual properties norming studies.
In conceptual properties norming studies (CPNs), participants list properties that describe a set of concepts. From CPNs, many different parameters are calculated, such as semantic richness. A generally overlooked issue is that those values are only point estimates of the true unknown population parameters. In the present work, we present an R package that allows us to treat those values as population parameter estimates. Relatedly, a general practice in CPNs is using an equal number of participants who list properties for each concept (i.e., standardizing sample size). As we illustrate through examples, this procedure has negative effects on data's statistical analyses. Here, we argue that a better method is to standardize coverage (i.e., the proportion of sampled properties to the total number of properties that describe a concept), such that a similar coverage is achieved across concepts. When standardizing coverage rather than sample size, it is more likely that the set of concepts in a CPN all exhibit a similar representativeness. Moreover, by computing coverage the researcher can decide whether the CPN reached a sufficiently high coverage, so that its results might be generalizable to other studies. The R package we make available in the current work allows one to compute coverage and to estimate the necessary number of participants to reach a target coverage. We show this sampling procedure by using the R package on real and simulated CPN data.


Effect of alteplase on the CT hyperdense artery sign and outcome after ischemic stroke.
To investigate whether the location and extent of the CT hyperdense artery sign (HAS) at presentation affects response to IV alteplase in the randomized controlled Third International Stroke Trial (IST-3). All prerandomization and follow-up (24-48 hours) CT brain scans in IST-3 were assessed for HAS presence, location, and extent by masked raters. We assessed whether HAS grew, persisted, shrank, or disappeared at follow-up, the association with 6-month functional outcome, and effect of alteplase. IST-3 is registered (ISRCTN25765518). HAS presence (vs absence) independently predicted poor 6-month outcome (increased Oxford Handicap Scale [OHS]) on adjusted ordinal regression analysis (odds ratio [OR] 0.66, p < 0.001). Outcome was worse in patients with more (vs less) extensive HAS (OR 0.61, p = 0.027) but not in proximal (vs distal) HAS (p = 0.420). Increasing age was associated with more HAS growth at follow-up (OR 1.01, p = 0.013). Treatment with alteplase increased HAS shrinkage/disappearance at follow-up (OR 0.77, p = 0.006). There was no significant difference in HAS shrinkage with alteplase in proximal (vs distal) or more (vs less) extensive HAS (p = 0.516 and p = 0.580, respectively). There was no interaction between presence vs absence of HAS and benefit of alteplase on 6-month OHS (p = 0.167). IV alteplase promotes measurable reduction in HAS regardless of HAS location or extent. Alteplase increased independence at 6 months in patients with and without HAS. This study provides Class I evidence that for patients within 6 hours of ischemic stroke with a CT hyperdense artery sign, IV alteplase reduced intra-arterial hyperdense thrombus.


Effect of User Practice on Prosthetic Finger Control With an Intuitive Myoelectric Decoder.
Machine learning-based myoelectric control is regarded as an intuitive paradigm, because of the mapping it creates between muscle co-activation patterns and prosthesis movements that aims to simulate the physiological pathways found in the human arm. Despite that, there has been evidence that closed-loop interaction with a classification-based interface results in user adaptation, which leads to performance improvement with experience. Recently, there has been a focus shift toward continuous prosthesis control, yet little is known about whether and how user adaptation affects myoelectric control performance in dexterous, intuitive tasks. We investigate the effect of short-term adaptation with independent finger position control by conducting real-time experiments with 10 able-bodied and two transradial amputee subjects. We demonstrate that despite using an intuitive decoder, experience leads to significant improvements in performance. We argue that this is due to the lack of an utterly natural control scheme, which is mainly caused by differences in the anatomy of human and artificial hands, movement intent decoding inaccuracies, and lack of proprioception. Finally, we extend previous work in classification-based and wrist continuous control by verifying that offline analyses cannot reliably predict real-time performance, thereby reiterating the importance of validating myoelectric control algorithms with real-time experiments.


