Future of electronic health records: implications for decision support.
The potential benefits of the electronic health record over traditional paper are many, including cost containment, reductions in errors, and improved compliance by utilizing real-time data. The highest functional level of the electronic health record (EHR) is clinical decision support (CDS) and process automation, which are expected to enhance patient health and healthcare. The authors provide an overview of the progress in using patient data more efficiently and effectively through clinical decision support to improve health care delivery, how decision support impacts anesthesia practice, and how some are leading the way using these systems to solve need-specific issues. Clinical decision support uses passive or active decision support to modify clinician behavior through recommendations of specific actions. Recommendations may reduce medication errors, which would result in considerable savings by avoiding adverse drug events. In selected studies, clinical decision support has been shown to decrease the time to follow-up actions, and prediction has proved useful in forecasting patient outcomes, avoiding costs, and correctly prompting treatment plan modifications by clinicians before engaging in decision-making. Clinical documentation accuracy and completeness is improved by an electronic health record and greater relevance of care data is delivered. Clinical decision support may increase clinician adherence to clinical guidelines, but educational workshops may be equally effective. Unintentional consequences of clinical decision support, such as alert desensitization, can decrease the effectiveness of a system. Current anesthesia clinical decision support use includes antibiotic administration timing, improved documentation, more timely billing, and postoperative nausea and vomiting prophylaxis. Electronic health record implementation offers data-mining opportunities to improve operational, financial, and clinical processes. Using electronic health record data in real-time for decision support and process automation has the potential to both reduce costs and improve the quality of patient care.


A case of proximal jejunal ectopic pancreas causing sporadic vomiting.
Aberrant rests of pancreatic tissue can be found throughout the gastrointestinal system and are known as pancreatic heterotopia or ectopic pancreas (EP). Authors report a 12-year-old girl with jejunal EP with a long-lasting history of sporadic bilious vomiting. Upper gastrointestinal (GI) study showed delayed passage beyond duodeno-jejunal junction. During laparotomy a 2x2 cm mass was encountered on the mesenteric border of the jejunum, 3 cm distal to the ligament of Treitz. Histopathologic examination revealed pancreatic tissue. The mass was excised and end-to-end anastomosis was performed. Postoperative course of the patient was uneventful and she is doing well after 10 months. Intestinal obstruction due to EP has been reported to occur only if it causes intussusception. Intestinal obstruction without intussusception due to jejunal EP has not been reported. In our case, the EP tissue was located just beneath the mucosa and involved the muscular layer. The foreign body effect of the EP tissue involving the muscular layer may cause dysmotility and/or local spasm, which we think were responsible for the long-lasting sporadic bilious vomiting in our patient.


A systematic review of the measurement properties of the patient-rated wrist evaluation.
Systematic review of measurement properties. To summarize the measurement properties of the Patient-Rated Wrist Evaluation (PRWE) questionnaire. The PRWE is a region-specific outcome measure initially developed for assessing pain and function in individuals with distal radius fracture. However, subsequent research has expanded its use to other wrist/hand conditions. A systematic review of the measurement properties of the PRWE can enhance the understanding of its clinical applicability across different wrist/hand pathologies. The MEDLINE, Embase, and CINAHL databases were searched using predefined search terms. A hand search of the bibliography of the primary studies was performed. Studies assessing at least 1 measurement property of the PRWE, either in the English version or versions in other languages, were included in this review. Two raters performed data extraction and critical appraisal of the primary studies using standardized instruments. A total of 22 primary studies met the inclusion criteria. The overall quality of the 22 studies ranged from 38% to 88%, with 9 scoring greater than 70%. Agreement between the raters who determined the quality of the studies was 0.75 (unweighted kappa). The measurement properties of the PRWE were summarized for different wrist/hand conditions. The PRWE is reliable, valid, and responsive across many wrist/hand conditions. Future studies should focus on determining values for the minimal detectable change and clinically important differences for the PRWE across different patient populations.


Functional annotation of putative QTL associated with black tea quality and drought tolerance traits.
The understanding of black tea quality and percent relative water content (%RWC) traits in tea (Camellia sinensis) by a quantitative trait loci (QTL) approach can be useful in elucidation and identification of candidate genes underlying the QTL which has remained to be difficult. The objective of the study was to identify putative QTL controlling black tea quality and percent relative water traits in two tea populations and their F1 progeny. A total of 1,421 DArTseq markers derived from the linkage map identified 53 DArTseq markers to be linked to black tea quality and %RWC. All 53 DArTseq markers with unique best hits were identified in the tea genome. A total of 5,592 unigenes were assigned gene ontology (GO) terms, 56% comprised biological processes, cellular component (29%) and molecular functions (15%), respectively. A total of 84 unigenes in 15 LGs were assigned to 25 different Kyoto Encyclopedia of Genes and Genomes (KEGG) database pathways based on categories of secondary metabolite biosynthesis. The three major enzymes identified were transferases (38.9%), hydrolases (29%) and oxidoreductases (18.3%). The putative candidate proteins identified were involved in flavonoid biosynthesis, alkaloid biosynthesis, ATPase family proteins related to abiotic/biotic stress response. The functional annotation of putative QTL identified in this current study will shed more light on the proteins associated with caffeine and catechins biosynthesis and % RWC. This study may help breeders in selection of parents with desirable DArTseq markers for development of new tea cultivars with desirable traits.


The Interaction Model of Client Health Behavior as a conceptual guide in the explanation of children's health behaviors.
This study used the Interaction Model of Client Health Behavior (IMCHB) as a conceptual guide to explain the correlates of children's diet and physical activity and explore the relationships of sex with their diet and physical activity of the school-aged child. A descriptive correlational study was conducted on 371 fifth-grade students and their parents. Information on the family's demographics, health experience, social influence, and environmental resources was collected, as well as data on the children's intrinsic motivation, cognitive appraisal, and affective response to food/physical activity. Children's self-reports on diet and physical activity were collected, as were parents' self-reports on health habits. Food preferences and diet self-efficacy explained the most variance in diet behavior for girls and boys. Girls scored healthier on food preferences and diet self-efficacy than did boys, but no difference was detected in their diet behavior. Girls participated in more low-intensity physical activity, but boys participated in more high-intensity physical activity than did girls. Findings provide strong support for the use of the IMCHB to explain children's diet but weak support for the explanation of children's physical activity. Further study of additional factors predictive of physical activity is indicated.


The impact of school water, sanitation, and hygiene interventions on the health of younger siblings of pupils: a cluster-randomized trial in Kenya.
We examined the impact of school water, sanitation, and hygiene (WASH) interventions on diarrhea-related outcomes among younger siblings of school-going children. We conducted a cluster-randomized trial among 185 schools in Kenya from 2007 to 2009. We assigned schools to 1 of 2 study groups according to water availability. Multilevel logistic regression models, adjusted for baseline measures, assessed differences between intervention and control arms in 1-week period prevalence of diarrhea and 2-week period prevalence of clinic visits among children younger than 5 years with at least 1 sibling attending a program school. Among water-scarce schools, comprehensive WASH improvements were associated with decreased odds of diarrhea (odds ratio [OR] = 0.44; 95% confidence interval [CI] = 0.27, 0.73) and visiting a clinic (OR = 0.36; 95% CI = 0.19, 0.68), relative to control schools. In our separate study group of schools with greater water availability, school hygiene promotion and water treatment interventions and school sanitation improvements were not associated with differences in diarrhea prevalence between intervention and control schools. In water-scarce areas, school WASH interventions that include robust water supply improvements can reduce diarrheal diseases among young children.


On the role of excitonic interactions in carotenoid-phthalocyanine dyads and implications for photosynthetic regulation.
In two recent studies, energy transfer was reported in certain phthalocyanine-carotenoid dyads between the optically forbidden first excited state of carotenoids (Car S(1)) and phthalocyanines (Pcs) in the direction Pc → Car S(1) (Kloz et al., J Am Chem Soc 133:7007-7015, 2011) as well as in the direction Car S(1) → Pc (Liao et al., J Phys Chem A 115:4082-4091, 2011). In this article, we show that the extent of this energy transfer in both directions is closely correlated in these dyads. This correlation and the additional observation that Car S(1) is instantaneously populated after Pc excitation provides evidence that in these compounds excitonic interactions can occur. Besides pure energy transfer and electron transfer, this is the third type of tetrapyrrole-carotenoid interaction that has been shown to occur in these model compounds and that has previously been proposed as a photosynthetic regulation mechanism. We discuss the implications of these models for photosynthetic regulation. The findings are also discussed in the context of a model in which both electronic states are disordered and in which the strength of the electronic coupling determines whether energy transfer, excitonic coupling, or electron transfer occurs.


Analysis of transitions at two-fold redundant sites in mammalian genomes. Transition redundant approach-to-equilibrium (TREx) distance metrics.
The exchange of nucleotides at synonymous sites in a gene encoding a protein is believed to have little impact on the fitness of a host organism. This should be especially true for synonymous transitions, where a pyrimidine nucleotide is replaced by another pyrimidine, or a purine is replaced by another purine. This suggests that transition redundant exchange (TREx) processes at the third position of conserved two-fold codon systems might offer the best approximation for a neutral molecular clock, serving to examine, within coding regions, theories that require neutrality, determine whether transition rate constants differ within genes in a single lineage, and correlate dates of events recorded in genomes with dates in the geological and paleontological records. To date, TREx analysis of the yeast genome has recognized correlated duplications that established a new metabolic strategies in fungi, and supported analyses of functional change in aromatases in pigs. TREx dating has limitations, however. Multiple transitions at synonymous sites may cause equilibration and loss of information. Further, to be useful to correlate events in the genomic record, different genes within a genome must suffer transitions at similar rates. A formalism to analyze divergence at two fold redundant codon systems is presented. This formalism exploits two-state approach-to-equilibrium kinetics from chemistry. This formalism captures, in a single equation, the possibility of multiple substitutions at individual sites, avoiding any need to "correct" for these. The formalism also connects specific rate constants for transitions to specific approximations in an underlying evolutionary model, including assumptions that transition rate constants are invariant at different sites, in different genes, in different lineages, and at different times. Therefore, the formalism supports analyses that evaluate these approximations. Transitions at synonymous sites within two-fold redundant coding systems were examined in the mouse, rat, and human genomes. The key metric (f2), the fraction of those sites that holds the same nucleotide, was measured for putative ortholog pairs. A transition redundant exchange (TREx) distance was calculated from f2 for these pairs. Pyrimidine-pyrimidine transitions at these sites occur approximately 14% faster than purine-purine transitions in various lineages. Transition rate constants were similar in different genes within the same lineages; within a set of orthologs, the f2 distribution is only modest overdispersed. No correlation between disparity and overdispersion is observed. In rodents, evidence was found for greater conservation of TREx sites in genes on the X chromosome, accounting for a small part of the overdispersion, however. The TREx metric is useful to analyze the history of transition rate constants within these mammals over the past 100 million years. The TREx metric estimates the extent to which silent nucleotide substitutions accumulate in different genes, on different chromosomes, with different compositions, in different lineages, and at different times.


