Effectiveness of Chlorhexidine Wipes for the Prevention of Multidrug-Resistant Bacterial Colonization and Hospital-Acquired Infections in Intensive Care Unit Patients: A Randomized Trial in Thailand.
To determine the effectiveness of daily bathing with 2% chlorhexidine-impregnated washcloths in preventing multidrug-resistant (MDR) gram-positive bacterial colonization and bloodstream infection. A randomized, open-label controlled trial was conducted in 4 medical intensive care units (ICUs) in Thailand from December 2013 to January 2015. Patients were randomized to receive cleansing with non-antimicrobial soap (control group) or 2% chlorhexidine-impregnated washcloths used to wipe the patient's body once daily (chlorhexidine group). Swabs were taken from nares, axilla, antecubital, groin, and perianal areas on admission and on day 3, 5, 7, and 14. The 5 outcomes were (1) favorable events ( all samples negative throughout ICU admission, or initially positive samples with subsequent negative samples); (2) MDR bacteria colonization-free time; (3) hospital-acquired infection; (4) length of ICU and hospital stay; (5) adverse skin reactions. A total of 481 patients were randomly assigned to the control group (241) or the chlorhexidine group (240). Favorable events at day 14 were observed in 34.8% of patients in the control group and 28.6% in the chlorhexidine group (P=.79). Median MDR bacteria colonization-free times were 5 days in both groups. The incidence rate of hospital-acquired infection and the length of the ICU and hospital stay did not differ significantly between groups. The incidence of adverse skin reactions in the chlorhexidine group was 2.5%. The effectiveness of 2% chlorhexidine-impregnated washcloths for the prevention of MDR gram-negative bacteria colonization and hospital-acquired infection in adult patients in ICU was not proven. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01989416.


Atrial fibrillation ablation in patients undergoing aortic valve replacement.
Current guidelines suggest that the use of a mechanical prosthesis is favored when patients are already receiving long-term anticoagulation for conditions such as atrial fibrillation (AF). Surgical AF ablation can restore normal sinus rhythm (NSR) and obviate the need for anticoagulation. The study aim was to determine the impact of concomitant AF ablation in patients with AF undergoing aortic valve replacement (AVR) on the restoration of NSR and subsequent requirement for anticoagulation. Between April 2004 and December 2009, a total of 124 patients (mean age 74 +/- 12 years) with pre-existing AF underwent AVR with or without coronary artery bypass grafting. The documented preoperative rhythm was long-standing persistent AF in 39 patients (32%), persistent AF in five (4%), and paroxysmal AF in 80 (65%). Eighty patients (65%) had concomitant surgical AF ablation. In the ablation group, bilateral pulmonary vein isolation was performed in 55 cases (69%), left atrial-maze in 15 (19%), and Cox-maze in 10 (13%). A left atrial appendage closure was performed in 70 patients (88%). Sinus rhythm, in addition to anti-arrhythmic and warfarin use, were assessed between three and 15 months after surgery. Postoperatively, 13 patients died and 18 were lost to follow up during the three- to 15-month window; consequently, 71 patients were available for analysis in the ablation group, and 22 in the non-ablation group. In-hospital mortality was 4% (the Ambler score predicted a median (IQR) of 6 (4-9)%). Freedom from AF when not receiving anti-arrhythmic drugs (AADs) occurred in 58 patients (82%) in the ablation group, compared to eight (36%) in the non-ablation group (p < 0.001). Fifty patients (70%) were free from warfarin in the ablation group, compared to six (27%) in the non-ablation group (p < 0.001). No differences were identified in freedom from AF between the surgical AF lesion sets. AF ablation, younger age, and paroxysmal AF were independently associated with freedom from AF when not receiving AADs. Surgical AF ablation is associated with an improved restoration of NSR in patients with AF requiring AVR. The need for anticoagulation is reduced in the majority of patients. A bioprosthetic valve may be an acceptable option for a patient with AF who requires AVR.


Illuminating the understudied GPCR-ome.
G-protein-coupled receptors (GPCRs) are the target of >30% of approved drugs. Despite their popularity, many of the >800 human GPCRs remain understudied. The Illuminating the Druggable Genome (IDG) project has generated many tools leading to important insights into the function and druggability of these so-called 'dark' receptors. These tools include assays, such as PRESTO-TANGO and TRUPATH, billions of small molecules made available via the ZINC virtual library, solved orphan GPCR structures, GPCR knock-in mice, and more. Together, these tools are illuminating the remaining 'dark' GPCRs.


It takes guts to learn: machine learning techniques for disease detection from the gut microbiome.
Associations between the human gut microbiome and expression of host illness have been noted in a variety of conditions ranging from gastrointestinal dysfunctions to neurological deficits. Machine learning (ML) methods have generated promising results for disease prediction from gut metagenomic information for diseases including liver cirrhosis and irritable bowel disease, but have lacked efficacy when predicting other illnesses. Here, we review current ML methods designed for disease classification from microbiome data. We highlight the computational challenges these methods have effectively overcome and discuss the biological components that have been overlooked to offer perspectives on future work in this area.


[Computer-assisted training programs in aphasia therapy].
This article shows how aphasic patients can use computer-aided training programs that enable them to train the language more or less independently apart from speech therapy. The computer offers help or feedback the moment it is asked for. The patient evaluates this as a mature method of therapy.