Anterior vena caval oxygen profiles in a deep-diving California sea lion: arteriovenous shunts, a central venous oxygen store and oxygenation during lung collapse.
Deep-diving California sea lions (Zalophus californianus) can maintain arterial hemoglobin saturation (SO2 ) above 90% despite lung collapse (lack of gas exchange) and extremely low posterior vena caval SO2 in the middle of the dive. We investigated anterior vena caval PO2 and SO2 during dives of an adult female sea lion to investigate two hypotheses: (1) posterior vena caval SO2 is not representative of the entire venous oxygen store and (2) a well-oxygenated (arterialized) central venous oxygen reservoir might account for maintenance of arterial SO2 during lung collapse. During deep dives, initial anterior vena caval SO2 was elevated at 83.6±8.4% (n=102), presumably owing to arteriovenous shunting. It remained high until the bottom phase of the dive and then decreased during ascent, whereas previously determined posterior vena caval SO2 declined during descent and then often increased during ascent. These divergent patterns confirmed that posterior vena caval SO2 was not representative of the entire venous oxygen store. Prior to and early during descent of deep dives, the high SO2 values of both the anterior and posterior venae cavae may enhance arterialization of a central venous oxygen store. However, anterior vena caval SO2 values at depths beyond lung collapse reached levels as low as 40%, making it unlikely that even a completely arterialized central venous oxygen store could account for maintenance of high arterial SO2 These findings suggest that maintenance of high arterial SO2 during deep dives is due to persistence of some gas exchange at depths beyond presumed lung collapse.


The transcriptional landscape of polyploid wheat.
The coordinated expression of highly related homoeologous genes in polyploid species underlies the phenotypes of many of the world's major crops. Here we combine extensive gene expression datasets to produce a comprehensive, genome-wide analysis of homoeolog expression patterns in hexaploid bread wheat. Bias in homoeolog expression varies between tissues, with ~30% of wheat homoeologs showing nonbalanced expression. We found expression asymmetries along wheat chromosomes, with homoeologs showing the largest inter-tissue, inter-cultivar, and coding sequence variation, most often located in high-recombination distal ends of chromosomes. These transcriptionally dynamic genes potentially represent the first steps toward neo- or subfunctionalization of wheat homoeologs. Coexpression networks reveal extensive coordination of homoeologs throughout development and, alongside a detailed expression atlas, provide a framework to target candidate genes underpinning agronomic traits in wheat.


The mammalian YL1 protein is a shared subunit of the TRRAP/TIP60 histone acetyltransferase and SRCAP complexes.
The multiprotein mammalian TRRAP/TIP60-containing histone acetyltransferase (HAT) complex performs critical functions in a variety of cellular processes including transcriptional activation, double strand DNA break repair, and apoptosis. We previously isolated the TRRAP/TIP60 complex from HeLa cells (Cai, Y., Jin, J., Tomomori-Sato, C., Sato, S., Sorokina, I., Parmely, T. J., Conaway, R. C., and Conaway, J. W. (2003) J. Biol. Chem. 278, 42733-42736). Analysis of proteins present in preparations of the TRRAP/TIP60 complex led to the identification of several new subunits, as well as several potential subunits including the YL1 protein. Here we present evidence that the YL1 protein is a previously unrecognized subunit of the TRRAP/TIP60 HAT complex. In addition, we present evidence that YL1 is also a component of a novel mammalian multiprotein complex that includes the SNF2-related helicase SRCAP and resembles the recently described Saccharomyces cerevisiae SWR1 chromatin remodeling complex. Taken together, our findings identify the YL1 protein as a new subunit of the TRRAP/TIP60 HAT complex, and they suggest that YL1 plays multiple roles in chromatin modification and remodeling in cells.


MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia.
Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in pre-symptomatic carriers of mutations in C9orf72, the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia was in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43Q331K disrupts neurodevelopment. Computerized tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43Q331K knock-in mice. By marrying in vivo imaging with targeted histology, we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. As well as helping to understand the earliest causes of disease, our MRI and histological markers will be valuable in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice.


Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload.
Induction of the cell cycle is emerging as an intervention to treat heart failure. Here, we tested the hypothesis that enhanced cardiomyocyte renewal in transgenic mice expressing cyclin D2 would be beneficial during hemodynamic overload. We induced pressure overload by transthoracic aortic constriction (TAC) or volume overload by aortocaval shunt in cyclin D2-expressing and WT mice. Although cyclin D2 expression dramatically improved survival following TAC, it did not confer a survival advantage to mice following aortocaval shunt. Cardiac function decreased following TAC in WT mice, but was preserved in cyclin D2-expressing mice. On the other hand, cardiac structure and function were compromised in response to aortocaval shunt in both WT and cyclin D2-expressing mice. The preserved function and improved survival in cyclin D2-expressing mice after TAC was associated with an approximately 50% increase in cardiomyocyte number and exaggerated cardiac hypertrophy, as indicated by increased septum thickness. Aortocaval shunt did not further impact cardiomyocyte number in mice expressing cyclin D2. Following TAC, cyclin D2 expression attenuated cardiomyocyte hypertrophy, reduced cardiomyocyte apoptosis, fibrosis, calcium/calmodulin-dependent protein kinase IIδ phosphorylation, brain natriuretic peptide expression, and sustained capillarization. Thus, we show that cyclin D2-induced cardiomyocyte renewal reduced myocardial remodeling and dysfunction after pressure overload but not after volume overload.