Multifaceted role of SMCR8 as autophagy regulator.
Through autophagy intracellular material is engulfed by double membrane vesicles and delivered to lysosomes for degradation. This process requires Rab GTPases, Rab GAPs and Rab GEFs for proper membrane trafficking, since they control vesicle budding, targeting and fusion. Deregulation of autophagy contributes to several human diseases including cancer, bacterial or viral infections and neurodegeneration. This review focuses on the complex roles of the newly identified protein SMCR8 and its interaction partners during formation and maturation of autophagosomes as well as regulation of lysosomal function and further discusses their implication in neurodegenerative diseases such as ALS and FTD.


Planned cesarean delivery and urinary retention associated with spinal morphine.
Cesarean delivery (CD) is the second most commonly performed surgery in the United States. As such, prevention of complications associated with this procedure is a top priority in nursing care. Nurses at the study institution perceived that postcesarean patients experienced increased urinary retention after use of spinal morphine for postoperative pain relief. This observation prompted a review of the literature indicating that limited research had been conducted in this area. The purpose of this study was to explore the relationship of postelective CD urinary retention and dose of spinal morphine. A retrospective, quasi-experimental, three-group design was used. Records of 150 patients, ages 17 to 39, undergoing elective primary or repeat CD were examined. Morphine doses included 100, 150, and 200 mcg. No statistically significant differences were found between the three groups.


Monitoring of allograft vasculopathy by intravascular ultrasound one month and one year after heart transplantation: A single center study.
The aim of this trial was to use intravascular ultrasound (IVUS) to determine whether cardiac allograft vasculopathy (CAV) starts progressing during the first year after heart transplantation (HTx). We retrospectively analyzed 51 patients (11 women) who received heart transplants in our center between January 2010 and September 2013 and underwent coronary angiography as well as IVUS examination one month and one year after HTx. Patients with proven calcification and fibrotic plates in the IVUS examination one month after HTx constituted a group with defined donor-transmitted atherosclerosis (DTA). In patients without DTA, measurements of maximal intimal thickening (MIT) were made in two predetermined locations. Eight of the 51 patients had DTA, while 43 did not. These were divided based on maximal intimal thickness (MIT) into a group with MIT < 0.5 mm (27) and MIT ≥ 0.5 mm (16). No patient with MIT < 0.5 mm developed allograft vasculopathy within one year after HTx. CAV developed in three patients (P = 0.045) out of the 16 patients with MIT ≥ 0.5. In patients with DTA, a statistically significant deterioration in percent area stenosis (PAS) occurred in both artery sections (P = 0.01). Our trial showed that CAV progresses during the first year after HTx significantly more frequently in patients with DTA and MIT ≥ 0.5 mm. It is essential in these patients to implement an IVUS control examination one year after transplantation. The results can lead to a change in treatment strategy to prevent further progress of the disease.


Two morphologically distinct blood-brain barriers preventing entry of cytochrome c into cerebrospinal fluid.
After intravenous injection, cytochrome c does not enter the cerebrospinal fluid. In most areas of the brain, the marker is prevented from leaving cerebral vessels by the capillary endothelium. In the choroid plexus, the marker passes freely out of capillaries into the extracellular space. However, it does not traverse tight junctions between epithelial cells and is rapidly incorporated into mnembrane-bound vesicles within the cell cytoplasm. Thereafter, cytochrome c is apparently removed by lysosomal degradation. These data suggest that there are at least two morphologically distinct blood-brain barriers to cytochrome c and that pinocytosis may be a mechanism for intracellular degradation rather than transcellular transport.


Agent-Based Modelling for Simulation-Based Design of Sustainable Faecal Sludge Management Systems.
Re-using faecal sludge (FS) to generate value has the potential to contribute towards solving the issue of long term sanitation solutions in growing urban areas across sub-Saharan Africa; however, hitherto, no design tools have been available that are capable of simulating a system involving economic factors, complex social issues and environmental circumstances. We hypothesized that Agent-Based Modelling (ABM), when deployed with appropriate rigour, can provide such a tool. Extensive field work was carried out in a Malawian city, investigating the adoption of Skyloo above-ground composting toilets by households, and the operation of the municipal FS site. 65 semi-structured interviews and 148 household interviews, together with observations, were carried out to characterize these processes, with the data acquired being used to construct two separate ABMs. The Skyloo ABM was run for various scenarios of start-up capital for business and payback of loans against the toilet cost to households. The municipal FS Site ABM was run for different patterns of dumping fee and enforcement structure. The field work demonstrated that there is potential for further expansion of FS reuse, with a market for agricultural application. The Skyloo ABM identified the significance of start-up capital for a business installing the toilet technology; the municipal FS Site ABM showed that existing fees, fines and regulatory structure were insufficient to reduce illegal dumping of FS to any useful degree, but that a monthly permit system would provide enhanced revenue to the city council compared with per-visit charging of disposal companies at the municipal FS site. Whilst each ABM ideally requires some additional data before full application, we have, for the first time, shown that ABM provides a basis for the simulation-based design of FS management systems, including complex social, economic and environmental factors.


Biomimetic nanoparticle technology for cardiovascular disease detection and treatment.
Cardiovascular disease (CVD), which encompasses a number of conditions that can affect the heart and blood vessels, presents a major challenge for modern-day healthcare. Nearly one in three people has some form of CVD, with many suffering from multiple or intertwined conditions that can ultimately lead to traumatic events such as a heart attack or stroke. While the knowledge obtained in the past century regarding the cardiovascular system has paved the way for the development of life-prolonging drugs and treatment modalities, CVD remains one of the leading causes of death in developed countries. More recently, researchers have explored the application of nanotechnology to improve upon current clinical paradigms for the management of CVD. Nanoscale delivery systems have many advantages, including the ability to target diseased sites, improve drug bioavailability, and carry various functional payloads. In this review, we cover the different ways in which nanoparticle technology can be applied towards CVD diagnostics and treatments. The development of novel biomimetic platforms with enhanced functionalities is discussed in detail.


Recanalisation and ulcer recurrence rates following ultrasound-guided foam sclerotherapy.
The aim was to assess vein recanalisation and ulcer recurrence in patients with chronic venous ulceration following ultrasound-guided foam sclerotherapy. Open (CEAP 6) or recently healed (CEAP 5) chronic venous leg ulcers were treated with foam sclerotherapy between July 2010 and August 2012. Venous duplex scans were performed two weeks and one and two years post treatment, recording recanalisation and reflux. One- and two-year ulcer recurrence rates were calculated using Kaplan-Meier survival analysis. A total of 100 legs were treated in 92 patients; 86 were CEAP 5 and 14 were CEAP 6. At two weeks complete or short segment occlusion was demonstrated in 99/100 legs. Complete follow-up was 93% at one year and 88% at two years. Complete and segmental recanalisation with new reflux was recorded in 11/93 (12%) legs and 25/93 (27%) legs, respectively (overall 36/93; 39%) at one year; and 6/88 (7%) legs and 15/88 (17%) legs, respectively (overall 21/88; 24%) at two years. Kaplan-Meier survival analysis shows 64% ulcers healed at 24 weeks and 86% at one year. Ulcer recurrence rate at one and two years was 2.3% and 5.1%. Over one-third of superficial veins treated with foam sclerotherapy recanalised at one year and just under a quarter of superficial veins recanalised at two years. Despite this, ulcer recurrence rates were low, and recanalisation failed to predict recurrence.


Eradication of multidrug-resistant A. baumannii in burn wounds by antiseptic pulsed electric field.
Emerging bacterial resistance to multiple drugs is an increasing problem in burn wound management. New non-pharmacologic interventions are needed for burn wound disinfection. Here we report on a novel physical method for disinfection: antiseptic pulsed electric field (PEF) applied externally to the infected burns. In a mice model, we show that PEF can reduce the load of multidrug resistant Acinetobacter baumannii present in a full thickness burn wound by more than four orders of magnitude, as detected by bioluminescence imaging. Furthermore, using a finite element numerical model, we demonstrate that PEF provides non-thermal, homogeneous, full thickness treatment for the burn wound, thus, overcoming the limitation of treatment depth for many topical antimicrobials. These modeling tools and our in vivo results will be extremely useful for further translation of the PEF technology to the clinical setting, as they provide the essential elements for planning of electrode design and treatment protocol.