Ultrahigh-resolution spectral domain optical coherence tomography imaging of the lamina cribrosa.
Study of the structure of the lamina cribrosa is critical in glaucoma research. The purpose of this study is to determine the optimal spectral domain optical coherence tomography imaging protocol for the digital isolation and display of the lamina cribrosa. Three-dimensional datasets centered on the lamina cribrosa were obtained with 200 X 200 to 512 X 512 A-scan densities. The effect of scan density and c-mode slab thickness was subjectively compared. Increasing slab thickness reduced the sharpness of visible prelamina and lamina cribrosa structures. In retrolamina structures, thin slabs provided good visualization, but increased slab size increased the visibility of deeper structures. Scan times as short as 2.3 seconds (256 X 256 A-scans) degraded visualization of the shape of the optic nerve head. The optical scan protocol for lamina cribrosa imaging appears to be a 3 x 3 mm 200 X 200 A-scan volume with the lamina cribrosa positioned near direct current.


Investigating the phenomenological matrix of mindfulness-related practices from a neurocognitive perspective.
There has been a great increase in literature concerned with the effects of a variety of mental training regimes that generally fall within what might be called contemplative practices, and a majority of these studies have focused on mindfulness. Mindfulness meditation practices can be conceptualized as a set of attention-based, regulatory, and self-inquiry training regimes cultivated for various ends, including wellbeing and psychological health. This article examines the construct of mindfulness in psychological research and reviews recent, nonclinical work in this area. Instead of proposing a single definition of mindfulness, we interpret it as a continuum of practices involving states and processes that can be mapped into a multidimensional phenomenological matrix which itself can be expressed in a neurocognitive framework. This phenomenological matrix of mindfulness is presented as a heuristic to guide formulation of next-generation research hypotheses from both cognitive/behavioral and neuroscientific perspectives. In relation to this framework, we review selected findings on mindfulness cultivated through practices in traditional and research settings, and we conclude by identifying significant gaps in the literature and outline new directions for research.


Increased plasma calcitonin in early acute renal failure.
1. High plasma immunoreactive calcitonin concentrations were observed in ten of eleven patients with acute renal failure, particularly in the oliguric phase. 2. Immunoreactive calcitonin decreased progressively with time, independently of recovery of renal function. 3. Radioimmunoassay curves obtained with serial dilutions of plasma from these patients were parallel to or superimposed upon those obtained with calcitonin standards.


'Candidatus Phytoplasma brasiliense' (16SrXV-A Subgroup) Associated with Cauliflower Displaying Stunt Symptoms in Brazil.
Cauliflower stunt, caused by a phytoplasma of the group 16SrIII-J, was reported in the beginning of 2012 and has occurred with high incidences of infected plants (up to 90%) in crops located in the state of São Paulo in the southeast region of Brazil (3). Diseased plants exhibit general stunting, malformation of inflorescence, reddening leaves, and vessel necrosis (3). Further investigations with plants displaying identical symptoms collected in Nova Bassano, state of Rio Grande do Sul, Brazilian south region, have revealed the presence of a phytoplasma distinct from 16SrIII-J subgroup. Four symptomatic plus four asymptomatic samples were assayed from a field, and the presence of phytoplasma was evidenced by nested PCR assays performed with primers P1/Tint followed by R16F2n/16R2 in three affected plants, which amplified genomic fragments of 1.2 kb from the 16S rRNA gene. No amplification occurred in non-affected samples. Nested PCR products analyzed by conventional RFLP (2) using the enzymes AluI, RsaI, KpnI, HpaII, MseI, HhaI, MboI, and BstUI pointed to the presence of a phytoplasma belonging to group 16SrXV-A in all three phytoplasma-positive samples. Virtual RFLP analysis based on restriction patterns, derived from in silico digestion with 17 endonucleases (4), confirmed the previous results obtained from those samples by conventional RFLP. The 16S rDNA sequences of this phytoplasma identified in cauliflower (GenBank Accession No. JN818845) shared 99% sequence similarity with the reference phytoplasma for subgroup 16SrXV-A (Hibiscus witches'-broom phytoplasma, AF147708), designated 'Candidatus Phytoplasma brasiliense.' Analysis of putative restriction sites showed excellent identity between the phytoplasma studied here and the reference phytoplasma. In addition, the arrangement of branches of a phylogenetic tree constructed with phytoplasmas representing diverse 16Sr groups and subgroups supported that the phytoplasma found in cauliflower is closed related to the representative of the subgroup 16SrXV-A. Association of distinct phytoplasmas with the same kind of disease is not rare and the present pathosystem constitutes a new example. Members of this subgroup have been described almost exclusively in Brazil and previously reported in Sida sp., periwinkle, and hibiscus (1). In some European countries, as well as in the United States and Canada, phytoplasmas belonging to group 16SrI has been associated with this type of disease, which has been reported for various species of the genus Brassica, as published in previous works (3). However, a representative of the group 16SrVI was described in infected plants in Iran (3). Although the 16SrIII-J phytoplasma is currently the most important agent of cauliflower stunt in Brazil, and members of 16SrI are prevalent in other countries, this study revealed that a 16Sr XV-A phytoplasma may be also associated with this important disease of brassicas. Besides, the findings here reported expand the natural host range, including cauliflower as new host for phytoplasmas affiliated with 16SrXV-A. References: (1) B. Eckstein et al. Plant Dis. 95:363, 2009. (2) I. M. Lee et al. Int. J. Syst. Bacteriol. 48:1153, 1998. (3) M. C. C. Rappussi et al. Eur. J. Plant. Pathol. 133:829, 2012. (4) Wei et al. Int. J. Syst. Evol. Microbiol. 57:1855, 2007.