Computed Tomography in the Management of Adrenal Tumors: Does Size Still Matter?
We sought to evaluate computed tomography (CT) imaging as a predictor of adrenal tumor pathology. A retrospective review was conducted of patients who underwent unilateral adrenalectomy for an adrenal mass between January 2005 and July 2015. Tumors were classified as benign, indeterminate, or malignant based on preoperative CT findings. Of 697 patients who underwent unilateral adrenalectomy, 216 met the inclusion criteria. Pathology was benign in 88.4%, indeterminate in 2.3%, and malignant in 9.3%, with a median tumor diameter of 2.7 cm (interquartile range, 1.7-4.1 cm) and 9.5 cm (interquartile range, 7.1-12 cm) in the benign and malignant groups, respectively (P < 0.001). Of the tumors with benign features on CT, 100% (143/143) had benign final pathology. Imaging characteristics of adrenal tumors on CT scan predict benign pathology 100% of the time. Regardless of size, when interpreted as benign on CT scan, laparoscopic adrenalectomy, if technically feasible, should be the technique used when surgery is offered, or close surveillance may be a safe alternative.


Urbanization in sub-saharan Africa and implication for malaria control.
Malaria not only remains a leading cause of morbidity and mortality, but it also impedes socioeconomic development, particularly in sub-Saharan Africa. Rapid and unprecedented urbanization, going hand-in-hand with often declining economies, might have profound implications for the epidemiology and control of malaria, as the relative disease burden increases among urban dwellers. Reviewing the literature and using a modeling approach, we find that entomologic inoculation rates in cities range from 0 to 54 per year, depending on the degree of urbanization, the spatial location within a city, and overall living conditions. Using the latest United Nations figures on urbanization prospects, nighttime light remotely sensed images, and the "Mapping Malaria Risk in Africa" results on climate suitability for stable malaria transmission, we estimate that 200 million people (24.6% of the total African population) currently live in urban settings where they are at risk of contracting the disease. Importantly, the estimated total surface area covered by these urban settings is only approximately 1.1-1.6% of the total African surface. Considering different plausible scenarios, we estimate an annual incidence of 24.8-103.2 million cases of clinical malaria attacks among urban dwellers in Africa. These figures translate to 6-28% of the estimated global annual disease incidence. Against this background, basic health care delivery systems providing early diagnosis and early treatment and preventive actions through mother and child health programs and the promotion of insecticide-treated bed nets for the rapidly growing numbers of the urban poor must be improved alongside well-tailored and integrated malaria control strategies. We propose environmental management and larviciding within well-specified productive sites as a main feature for such an integrated control approach. Mitigation of the current burden of malaria in urban African settings, in turn, is a necessity for stimulating environmentally and socially sustainable development.


Optimization of Invasion-Specific Effects of Betulin Derivatives on Prostate Cancer Cells through Lead Development.
The anti-invasive and anti-proliferative effects of betulins and abietane derivatives was systematically tested using an organotypic model system of advanced, castration-resistant prostate cancers. A preliminary screen of the initial set of 93 compounds was performed in two-dimensional (2D) growth conditions using non-transformed prostate epithelial cells (EP156T), an androgen-sensitive prostate cancer cell line (LNCaP), and the castration-resistant, highly invasive cell line PC-3. The 25 most promising compounds were all betulin derivatives. These were selected for a focused secondary screen in three-dimensional (3D) growth conditions, with the goal to identify the most effective and specific anti-invasive compounds. Additional sensitivity and cytotoxicity tests were then performed using an extended cell line panel. The effects of these compounds on cell cycle progression, mitosis, proliferation and unspecific cytotoxicity, versus their ability to specifically interfere with cell motility and tumor cell invasion was addressed. To identify potential mechanisms of action and likely compound targets, multiplex profiling of compound effects on a panel of 43 human protein kinases was performed. These target de-convolution studies, combined with the phenotypic analyses of multicellular organoids in 3D models, revealed specific inhibition of AKT signaling linked to effects on the organization of the actin cytoskeleton as the most likely driver of altered cell morphology and motility.


Antimorphic goosecoids.
goosecoid (gsc) is a homeobox gene expressed in the Spemann organizer that has been implicated in vertebrate axis formation. Here antimorphic gscs are described. One antimorphic gsc (MTgsc) was fortuitously created by adding 5 myc epitopes to the N terminus of gsc. The other antimorph (VP16gsc) contains the transcriptional activation domain of VP16. mRNA injection of either antimorph inhibits dorsal gastrulation movements and leads to embryos with severe axial defects. They upregulate ventral gene expression in the dorsal marginal zone and inhibit dorsal mesoderm differentiation. Like the VP16 domain, the N-terminal myc tags act by converting wild-type gsc from a transcriptional repressor into an activator. However, unlike MTgsc, VP16gsc is able at low dose to uncouple head from trunk formation, indicating that different antimorphs may elicit distinct phenotypes. The experiments reveal that gsc and/or gsc-related genes function in axis formation and gastrulation. Moreover, this work warns against using myc tags indiscriminately for labeling DNA-binding proteins.


Effect of integrated responsive stimulation and nutrition interventions in the Lady Health Worker programme in Pakistan on child development, growth, and health outcomes: a cluster-randomised factorial effectiveness trial.
Stimulation and nutrition delivered through health programmes at a large scale could potentially benefit more than 200 million young children worldwide who are not meeting their developmental potential. We investigated the feasibility and effectiveness of the integration of interventions to enhance child development and growth outcomes in the Lady Health Worker (LHW) programme in Sindh, Pakistan. We implemented a community-based cluster-randomised effectiveness trial through the LHW programme in rural Sindh, Pakistan, with a 2 × 2 factorial design. We randomly allocated 80 clusters (LHW catchments) of children to receive routine health and nutrition services (controls; n=368), nutrition education and multiple micronutrient powders (enhanced nutrition; n=364), responsive stimulation (responsive stimulation; n=383), or a combination of both enriched interventions (n=374). The allocation ratio was 1:20 (ie, 20 clusters per intervention group). The data collection team were masked to the allocated intervention. All children born in the study area between April, 2009, and March, 2010, were eligible for enrolment if they were up to 2·5 months old without signs of severe impairments. Interventions were delivered by LHWs to families with children up to 24 months of age in routine monthly group sessions and home visits. The primary endpoints were child development at 12 and 24 months of age (assessed with the Bayley Scales of Infant and Toddler Development, Third Edition) and growth at 24 months of age. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT007159636. 1489 mother-infant dyads were enrolled into the study, of whom 1411 (93%) were followed up until the children were 24 months old. Children who received responsive stimulation had significantly higher development scores on the cognitive, language, and motor scales at 12 and 24 months of age, and on the social-emotional scale at 12 months of age, than did those who did not receive the intervention. Children who received enhanced nutrition had significantly higher development scores on the cognitive, language, and social-emotional scales at 12 months of age than those who did not receive this intervention, but at 24 months of age only the language scores remained significantly higher. We did not record any additive benefits when responsive stimulation was combined with nutrition interventions. Responsive stimulation effect sizes (Cohen's d) were 0·6 for cognition, 0·7 for language, and 0·5 for motor development at 24 months of age; these effect sizes were slightly smaller for the combined intervention group and were low to moderate for the enhanced nutrition intervention alone. Children exposed to enhanced nutrition had significantly better height-for-age Z scores at 6 months (p<0·0001) and 18 months (p=0·02) than did children not exposed to enhanced nutrition. Longitudinal analysis showed a small benefit to linear growth from enrolment to 24 months (p=0·026) in the children who received the enhanced nutrition intervention. The responsive stimulation intervention can be delivered effectively by LHWs and positively affects development outcomes. The absence of a major effect of the enhanced nutrition intervention on growth shows the need for further analysis of mediating variables (eg, household food security status) that will help to optimise future nutrition implementation design. UNICEF.


Enhanced tumor cell isolation by a biomimetic combination of E-selectin and anti-EpCAM: implications for the effective separation of circulating tumor cells (CTCs).
The selective detection of circulating tumor cells (CTCs) is of significant clinical importance for the clinical diagnosis and prognosis of cancer metastasis. However, largely because of the extremely low number of CTCs (as low as 1 in 10(9) hematologic cells) in the blood of patients, effective detection and separation of the rare cells remain a tremendous challenge. Cell rolling is known to play a key role in physiological processes such as the recruitment of leukocytes to sites of inflammation and selectin-mediated CTC metastasis. Furthermore, because CTCs typically express the epithelial-cell adhesion molecule (EpCAM) on the surface whereas normal hematologic cells do not, substrates with immobilized antibody against EpCAM may specifically interact with CTCs. In this article, we created biomimetic surfaces functionalized with P- and E-selectin and anti-EpCAM that induce different responses in HL-60 (used as a model of leukocytes in this study) and MCF-7 (a model of CTCs) cells. HL-60 and MCF-7 cells showed different degrees of interaction with P-/E-selectin and anti-EpCAM at a shear stress of 0.32 dyn/cm(2). HL-60 cells exhibited rolling on P-selectin-immobilized substrates at a velocity of 2.26 +/- 0.28 microm/s whereas MCF-7 cells had no interaction with the surface. Both cell lines, however, had interactions with E-selectin, and the rolling velocity of MCF-7 cells (4.24 +/- 0.31 microm/s) was faster than that of HL-60 cells (2.12 +/- 0.15 microm/s). However, only MCF-7 cells interacted with anti-EpCAM-coated surfaces, forming stationary binding under flow. More importantly, the combination of the rolling (E-selectin) and stationary binding (anti-EpCAM) resulted in substantially enhanced separation capacity and capture efficiency (more than 3-fold enhancement), as compared to a surface functionalized solely with anti-EpCAM that has been commonly used for CTC capture. Our results indicate that cell-specific detection and separation may be achieved through mimicking the biological processes of combined dynamic cell rolling and stationary binding, which will likely lead to a CTC detection device with significantly enhanced specificity and sensitivity without a complex fabrication process.


Prediction of Skin Necrosis after Mastectomy for Breast Cancer Using Indocyanine Green Angiography Imaging.
In immediate tissue expander reconstruction following total mastectomy for breast cancer, indocyanine green angiography (ICGA)-guided skin trimming is useful for the prevention of complications. However, instances of unclear ICGA contrast can occur with this method, which are difficult to judge as to whether preventive trimming is warranted. To further improve the mastectomy flap necrosis rate, more accurate objective parameters are necessary. The degree of clinical improvement was compared between 81 patients trimmed according to the surgeon's judgment (non-ICGA group) and 100 patients with ICGA-guided trimming (ICGA group). We then retrospectively measured 3 parameters [relative perfusion (RP); time (T) to reach RPmax; and slope (S = RP/T) reflecting the rate of increase to RPmax] by using region of interest analysis software and examined their relationships with skin necrosis. The rate of grade III necrosis (reaching the subcutaneous fat layer) was significantly lower in the ICGA group (4.8%) than in the non-ICGA group (17.8%; P < 0.05). The specificity of RP for the diagnosis of skin necrosis was high (98.5%; cutoff value, 34). However, the sensitivities of slope parameters were higher than RP. ICGA-guided trimming decreased the rate of deep skin necrosis requiring additional surgical treatment. Region of interest analysis indicated that a relatively low percentage luminescence (RP < 34) was indicative of the need for skin trimming, combined with a slow increase in the perfusion of the mastectomy skin flaps.


Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature.
Red blood cell (RBC) transfusions are common in intensive care unit, trauma, and surgical patients. However, the hematocrit that should be maintained in any particular patient because the risks of further transfusion of RBC outweigh the benefits remains unclear. A systematic review of the literature to determine the association between red blood cell transfusion, and morbidity and mortality in high-risk hospitalized patients. MEDLINE, Embase, Cochrane Register of Controlled Trials, and citation review of relevant primary and review articles. Cohort studies that assessed the independent effect of RBC transfusion on patient outcomes. From 571 articles screened, 45 met inclusion criteria and were included for data extraction. Forty-five studies including 272,596 were identified (the outcomes from one study were reported in four separate publications). The outcome measures were mortality, infections, multiorgan dysfunction syndrome, and acute respiratory distress syndrome. The overall risks vs. benefits of RBC transfusion on patient outcome in each study was classified as (i) risks outweigh benefits, (ii) neutral risk, and (iii) benefits outweigh risks. The odds ratio and 95% confidence interval for each outcome measure was recorded if available. The pooled odds ratios were determined using meta-analytic techniques. Forty-five observational studies with a median of 687 patients/study (range, 63-78,974) were analyzed. In 42 of the 45 studies the risks of RBC transfusion outweighed the benefits; the risk was neutral in two studies with the benefits outweighing the risks in a subgroup of a single study (elderly patients with an acute myocardial infarction and a hematocrit <30%). Seventeen of 18 studies, demonstrated that RBC transfusions were an independent predictor of death; the pooled odds ratio (12 studies) was 1.7 (95% confidence interval, 1.4-1.9). Twenty-two studies examined the association between RBC transfusion and nosocomial infection; in all these studies blood transfusion was an independent risk factor for infection. The pooled odds ratio (nine studies) for developing an infectious complication was 1.8 (95% confidence interval, 1.5-2.2). RBC transfusions similarly increased the risk of developing multi-organ dysfunction syndrome (three studies) and acute respiratory distress syndrome (six studies). The pooled odds ratio for developing acute respiratory distress syndrome was 2.5 (95% confidence interval, 1.6-3.3). Despite the inherent limitations in the analysis of cohort studies, our analysis suggests that in adult, intensive care unit, trauma, and surgical patients, RBC transfusions are associated with increased morbidity and mortality and therefore, current transfusion practices may require reevaluation. The risks and benefits of RBC transfusion should be assessed in every patient before transfusion.


Noninvasive visualization of retinoblastoma growth and metastasis via bioluminescence imaging.
To establish human retinoblastoma (RB) animal models that allow sensitive, noninvasive and continuous monitoring of tumor growth and metastasis in vivo. The human RB tumor cell lines HXO-Rb44 and Y79 were engineered to express a fusion reporter gene allowing for bioluminescence and fluorescence imaging. Intraocular and metastatic tumors were induced in immunodeficient nude mice by injection of bioluminescent RB cells into eye compartments and into the left ventricle or tail vein. The growth kinetics of intraocular and metastatic tumors was quantitatively and continuously monitored via bioluminescence imaging (BLI). Intraocular injection of HXO-Rb44-GFP-luc cells resulted in 100%, 80%, and 80% successful RB tumor development in the anterior chamber, vitreal cavity and subretinal space, respectively. The subretinal injection of Y79-GFP-luc cells resulted in 100% tumor development. BLI signal intensity correlated with the number of tumor cells injected as well as the weight of the tumor-bearing eyes. After bilateral subretinal injection of HXO-Rb44-GFP-luc cells, one of six RB tumor mice developed brain metastasis. Intracardiac injection of HXO-Rb44-GFP-luc cells resulted in metastatic disease in 9 of 15 nude mice, whereas tail vein injection resulted in metastasis in 1 of 16. Metastases were developed in multiple organs, including lymph nodes, bone, and brain, resembling the metastatic profile in patients with RB. BLI allowed sensitive, noninvasive, and quantitative localization and monitoring of intraocular and metastatic RB tumor growth in vivo and thus may be a useful tool to study RB biology as well as anti-RB therapies.


Symptomatic treatment of the cough in whooping cough.
Around 16 million cases of whooping cough (pertussis) occur worldwide each year, mostly in low-income countries. Much of the morbidity of whooping cough in children and adults is due to the effects of the paroxysmal cough. Cough treatments proposed include corticosteroids, beta2-adrenergic agonists, pertussis-specific immunoglobulin, antihistamines and possibly leukotriene receptor antagonists (LTRAs). To assess the effectiveness and safety of interventions to reduce the severity of paroxysmal cough in whooping cough in children and adults. We updated our searches of the Cochrane Central Register of Controlled Trials (CENTRAL, 2014, Issue 1), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, the Database of Abstracts of Reviews of Effects (DARE 2014, Issue 2), accessed from The Cochrane Library, MEDLINE (1950 to 30 January 2014), EMBASE (1980 to 30 January 2014), AMED (1985 to 30 January 2014), CINAHL (1980 to 30 January 2014) and LILACS (30 January 2014). We searched Current Controlled Trials to identify trials in progress. We selected randomised controlled trials (RCTs) and quasi-RCTs of any intervention (excluding antibiotics and vaccines) to suppress the cough in whooping cough. Two review authors (SB, MT) independently selected trials, extracted data and assessed the quality of each trial for this review in 2009. Two review authors (SB, KW) independently reviewed additional studies identified by the updated searches in 2012 and 2014. The primary outcome was frequency of paroxysms of coughing. Secondary outcomes were frequency of vomiting, frequency of whoop, frequency of cyanosis (turning blue), development of serious complications, mortality from any cause, side effects due to medication, admission to hospital and duration of hospital stay. We included 12 trials of varying sample sizes (N = 9 to 135), mainly from high-income countries, including a total of 578 participants. Ten trials recruited children (N = 448 participants). Two trials recruited adolescents and adults (N = 130 participants). We considered only three trials to be of high methodological quality (one trial each of diphenhydramine, pertussis immunoglobulin and montelukast). Included studies did not show a statistically significant benefit for any of the interventions. Only six trials, including a total of 196 participants, reported data in sufficient detail for analysis. Diphenhydramine did not change coughing episodes; the mean difference (MD) of coughing spells per 24 hours was 1.9; 95% confidence interval (CI) -4.7 to 8.5 (N = 49 participants from one trial). One trial on pertussis immunoglobulin reported a possible mean reduction of -3.1 whoops per 24 hours (95% CI -6.2 to 0.02, N = 47 participants) but no change in hospital stay (MD -0.7 days; 95% CI -3.8 to 2.4, N = 46 participants). Dexamethasone did not show a clear decrease in length of hospital stay (MD -3.5 days; 95% CI -15.3 to 8.4, N = 11 participants from one trial) and salbutamol showed no change in coughing paroxysms per day (MD -0.2; 95% CI -4.1 to 3.7, N = 42 participants from two trials). Only one trial comparing pertussis immunoglobulin versus placebo (N = 47 participants) reported data on adverse events: 4.3% in the treatment group (rash) versus 5.3% in the placebo group (loose stools, pain and swelling at injection site). There is insufficient evidence to draw conclusions about the effectiveness of interventions for the cough in whooping cough. More high-quality trials are needed to assess the effectiveness of potential antitussive treatments in patients with whooping cough.


Medical regulation and health outcomes: the effect of the physician examination requirement.
This article investigates the effect on health outcomes of the regulation prohibiting physicians from prescribing drugs without a prior physical examination. This requirement could improve health by reducing illegal access to prescription drugs. However, it reduces access to health care by making it more difficult for patients and physicians to use many forms of telemedicine. Thus, this regulation generates a trade-off between access and safety. Using matching techniques, we find that the physician examination requirement leads to an increase of 1% in mortality rates from disease, the equivalent of 8.5 more deaths per 100,000 people, and a decrease of 6.7% in injury mortality, the equivalent of 2.5 deaths per 100,000 people. The magnitude of these effects is larger in rural areas and in areas with low physician density and is accompanied by an 18% increase in the number of days lost each month to illness.


Morphologic findings of the ischemic myocardium.
This study assesses the relation between qualitative and quantitative findings of myocytes and interstitial connective tissue in the ischemic heart disease. Qualitative and quantitative changes of myocytes and interstitial connective tissue were studied on the serial cross myocardial sections from 20 autopsied hearts with ischemic lesions, stained by immunohistochemistry using a monoclonal antibody (von Willebrand factor) and with hematoxylin-eosin method. Myocardial sections included proximal and distal part of occlusion and area of occlusion of coronary vessels. The volume densities (V V) of the cardiac myocytes and interstitial fibrosis in the group with coronary occlusion were examined stereologically and compared with control group. The findings showed a significant reduction in the volume density of myocytes and an increase in the volume density of interstitial fibrosis in patients with coronary occlusion compared with control group. Significant reduction in the volume density of myocytes and an increase in volume density of interstitial fibrosis were greater in the distal part of occlusion and area of occlusion, than in the proximal part of the occlusion. Our stereological results give useful quantitative information's of changes in myocardium parts during coronary occlusion as well as in normal conditions, and represent objective proof of significant changes in ischemic myocardium described by qualitative analyses.