Meanings of being critically ill in a sound-intensive ICU patient room - a phenomenological hermeneutical study.
The aim of this study was to illuminate the meanings of being critically ill in a sound-intensive ICU patient room, as disclosed through patients' narratives. Patient rooms in ICUs are filled with loud activity and studies have revealed sound levels comparable to those of a busy road above the patient's head. There is a risk that the sound or noise is disturbing and at worst a major problem for the patient, but there is a lack of knowledge concerning the patients' own experiences. Thirteen patients were asked to narrate their experiences of the sound environment in ICU patient rooms. The interviews were analyzed using a phenomenological- hermeneutical method inspired by the philosophy of Ricoeur. Six themes emerged from the analysis. The meanings of being a patient in a sound- intensive environment were interpreted as never knowing what to expect next regarding noise, but also of being situated in the middle of an uncontrollable barrage of noise, unable to take cover or disappear. This condition is not to be seen as static; for some patients there is movement and change over time. The meanings indicate that the unpredictable shifts between silence and disturbing sounds stress the critically ill patient and impede sleep and recovery. Our findings indicate the need to reduce disturbing and unexpected sounds and noise around critically ill patients in high-tech environments in order to facilitate wellbeing, sleep and recovery. Nurses have a vital role in developing such an environment.


Bacteroides ovatus Promotes IL-22 Production and Reduces Trinitrobenzene Sulfonic Acid-Driven Colonic Inflammation.
The intestinal microbiota influences the development and function of the mucosal immune system. However, the exact mechanisms by which commensal microbes modulate immunity is not clear. We previously demonstrated that commensal Bacteroides ovatus ATCC 8384 reduces mucosal inflammation. Herein, we aimed to identify immunomodulatory pathways employed by B. ovatus. In germ-free mice, mono-association with B. ovatus shifted the CD11b+/CD11c+ and CD103+/CD11c+ dendritic cell populations. Because indole compounds are known to modulate dendritic cells, B. ovatus cell-free supernatant was screened for tryptophan metabolites by liquid chromatography-tandem mass spectrometry and larger quantities of indole-3-acetic acid were detected. Analysis of cecal and fecal samples from germ-free and B. ovatus mono-associated mice confirmed that B. ovatus could elevate indole-3-acetic acid concentrations in vivo. Indole metabolites have previously been shown to stimulate immune cells to secrete the reparative cytokine IL-22. Addition of B. ovatus cell-free supernatant to immature bone marrow-derived dendritic cells stimulated IL-22 secretion. The ability of IL-22 to drive repair in the intestinal epithelium was confirmed using a physiologically relevant human intestinal enteroid model. Finally, B. ovatus shifted the immune cell populations in trinitrobenzene sulfonic acid-treated mice and up-regulated colonic IL-22 expression, effects that correlated with decreased inflammation. Our data suggest that B. ovatus-produced indole-3-acetic acid promotes IL-22 production by immune cells, yielding beneficial effects on colitis.