Patients' self-reported nausea: Validation of the Numerical Rating Scale and of a daily summary of repeated Numerical Rating Scale scores.
To validate the Numeric Rating Scale (NRS) for postoperative nausea assessments, and determine whether a central tendency, median, based on patients' self-rated nausea is a clinically applicable daily measure to describe patients' nausea after major surgery. Postoperative nausea causes major discomfort, risks for complications and prolonged hospital stays. The NRS is recommended for the assessment of pain but is little explored for assessing nausea. A repeated measure design was carried out on patients who had undergone major surgery in three Swedish hospitals. Nonparametric statistical methods were used to analyse (a) associations between the NRS and a verbal scale (no, mild, moderate and severe) and (b) to analyse associations between Measure 1 (nausea scores postoperative Day 1) and Measure 2 (retrospective nausea scores at rest and during activity, postoperative Day 2). Reporting of this research adheres to the Strobe Guidelines. The mean age of the 479 patients (44% women) in the sample was 65 years (range, 22-93 years). Self-assessed nausea scores from the NRS and the verbal scale correlated well (rS pearman = 0.79). Correlation between nausea at rest and nausea during activity was rS pearman = 0.81. The calculated median scores (Measure 1) showed only moderate correlations with retrospective nausea scores (Measure 2); 4-9 ratings, rS pearman = 0.41; 6-9 ratings, rS pearman = 0.54. Numeric Rating Scale scores showed strong associations with a verbal scale; therefore, the NRS seems to be a valid tool to measure nausea intensity. The quality of daily summarised median nausea scores needs to be further explored before clinical use. The use of the NRS in assessments of nausea in postoperative care will facilitate communication between patients and health care professionals regarding nausea intensity. When documenting nausea, it seems unnecessary to distinguish nausea at rest from nausea during activity.


Atomistic investigations on the mechanical properties and fracture mechanisms of indium phosphide nanowires.
The mechanical properties of indium phosphide (InP) nanowires are an emerging issue due to the promising applications of these nanowires in nanoelectromechanical and microelectromechanical devices. In this study, molecular dynamics simulations of zincblende (ZB) and wurtzite (WZ) crystal structured InP nanowires (NWs) are presented under uniaxial tension at varying sizes and temperatures. It is observed that the tensile strengths of both types of NWs show inverse relationships with temperature, but are independent of the size of the nanowires. Moreover, applied load causes brittle fracture by nucleating cleavage on ZB and WZ NWs. When the tensile load is applied along the [001] direction, the direction of the cleavage planes of ZB NWs changes with temperature. It is found that the {111} planes are the cleavage planes at lower temperatures; on the other hand, the {110} cleavage planes are activated at elevated temperatures. In the case of WZ NWs, fracture of the material is observed to occur by cleaving along the (0001) plane irrespective of temperature when the tensile load is applied along the [0001] direction. Furthermore, the WZ NWs of InP show considerably higher strength than their ZB counterparts. Finally, the impact of strain rate on the failure behavior of InP NWs is also studied, and higher fracture strengths and strains at higher strain rates are found. With increasing strain rate, the number of cleavages also increases in the NWs. This paper also provides in-depth understanding of the failure behavior of InP NWs, which will aid the design of efficient InP NWs-based devices.


Recent advances in diagnosing pathogenic equine gastrointestinal helminths: the challenge of prepatent detection.
Parasites infecting horses are ubiquitous and clinically important across the world. The major parasitic threats to equine health are cyathostomins, Parascaris equorum, Anoplocephala perfoliata, and Strongylus vulgaris. Increasing levels of anthelmintic resistance reported world wide in equine parasites have led to recommendations of constructing sustainable parasite control programmes based on systematic surveillance of parasite levels. Regulations at the European Union level now make anthelmintics available on prescription-only basis and disallow prophylactic treatment. This emphasizes the needs for reliable and practical diagnostic tools for detection of major parasites infecting equines. The current, widely used coprological techniques are important and useful, but they do have considerable limitations as they are incapable of diagnosing the pathogenic migrating stages. Species-specific molecular assays have been developed for diagnosing patent infections with 21 cyathostomin species, A. perfoliata, and S. vulgaris, but none of these have found use in practice. An antibody-directed enzyme-linked immunosorbent assay (ELISA) has been developed, validated and made commercially available for diagnosing A. perfoliata infection, but interpretation is complicated by the fact that horses not harbouring tapeworms can maintain elevated antibody titres. Recent work with a coproantigen ELISA has shown promise for reliable detection of current A. perfoliata infection. Perhaps most remarkable is the fact that the pathogenic larval stages of cyathostomins and large strongyles cannot be detected by any of the available diagnostics. With the lengthy prepatency periods characterizing these parasites, there is a huge need for developing such assays. The recent identification of a possible diagnostic marker for encysted cyathostomins holds great promise, and could become very useful in clinical practice. Several attempts have been made to construct assays for diagnosing the highly pathogenic migrating larvae of S. vulgaris, but none of these have performed sufficiently to make a useful test. The present review illustrates that classical coprological techniques remain the cornerstone of equine parasitology diagnosis and surveillance, and will remain so in a foreseeable future. However, promising progress has been made for developing assays capable of diagnosing prepatent stages of strongyle infection, and there is reason to hope for validated and useful assays in the relative near future.


r-bPiDI, an α6β2* Nicotinic Receptor Antagonist, Decreases Nicotine-Evoked Dopamine Release and Nicotine Reinforcement.
α6β2* nicotinic acetylcholine receptors (nAChRs) expressed by dopaminergic neurons mediate nicotine-evoked dopamine (DA) release and nicotine reinforcement. α6β2* antagonists inhibit these effects of nicotine, such that α6β2* receptors serve as therapeutic targets for nicotine addiction. The present research assessed the neuropharmacology of 1,10-bis(3-methyl-5,6-dihydropyridin-1(2H)-yl)decane (r-bPiDI), a novel small-molecule, tertiary amino analog of its parent compound, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI). bPiDI was previously shown to inhibit both nicotine-evoked DA release and the reinforcing effects of nicotine. In the current study, r-bPiDI inhibition of [(3)H]nicotine and [(3)H]methyllycaconitine binding sites was evaluated to assess interaction with the recognition binding sites on α4β2* and α7* nAChRs, respectively. Further, r-bPiDI inhibition of nicotine-evoked DA release in vitro in the absence and presence of α-conotoxin MII and following chronic in vivo nicotine administration were determined. The ability of r-bPiDI to decrease nicotine self-administration and food-maintained responding was also assessed. Results show that r-bPiDI did not inhibit [(3)H]nicotine or [(3)H]methyllycaconitine binding, but potently (IC50 = 37.5 nM) inhibited nicotine-evoked DA release from superfused striatal slices obtained from either drug naïve rats or from those repeatedly treated with nicotine. r-bPiDI inhibition of nicotine-evoked DA release was not different in the absence or presence of α-conotoxin MII, indicating that r-bPiDI acts as a potent, selective α6β2* nAChR antagonist. Acute systemic administration of r-bPiDI specifically decreased nicotine self-administration by 75 %, and did not alter food-maintained responding, demonstrating greater specificity relative to bPiDI and bPiDDB, as well as the tertiary amino analog r-bPiDDB. The current work describes the discovery of r-bPiDI, a tertiary amino, α-conotoxin MII-like small molecule that acts as a potent and selective antagonist at α6β2* nAChRs to specifically decrease nicotine self-administration in rats, thus, establishing r-bPiDI as a lead compound for development as a treatment for nicotine addiction.


Airborne Algae: Their Abundance and Heterogeneity.
The literature on the occurrence of airborne algae is reviewed briefly. Airborne algae were isolated into culture in both quantity and diversity. Qualitative experiments and culture techniques are discussed, as are quantitative sampling techniques and preliminary correlations of the occurrence of algae, fungi, and pollen in the air. The data disclose an important pathway for the dispersion of soil algae and support an observation that algae may be important as causal agents in inhalant allergies.


Ab initio molecular dynamics of thiophene: the interplay of internal conversion and intersystem crossing.
The fast and slow components of the relaxation of photoexcited thiophene have been investigated by means of SHARC (surface hopping including arbitrary couplings) molecular dynamics based on multiconfiguration electronic structure calculations. Triplet states are included to ascertain their role in the relaxation process. After thiophene is excited to the S1 state, ultrafast dynamics (τfast = 96 fs) initiates a ring opening due to cleavage of a carbon sulfur bond and simultaneous ring puckering. This time constant is in agreement with previous experimental and theoretical studies. The subsequent dynamics of the open-ring structures is characterized by the interplay of internal conversion and intersystem crossing. For the open-ring structures, the S0, S1, T1 and T2 states are nearly degenerate and the spin-orbit couplings are large. The underlying potential energy surface is flat and long-lived open-ring structures in the singlet as well as in the triplet states are formed. Both the participation of triplet states and the shape of the energy surface explain the experimentally observed slow ring closure in the ground state.


From Constellation Dithering to NOMA Multiple Access: Security in Wireless Systems.
In recent years, there has been a noticeable increase in interest in the possibilities of embedding additional data in the constellation of an already existing information signal in radio technology. This solution more precisely is based on adding a low power signal (or signals) to a stronger signal (cover). As will be described in the article, this technique is used in numerous radio communication areas, such as watermarking, covert channel creation, and multiple access techniques. Typically, those areas are considered as independent research topics. Our comparison suggests that these areas are closely related. In this article, a comprehensive survey of the implementation of signal superposition is conducted with an emphasis on the similarities and differences between individual solutions. Since the nature of the signal model entails certain problems in the security area, we provide the reader with a review of the state-of-the-art research on this topic, including the PLS (physical layer security) and LPD (low probability of detection) issues.


α4-integrin deficiency in B cells does not affect disease in a T-cell-mediated EAE disease model.
The goal of this study was to investigate the role of CD 19+ B cells within the brain and spinal cord during CNS autoimmunity in a peptide-induced, primarily T-cell-mediated experimental autoimmune encephalomyelitis (EAE) model of MS. We hypothesized that CD19+ B cells outside the CNS drive inflammation in EAE. We generated CD19.Cre+/- α4-integrinfl/fl mice. EAE was induced by active immunization with myelin oligodendrocyte glycoprotein peptide (MOGp35-55). Multiparameter flow cytometry was used to phenotype leukocyte subsets in primary and secondary lymphoid organs and the CNS. Serum cytokine levels and Ig levels were assessed by bead array. B-cell adoptive transfer was used to determine the compartment-specific pathogenic role of antigen-specific and non-antigen-specific B cells. A genetic ablation of α4-integrin in CD19+/- B cells significantly reduced the number of CD19+ B cells in the CNS but does not affect EAE disease activity in active MOGp35-55-induced disease. The composition of B-cell subsets in the brain, primary lymphoid organs, and secondary lymphoid organs of CD19.Cre+/- α4-integrinfl/fl mice was unchanged during MOGp35-55-induced EAE. Adoptive transfer of purified CD19+ B cells from CD19.Cre+/- α4-integrinfl/fl mice or C57BL/6 wild-type (WT) control mice immunized with recombinant rMOG1-125 or ovalbumin323-339 into MOGp35-55-immunized CD19.Cre+/- α4-integrinfl/fl mice caused worse clinical EAE than was observed in MOGp35-55-immunized C57BL/6 WT control mice that did not receive adoptively transferred CD19+ B cells. Observations made in CD19.Cre+/- α4-integrinfl/fl mice in active MOGp35-55-induced EAE suggest a compartment-specific pathogenic role of CD19+ B cells mostly outside of the CNS that is not necessarily antigen specific.


Connecting rehabilitation and everyday life--the lived experiences among women with stress-related ill health.
The aim was to describe and understand how connecting rehabilitation experiences and everyday life was characterised in the lived experiences during the rehabilitation in women with stress-related ill health. Five women were interviewed on three occasions during a rehabilitation programme and once 3 months later. Data were analysed using the Empirical, Phenomenological and Psychological method. The participants experienced connections between their rehabilitation and their previous, present and future everyday life influencing both rehabilitation and everyday life in a back-and-forth process. These connections were experienced in mind or in doing, mostly targeting the private arena in everyday life. Connecting rehabilitation experiences to their working situations was more challenging and feelings of frustration and being left alone were experienced. Although the participants described constructive connections between rehabilitation experiences and the private arena in everyday life, they mostly failed to experience connections that facilitated a positive return to work. Recommended support in the return to work process in rehabilitation comprises the provision of practical work-related activities during rehabilitation; being supportive in a constructive dialogue between the participant and the workplace, and continuing this support in follow-ups after the actual rehabilitation period. Rehabilitation for persons with stress-related ill health needs to focus on the private arena as well as the work situation in everyday life. Creative activities may enable experiences that inspire connections in mind and connections targeting the private arena in everyday life. The work situation needs to be thoroughly discussed during rehabilitation for enabling the participants to experience a support in the return to work process. Rehabilitation including practical work-related activities, support in a constructive dialogue between the participant and the manager at the workplace, and continued support in follow-ups targeting the workplace might be beneficial for successfully return to work.


In vitro and in vivo 31P nuclear magnetic resonance measurements of metabolic changes post radiation.
Radiation-induced metabolic changes previously observed in tumors using phosphorus nuclear magnetic resonance spectroscopy include changes in the relative amounts of the phospholipid precursors phosphoethanolamine and phosphocholine, increases in membrane catabolites, and increases in energy status. To elucidate the degree to which these in vivo alterations are a result of intrinsic cellular changes versus radiation-induced systemic effects, the Radiation-Induced Fibrosarcoma-1 tumor model was studied before and over the course of 7 days after a single dose of 17 Gy. In vivo studies were performed with tumors implanted in C3H/He mice; in vitro studies used cells that were perfused in agarose gel threads after being grown, radiated, and maintained in monolayer. The statistically significant increases in the downfield component of the phosphomonoester peak, which consists primarily of phosphoethanolamine, compared to the upfield component, phosphocholine, were qualitatively similar in vivo and in vitro post radiation. Statistically significant increases in the membrane catabolite glycerophosphocholine, a phosphodiester, were also observed in both tumors and cell culture after irradiation, with a greater percentage change in vitro. This suggests that changes in the phosphomonoester and phosphodiester concentrations are primarily an intrinsic effect of radiation on cellular metabolism, modulated to a lesser degree by systemic effects. In contrast, the statistically significant increases in energy status after the 17-Gy dose showed markedly different temporal responses in the two systems. Therefore, energy status changes observed in vivo are due largely to systemic changes, such as changes in blood flow. Flow cytometry data obtained from the cultured cells showed a sustained increase in the G2-M fraction starting at 24 h, the first time point measured after irradiation, which continued for the 7 days studied post radiation. These data indicate that the in vivo changes detected by nuclear magnetic resonance in phospholipid precursors and catabolites occur directly at the cellular level and may reflect cell death or growth inhibition after antineoplastic therapy.


Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model.
Biallelic CEBPA mutations and FMS-like tyrosine kinase receptor 3 (FLT3) length mutations are frequently identified in human acute myeloid leukemia (AML) with normal cytogenetics. However, the molecular and cellular mechanisms of oncogene cooperation remain unclear because of a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of an internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed CCAAT/enhancer binding protein alpha (C/EBPα) mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMPs) otherwise prevented by a block in differentiation and skewed lineage priming induced by biallelic C/EBPα mutations. These cellular changes are accompanied by an upregulation of hematopoietic stem cell and STAT5 target genes. By gene expression analysis in premalignant populations, we further show a role of FLT3 ITD in activating genes involved in survival/transformation and chemoresistance. Both multipotent progenitors and GMP cells contain the potential to induce AML similar to corresponding cells in human AML samples showing that this model resembles human disease.


Small volume resuscitation with hypertonic saline is more effective in ameliorating trauma-hemorrhagic shock-induced lung injury, neutrophil activation and red blood cell dysfunction than pancreatitic protease inhibition.
Recognition of the limitations of standard crystalloid resuscitation has led to the search for alternative resuscitation strategies that might better limit the development of trauma-hemorrhage-induced organ dysfunction and systemic inflammation. Thus, the goal of this study was to compare the effects of two resuscitation strategies alone, and in combination, with those of standard resuscitation with Ringers lactate (RL). The two strategies were small volume resuscitation with hypertonic saline (HTS) and intraluminal inhibition of pancreatic proteases with the serine protease inhibitor nafamostat. Male rats were subjected to trauma-hemorrhagic shock (T/HS) or trauma sham-shock (T/SS) and resuscitated with RL, HTS, nafamostat, or the combination of HTS and nafamostat. The T/HS model consisted of a laparotomy plus 90 minutes of shock (MAP 30 mm Hg). Three hours after the end of the shock or sham-shock period, lung permeability, pulmonary neutrophil sequestration, neutrophil activation, red blood cell deformability, and gut injury were assessed. Both HTS and nafamostat reduced T/HS-induced pulmonary permeability and neutrophil sequestration, as well as neutrophil activation as compared with resuscitation with RL. However, HTS was more effective than nafamostat in reducing T/HS-induced acute lung injury and neutrophil activation. Additionally, HTS, but not nafamostat, reduced T/HS-induced RBC rigidification. Lastly, gut injury after T/HS was reduced to the greatest extent by the combination of HTS plus nafamostat. Small volume resuscitation with HTS is more effective than RL and nafamostat in limiting T/HS-induced acute lung injury, neutrophil activation and red blood cell injury.


Negative regulation of DsbA-L gene expression by the transcription factor Sp1.
Disulfide-bond A oxidoreductase-like protein (DsbA-L) possesses beneficial effects such as promoting adiponectin multimerization and stability, increasing insulin sensitivity, and enhancing energy metabolism. The expression level of DsbA-L is negatively correlated with obesity in mice and humans, but the underlying mechanisms remain unknown. To address this question, we generated reporter gene constructs containing the promoter sequence of the mouse DsbA-L gene. Deletion analysis showed that the proximal promoter of mouse DsbA-L is located between -186 and -34 bp relative to the transcription start site. In silico analysis identified a putative Sp1 transcription factor binding site in the first intron of the DsbA-L gene. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis indicated that Sp1 bound to this intron region in vitro and in intact cells. Overexpression of Sp1 or suppressing Sp1 expression by siRNA reduced or increased DsbA-L promoter activity, respectively. The binding activity of Sp1 was gradually decreased during 3T3-L1 cell differentiation and was significantly increased in adipose tissues of obese mice. Our results identify Sp1 as an inhibitor of DsbA-L gene transcription, and the Sp1-mediated inhibition of DsbA-L gene expression may provide a mechanism underlying obesity-induced adiponectin downregulation and insulin resistance.


Spatial prediction of Plasmodium falciparum prevalence in Somalia.
Maps of malaria distribution are vital for optimal allocation of resources for anti-malarial activities. There is a lack of reliable contemporary malaria maps in endemic countries in sub-Saharan Africa. This problem is particularly acute in low malaria transmission countries such as those located in the horn of Africa. Data from a national malaria cluster sample survey in 2005 and routine cluster surveys in 2007 were assembled for Somalia. Rapid diagnostic tests were used to examine the presence of Plasmodium falciparum parasites in finger-prick blood samples obtained from individuals across all age-groups. Bayesian geostatistical models, with environmental and survey covariates, were used to predict continuous maps of malaria prevalence across Somalia and to define the uncertainty associated with the predictions. For analyses the country was divided into north and south. In the north, the month of survey, distance to water, precipitation and temperature had no significant association with P. falciparum prevalence when spatial correlation was taken into account. In contrast, all the covariates, except distance to water, were significantly associated with parasite prevalence in the south. The inclusion of covariates improved model fit for the south but not for the north. Model precision was highest in the south. The majority of the country had a predicted prevalence of < 5%; areas with > or = 5% prevalence were predominantly in the south. The maps showed that malaria transmission in Somalia varied from hypo- to meso-endemic. However, even after including the selected covariates in the model, there still remained a considerable amount of unexplained spatial variation in parasite prevalence, indicating effects of other factors not captured in the study. Nonetheless the maps presented here provide the best contemporary information on malaria prevalence in Somalia.