Successful epilepsy surgery in frontal lobe epilepsy with startle seizures: a SEEG study.
Pre-surgical assessment and surgical management of frontal epilepsy with normal MRI is often challenging. We present a case of a 33-year-old, right-handed, educated male. During childhood, his seizures presented with mandibular myoclonus and no particular trigger. As a young adult, he developed seizures with a startle component, triggered by unexpected noises. During his ictal episodes, he felt fear and grimaced with sudden head flexion and tonic axial posturing. Similar seizures also occurred without startle. Neuropsychological assessment showed executive dysfunction and verbal memory deficit. The cerebral MRI was normal. Electro-clinical reasoning, investigations performed, the results obtained and follow-up are discussed in detail. [Published with video sequence].


Antibody and B-cell Immune Responses Against Bordetella Pertussis Following Infection and Immunization.
Neither immunization nor recovery from natural infection provides life-long protection against Bordetella pertussis. Replacement of a whole-cell pertussis (wP) vaccine with an acellular pertussis (aP) vaccine, mutations in B. pertussis strains, and better diagnostic techniques, contribute to resurgence of number of cases especially in young infants. Development of new immunization strategies relies on a comprehensive understanding of immune system responses to infection and immunization and how triggering these immune components would ensure protective immunity. In this review, we assess how B cells, and their secretory products, antibodies, respond to B. pertussis infection, current and novel vaccines and highlight similarities and differences in these responses. We first focus on antibody-mediated immunity. We discuss antibody (sub)classes, elaborate on antibody avidity, ability to neutralize pertussis toxin, and summarize different effector functions, i.e. ability to activate complement, promote phagocytosis and activate NK cells. We then discuss challenges and opportunities in studying B-cell immunity. We highlight shared and unique aspects of B-cell and plasma cell responses to infection and immunization, and discuss how responses to novel immunization strategies better resemble those triggered by a natural infection (i.e., by triggering responses in mucosa and production of IgA). With this comprehensive review, we aim to shed some new light on the role of B cells and antibodies in the pertussis immunity to guide new vaccine development.


A phase I and pharmacologic study of capecitabine and paclitaxel in breast cancer patients.
Based on preclinical studies demonstrating that treatment with paclitaxel upregulates intratumoral thymidine phosphorylase (dTHdPase), which catalyzes the final step in the conversion of the oral fluoropyrimidine capecitabine to 5-fluorouracil (5-FU), as well as the overlapping spectra of activity for these agents, particularly in metastatic breast cancer, this phase I study evaluated the feasibility of administering capecitabine on an intermittent schedule in combination with paclitaxel in previously-treated patients with locally advanced or metastatic breast cancer. The study also sought to recommend doses for subsequent disease-specific studies, identify clinically significant pharmacokinetic interactions, and detect preliminary antitumor activity. Nineteen previously treated women with metastatic breast cancer whose prior treatment included neither paclitaxel or capecitabine received one hundred one courses of capecitabine and paclitaxel. Paclitaxel was administered as a three-hour intravenous (i.v.) infusion at a fixed dose of 175 mg/m2 and capecitabine was administered as 2 divided daily doses for 14 days followed by a seven-day rest period every 3 weeks. The dose of capecitabine was increased from a starting dose of 1650 mg/m2/d. The plasma sampling scheme in the first course permitted characterization of the pharmacokinetics of each agent given alone and concurrently to detect major pharmacokinetic interactions. Palmar plantar erythrodysesthesia (hand foot syndrome) and neutropenia were the principal dose-limiting toxicities (DLT). Other toxicities included diarrhea and transient hyperbilirubinemia. Three of eight new patients treated with capecitabine 2000 mg/m2/d and paclitaxel 175 mg/m2 experienced DLT in the first course, whereas none of eleven new patients treated with capecitabine 1650 mg/m2/d and paclitaxel 175 mg/m2 developed DLT. Pharmacokinetic studies indicated that capecitabine did not grossly affect the pharmacokinetics of paclitaxel, and there were no major effects of paclitaxel on the pharmacokinetics of capecitabine and capecitabine metabolites. However, AUC values for the major 5-FU catabolite, fluorobeta-alanine (FBAL), were significantly lower in the presence of paclitaxel. Two complete and seven partial responses (56% response rate) were observed in sixteen patients with measurable disease; four of six patients whose disease was previously treated with high-dose chemotherapy and hematopoietic stem-cell support had major responses. Seven of nineteen patients had stable disease as their best response. Recommended combination doses of capecitabine on an intermittent schedule and paclitaxel are capecitabine 1650 mg/m2/d orally for 14 days and paclitaxel 175 mg/m2 i.v. every 3 weeks. The favorable preclinical interactions between capecitabine and paclitaxel, as well as the acceptable toxicity profile and antitumor activity in patients with metastatic breast cancer, support further clinical evaluations to determine an optimal role for the combination of capecitabine and paclitaxel in breast cancer and other relevant malignancies.