Atomic structure of a nudivirus occlusion body protein determined from a 70-year-old crystal sample.
Infectious protein crystals are an essential part of the viral lifecycle for double-stranded DNA Baculoviridae and double-stranded RNA cypoviruses. These viral protein crystals, termed occlusion bodies or polyhedra, are dense protein assemblies that form a crystalline array, encasing newly formed virions. Here, using X-ray crystallography we determine the structure of a polyhedrin from Nudiviridae. This double-stranded DNA virus family is a sister-group to the baculoviruses, whose members were thought to lack occlusion bodies. The 70-year-old sample contains a well-ordered lattice formed by a predominantly α-helical building block that assembles into a dense, highly interconnected protein crystal. The lattice is maintained by extensive hydrophobic and electrostatic interactions, disulfide bonds, and domain switching. The resulting lattice is resistant to most environmental stresses. Comparison of this structure to baculovirus or cypovirus polyhedra shows a distinct protein structure, crystal space group, and unit cell dimensions, however, all polyhedra utilise common principles of occlusion body assembly.


Comparisons of the effect of naturally acquired maternal pertussis antibodies and antenatal vaccination induced maternal tetanus antibodies on infant's antibody secreting lymphocyte responses and circulating plasma antibody levels.
The goal of this study was to explore the effects of trans-placental tetanus toxoid (TT) and pertussis (PT) antibodies on an infant's response to vaccination in the context of antenatal immunization with tetanus but not with pertussis. 38 mothers received a single dose of TT vaccine during pregnancy. Infants received tetanus and pertussis vaccines at 6, 10 and 14 wk of age. TT and PT anti-IgG secretion by infant lymphocytes was measured at 15 wk. Plasma antibodies were measured at 6 wk (pre-vaccination), 15 wk and 1 y of age. Prior to vaccination, TT and PT antibody were detected in 94.6% and 15.2% of infants. At 15 wk anti-TT-IgG and anti-PT-IgG in plasma was increased by 7-9 fold over pre-vaccination levels, while at 1 y plasma anti-TT-IgG was decreased by approximately 5-fold from the peak and had returned to near the pre-vaccination level. At 1 y plasma anti-PT-IgG was decreased by 2-fold 1 yfrom the 15 wk level. However, 89.5% and 82.3% of infants at 1 y had protective levels of anti-TT and anti-PT IgG, respectively. Pre-vaccination plasma IgG levels were associated with lower vaccine-specific IgG secretion by infant lymphocytes at 15 wk (p < 0.10). This apparent inhibition was seen for anti-TT-IgG at both 15 wk (p < 0.05) and t 1 y (p < 0.10) of age. In summary, we report an apparent inhibitory effect of passively derived maternal antibody on an infants' own antibody response to the same vaccine. However, since the cut-off values for protective titers are low, infants had protective antibody levels throughout infancy.


Understanding and using patient experiences as evidence in healthcare priority setting.
In many countries, committees make priority-setting decisions in order to control healthcare costs. These decisions take into account relevant criteria, including clinical effectiveness, cost-effectiveness, and need, and are supported by evidence usually drawn from clinical and economic studies. These sources of evidence do not include the specific perspective and information that patients can provide about the condition and treatment. Drawing on arguments from political philosophy and ethics that are the ethical basis for many priority-setting bodies, the authors argue that criteria like need and its effects on patients and caregivers are best supported by evidence generated from patients' experiences. Social sciences and mixed-methods research support the generation and collection of robust evidence. Patient experience is required for a decision-making process that considers all relevant evidence. For fair priority-setting, decision-makers should consider relevant evidence and reasons, so patient experience evidence should not be ignored. Patient experience must be gathered in a way that generates high quality and methodologically rigorous evidence. Established quantitative and qualitative methods can assure that evidence is systematic, adherent to quality standards, and valid. Patient, like clinical, evidence should be subject to a transparent review process. Considering all relevant evidence gives each person an equal opportunity at having their treatment funded. Patient experience gives context to the clinical evidence and also directly informs our understanding of the nature of the condition and its effects, including patients' needs, how to meet them, and the burden of illness. Such evidence also serves to contextualise reported effects of the treatment. The requirement to include patient experience as evidence has important policy implications for bodies that make priority-setting decisions since it proposes that new types of evidence reviews are commissioned and considered.


Ethical issues in the design of randomized trials: to sham or not to sham.
The placebo effect is based on the expectations of the patient regarding the effectiveness of the treatment. The high levels of stress and rituals involved with surgery can lead to a strong placebo effect. However, the ethical principles of performing sham surgery to measure any placebo effect have been questioned, and sham-controlled surgical trials are rarely conducted. While there are a number of ethical principles that must be considered to justify the implementation of a sham-controlled surgical clinical trial, four areas deserve particular attention: equipoise, risk minimization, informed consent, and deception. Particularly in orthopaedics, where equipoise is common, sham-controlled trials may be important to ensure that inferior or ineffective treatments do not become standard practice.


Regulatory T cells confer a circadian signature on inflammatory arthritis.
The circadian clock is an intrinsic oscillator that imparts 24 h rhythms on immunity. This clock drives rhythmic repression of inflammatory arthritis during the night in mice, but mechanisms underlying this effect are not clear. Here we show that the amplitude of intrinsic oscillators within macrophages and neutrophils is limited by the chronic inflammatory environment, suggesting that rhythms in inflammatory mediators might not be a direct consequence of intrinsic clocks. Anti-inflammatory regulatory T (Treg) cells within the joints show diurnal variation, with numbers peaking during the nadir of inflammation. Furthermore, the anti-inflammatory action of Treg cells on innate immune cells contributes to the night-time repression of inflammation. Treg cells do not seem to have intrinsic circadian oscillators, suggesting that rhythmic function might be a consequence of external signals. These data support a model in which non-rhythmic Treg cells are driven to rhythmic activity by systemic signals to confer a circadian signature to chronic arthritis.


Specimen-induced distortions in light microscopy.
Specimen-induced aberrations affect the imaging properties in optical 3D microscopy, especially when high numerical aperture lenses are used. Studies on aberrations are often properly concerned with the degradation of image quality such as compromised resolution or reduced signal intensity. Apart from these, aberration effects can also introduce geometric image distortions. The effects, discussed here are particularly strong when thick biological specimens are investigated. Using a high numerical aperture interferometer, we measured wavefront aberrations in transmission mode and quantified geometric distortions associated with specimen-induced aberrations. This assessment for a range of biological specimens allows estimation of the accuracy of spatial measurements. The results show that high-resolution spatial measurements can be significantly compromised by specimen-induced aberrations.


Genomic chaos in peripheral blood lymphocytes of Hodgkin's lymphoma patients one year after ABVD chemotherapy/radiotherapy.
Hodgkin's lymphoma (HL) is a lymphoid malignancy representing 5% of all cancers in children, 16% in adolescents, and 30-40% of all malignant lymphomas and has a survival rate of ~95% at 10 years. One of the most common treatment schemes uses a cocktail of genotoxic agents including adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) with or without radiotherapy. We investigated the occurrence of chromosomal damage in peripheral blood lymphocytes from five patients diagnosed with HL who provided samples before (BT), during chemotherapy (DT) and ~1 year after ABVD chemotherapy/radiotherapy (AT). Five healthy subjects served as controls. Chromosomal abnormalities were evaluated by multicolor fluorescence in situ hybridization. The average frequencies of structural chromosomal aberrations in HL samples were 0.11, 0.22, and 0.96 per cell in BT, DT, and AT samples, respectively. These frequencies were significantly different (P < 0.0001) with respect to control subjects (0.02 per cell). Interestingly, the highest frequency of structural damage, including genomic chaos and nonclonal abnormalities, was observed in the AT samples indicating that new aberrations were continuously produced. Rejoined structural chromosomal aberrations were the most common type of aberrations, although aneuploidies were also significantly increased. Finally, we found several chromosomal abnormalities linked to cancer secondary to treatment in all five HL patients. Our results show that ABVD chemotherapy plus radiotherapy is inducing genomic chaos in vivo; moreover, the persistence of genomic instability in the hematopoietic stem cells from HL patients may play a role in the occurrence of secondary cancer that is observed in 5-20% of HL patients. Environ. Mol. Mutagen. 59:755-768, 2018. © 2018 Wiley Periodicals, Inc.


Demonstration of Epstein-Barr virus-specific DNA polymerase in chemically induced Raji cells and its antibody in serum from patients with nasopharyngeal carcinoma.
Epstein-Barr virus (EBV) has been found to be associated with nasopharyngeal carcinoma (NPC), and antibodies with high frequency and titer to EBV proteins have been found in sera from NPC patients. Raji cells, an EBV genome-carrying nonproducer cell line, treated with 12-O-tetradecanoylphorbol-13-acetate and n-butyrate induced a unique EBV DNA polymerase which has properties similar to the EBV DNA polymerase induced by 12-O-tetradecanoylphorbol-13-acetate in P3HR-1 cells, an EBV producer cell line. The possible presence of antibodies to this EBV DNA polymerase in NPC patient serum was examined. The mean number of EBV DNA polymerase units neutralized was 380 +/- 168 units/ml serum (mean +/- SD) in 48 sera from patients with NPC, whereas that in the sera from 52 healthy donors was 62 +/- 56 units/ml (p less than 0.01). The EBV DNA polymerase antibody was found to be associated with the immunoglobulin G but not the immunoglobulin A fraction, and its titer was not correlated with the titers against EBV DNase or virus capsid antigen-immunoglobulin A. Whether the EBV DNA polymerase antibody is against the EBV DNA polymerase core protein or its stimulating protein is still being investigated. This study demonstrated the high frequency and high titer of antibody against EBV DNA polymerase in serum from NPC patients and suggested the potential of utilizing this antibody titer to complement other methods for the early diagnosis or prognosis of NPC.


Monitoring two-dimensional coordination reactions: directed assembly of co-terephthalate nanosystems on Au(111).
We report scanning tunneling microscopy observations on the formation of 2D Co-based coordination compounds on the reconstructed Au(111) surface. Preorganized arrays of Co bilayer islands are shown to be local reaction sites, which are consumed in the formation of Co-terephthalate aggregates and regular nanoporous grids. The latter exhibit a planar geometry stabilized by the smooth substrate. The nanogrids are based on a rectangular motif, which is understood as an intrinsic feature of a 2D cobaltous terephthalate sheet and dominates over the templating influence of the quasihexagonal substrate atomic lattice. The dynamics of the Co island dissolution and metallosupramolecular self-assembly could be monitored in situ. Complementary first-principles calculations were performed to analyze the underlying driving forces and to examine general trends in 2D metal-carboxylate formation. The findings indicate the wide applicability of coordination chemistry concepts at surfaces, which moreover can be spatially confined by using templated substrates, and its potential to synthesize arrangements unavailable in bulk materials.


Use of biologicals in allergic and type-2 inflammatory diseases during the current COVID-19 pandemic: Position paper of Ärzteverband Deutscher Allergologen (AeDA)A, Deutsche Gesellschaft für Allergologie und Klinische Immunologie (DGAKI)B, Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA)C, Österreichische Gesellschaft für Allergologie und Immunologie (ÖGAI)D, Luxemburgische Gesellschaft für Allergologie und Immunologie (LGAI)E, Österreichische Gesellschaft für Pneumologie (ÖGP)F in co-operation with the German, Austrian, and Swiss ARIA groupsG, and the European Academy of Allergy and Clinical Immunology (EAACI)H.
Since the beginning of the COVID-19 pandemic, the treatment of patients with allergic and atopy-associated diseases has faced major challenges. Recommendations for "social distancing" and the fear of patients becoming infected during a visit to a medical facility have led to a drastic decrease in personal doctor-patient contacts. This affects both acute care and treatment of the chronically ill. The immune response after SARS-CoV-2 infection is so far only insufficiently understood and could be altered in a favorable or unfavorable way by therapy with monoclonal antibodies. There is currently no evidence for an increased risk of a severe COVID-19 course in allergic patients. Many patients are under ongoing therapy with biologicals that inhibit type 2 immune responses via various mechanisms. There is uncertainty about possible immunological interactions and potential risks of these biologicals in the case of an infection with SARS-CoV-2. A selective literature search was carried out in PubMed, Livivo, and the internet to cover the past 10 years (May 2010 - April 2020). Additionally, the current German-language publications were analyzed. Based on these data, the present position paper provides recommendations for the biological treatment of patients with allergic and atopy-associated diseases during the COVID-19 pandemic. In order to maintain in-office consultation services, a safe treatment environment must be created that is adapted to the pandemic situation. To date, there is a lack of reliable study data on the care for patients with complex respiratory, atopic, and allergic diseases in times of an imminent infection risk from SARS-CoV-2. Type-2-dominant immune reactions, as they are frequently seen in allergic patients, could influence various phases of COVID-19, e.g., by slowing down the immune reactions. Theoretically, this could have an unfavorable effect in the early phase of a SARS-Cov-2 infection, but also a positive effect during a cytokine storm in the later phase of severe courses. However, since there is currently no evidence for this, all data from patients treated with a biological directed against type 2 immune reactions who develop COVID-19 should be collected in registries, and their disease courses documented in order to be able to provide experience-based instructions in the future. The use of biologicals for the treatment of bronchial asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, and spontaneous urticaria should be continued as usual in patients without suspected infection or proven SARS-CoV-2 infection. If available, it is recommended to prefer a formulation for self-application and to offer telemedical monitoring. Treatment should aim at the best possible control of difficult-to-control allergic and atopic diseases using adequate rescue and add-on therapy and should avoid the need for systemic glucocorticosteroids. If SARS-CoV-2 infection is proven or reasonably suspected, the therapy should be determined by weighing the benefits and risks individually for the patient in question, and the patient should be involved in the decision-making. It should be kept in mind that the potential effects of biologicals on the immune response in COVID-19 are currently not known. Telemedical offers are particularly desirable for the acute consultation needs of suitable patients.


Novel anti-malarial combinations and their toxicity.
Artemisinin combination therapy for the treatment of uncomplicated malaria includes artemether plus lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine, artesunate plus sulfadoxine-pyrimethamine and dihydroartemisinin plus piperaquine. These drugs are safe and efficacious at present. The emergence of artemisinin resistant parasites in SE Asia means that there is a need to optimise drug dosing and investigate novel therapies to maintain the impressive reduction in malaria mortality which has been seen in the past decade.


Rapid additive-free bacteria lysis using traveling surface acoustic waves in microfluidic channels.
We report an additive-free method to lyse bacteria and extract nucleic acids and protein using a traveling surface acoustic wave (TSAW) coupled to a microfluidic device. We characterize the effects of the TSAW on E. coli by measuring the viability of cells exposed to the sound waves and find that about 90% are dead. In addition, we measure the protein and nucleic acids released from the cells and show that we recover about 20% of the total material. The lysis method should work for all types of bacteria. These results demonstrate the feasibility of using TSAW to lyse bacteria in a manner that is independent of the type of bacteria.


Vang-like protein 2 and Rac1 interact to regulate adherens junctions.
The Wnt planar cell polarity (Wnt/PCP) pathway signals through small Rho-like GTPases to regulate the cytoskeleton. The core PCP proteins have been mapped to the Wnt/PCP pathway genetically, but the molecular mechanism of their action remains unknown. Here, we investigate the function of the mammalian PCP protein Vang-like protein 2 (Vangl2). RNAi knockdown of Vangl2 impaired cell-cell adhesion and cytoskeletal integrity in the epithelial cell lines HEK293T and MDCK. Similar effects were observed when Vangl2 was overexpressed in HEK293T, MDCK or C17.2 cells. The effects of Vangl2 overexpression could be blocked by knockdown of the small GTPase Rac1 or by dominant-negative Rac1. In itself, knockdown of Rac1 impaired cytoskeletal integrity and reduced cell-cell adhesion. We found that Vangl2 bound and re-distributed Rac1 within the cells but did not alter Rac1 activity. Moreover, both transgenic mouse embryos overexpressing Vangl2 in neural stem cells and loop-tail Vangl2 loss-of-function embryos displayed impaired adherens junctions, a cytoskeletal unit essential for neural tube rigidity and neural tube closure. In vivo, Rac1 was re-distributed within the cells in a similar way to that observed by us in vitro. We propose that Vangl2 affects cell adhesion and the cytoskeleton by recruiting Rac1 and targeting its activity in the cell to adherens junctions.


Dyadic coping and relationship functioning in couples coping with cancer: a systematic review.
Cancer not only affects the patient but also the partner. In fact, couples may react as a unit rather than as individuals while coping with cancer (i.e., dyadic coping). We assessed (1) the relationship between dyadic coping and relationship functioning in couples coping with cancer and (2) whether intervention studies aimed at improving dyadic coping were able to enhance the relationship functioning of these couples. Recommendations for future studies are provided. A systematic search was conducted to identify all eligible papers between January 1990 and September 2012. The databases PubMed, PsycINFO, the Cochrane Library, and EMBASE were screened. Most studies (n = 33) used an appropriate study design, adequate measurements, adequate analytical techniques, and a sufficient number of included participants to answer addressed research questions. However, the definition and assessment of dyadic coping strategies differed, which hampered comparison. Coping styles characterized by open and constructive (cancer-related) communication, supportive behaviours, positive dyadic coping, and joint problem solving were related to higher relationship functioning, whereas dysfunctional communication patterns (e.g., protective buffering, demand-withdraw communication), unsupportive behaviours, and negative dyadic coping were related to lower relationship functioning. The results of the intervention studies were inconsistent: while some studies reported a beneficial effect on relationship functioning, other studies report no such effect, or only found a positive effect in couples with fewer personal relationship resources. This review showed that adequate dyadic coping may improve relationship functioning, while dysfunctional dyadic coping may impede relationship functioning. In order to increase the comparability of the reported findings, a more uniformly conceptualized perspective on dyadic coping is needed. A better understanding of the dyadic challenges couples coping with cancer may face and more insight on how to expand the dyadic coping of these coupes might facilitate improvements in the quality of cancer care. Couple-based intervention studies may increase the couples' relationship functioning. However, future research is needed to examine more specifically which couples may benefit from such interventions. Statement of contribution What is already known on this subject? Dyadic coping may influence the distress experienced by both members of the couple and their relationship functioning. Several reviews already reported on the potential of couple-based interventions to improve the dyadic coping of couples coping with cancer and on the beneficial effects of this coping on the psychosocial adjustment and relationship functioning of patients and partners (e.g., Badr & Krebs, 2012; Martire, Shulz, Helgeson, Small, & Saghafi, 2010; Regan et al., 2012). However, even though we now know that couple-based intervention might be useful, no systematic review has been conducted that focuses specifically on the mechanisms of dyadic coping itself. What does this study add? This review showed the importance of stress communication, supportive behaviours, and positive dyadic coping for the maintenance or enhancement of relationship functioning in couples coping with cancer. In addition, the dyadic intervention studies send an important message that encourages to further examine the potential benefit of such interventions in future. However, more consensus in the conceptualization and assessment of the dyadic coping styles is needed in order to increase the comparability of the reported findings.