Amyloid myopathy masquerading as polymyositis.
It is not well appreciated that the clinical presentation of amyloid myopathy can mimic that of polymyositis. By retrospective clinicopathologic analysis we determined distinctive features of amyloid myopathy that differentiate the 2 diseases. Two patients with clinical and histologic evidence of an inflammatory myopathy had fatal outcomes despite appropriate treatment for polymyositis. Their clinical course and original pathologic specimens were reviewed. In addition, original tissue samples were obtained and analyzed using Congo red staining and immunoperoxidase. The initial diagnosis of polymyositis was supported in both cases by muscle biopsies showing inflammatory infiltrates and elevations of creatine phosphokinase and by classic electromyography. Retrospective evaluation of the initial muscle biopsies disclosed subtle but incontrovertible evidence of vascular amyloid. Further analysis of the original specimens confirmed the presence of immunoglobin light chain (AL) amyloid. Amyloid myopathy can mimic polymyositis. Both can have similar clinical symptoms, as well as inflammatory infiltrates on muscle biopsy. Failure to recognize amyloid myopathy deprives patients of potentially life prolonging treatment. Congo red staining and immunohistochemical analysis of tissue could prevent misdiagnosis.


Visual threshold is set by linear and nonlinear mechanisms in the retina that mitigate noise: how neural circuits in the retina improve the signal-to-noise ratio of the single-photon response.
In sensory biology, a major outstanding question is how sensory receptor cells minimize noise while maximizing signal to set the detection threshold. This optimization could be problematic because the origin of both the signals and the limiting noise in most sensory systems is believed to lie in stimulus transduction. Signal processing in receptor cells can improve the signal-to-noise ratio. However, neural circuits can further optimize the detection threshold by pooling signals from sensory receptor cells and processing them using a combination of linear and nonlinear filtering mechanisms. In the visual system, noise limiting light detection has been assumed to arise from stimulus transduction in rod photoreceptors. In this context, the evolutionary optimization of the signal-to-noise ratio in the retina has proven critical in allowing visual sensitivity to approach the limits set by the quantal nature of light. Here, we discuss how noise in the mammalian retina is mitigated to allow for highly sensitive night vision.


Discovery of Selective and Orally Available Galectin-1 Inhibitors.
A new series of orally available α-d-galactopyranosides with high affinity and specificity toward galectin-1 have been discovered. High affinity and specificity were achieved by changing six-membered aryl-triazolyl substituents in a series of recently published galectin-3-selective α-d-thiogalactosides (e.g., GB1107 Kd galectin-1/3 3.7/0.037 μM) for five-membered heterocycles such as thiazoles. The in vitro pharmacokinetic properties were optimized, resulting in several galectin-1 inhibitors with favorable properties. One compound, GB1490 (Kd galectin-1/3 0.4/2.7 μM), was selected for further characterization toward a panel of galectins showing a selectivity of 6- to 320-fold dependent on galectin. The X-ray structure of GB1490 bound to galectin-1 reveals the compound bound in a single conformation in the carbohydrate binding site. GB1490 was shown to reverse galectin-1-induced apoptosis of Jurkat cells at low μM concentrations. No cell cytotoxicity was observed for GB1490 up to 90 μM in the A549 cells. In pharmacokinetic studies in mice, GB1490 showed high oral bioavailability (F% > 99%).


Genetic heterogeneity of Usher syndrome type II in a Dutch population.
The Usher syndromes are a group of autosomal recessive disorders characterised by retinitis pigmentosa (RP) with congenital, stable (non-progressive) sensorineural hearing loss. Profound deafness, RP, and no vestibular responses are features of Usher type I, whereas moderate to severe hearing loss and RP with normal vestibular function describe Usher type II. The gene responsible for most cases of Usher II, USH2a, is on chromosome 1q41; at least one other Usher II gene (as yet unlinked) is known to exist. Usher III presents with a progressive hearing loss that can mimic the audiometric profile seen in Usher II. A gene causing Usher III in a group of Finnish families, USH3, resides on chromosome 3q. Since the phenotypes for Usher II and III overlap, it is important to determine how frequently Usher IIa, Usher IIb, and Usher III occur in a clinical population of non-Usher I patients. DNA was collected from 29 Dutch families and genotyped with six DNA markers known to flank the USH2a gene closely, and with five markers that flank USH3. Results of haplotype and linkage analysis were consistent with linkage to the USH2a locus in 26 of these 29 Dutch families. Three families displayed no linkage to 1q41 markers, and one of these three families appeared unlinked to 3q markers as well; current haplotypes of the other two families are inconclusive for linkage with the USH3 locus without further genotyping. While an A test for heterogeneity of USH2a was statistically significant, no convincing evidence of linkage to USH3 was found in this Dutch sample. Consequently, the frequency of the unlinked variety of Usher IIa (Usher IIb) in The Netherlands was estimated as 0.104. To determine if marker alleles could be used to differentiate Usher type IIa from Usher IIb, parental chromosomes of the 26 Usher IIa families were analysed for significant non-random association of specific alleles from flanking loci with USH2a, but no linkage disequilibrium was observed in this Dutch population.


The efficacy of a work-station intervention programme to improve functional ability and flexibility in ageing clients with Cerebral Palsy: a pilot study.
Health care workers associated with the long-term care of ageing clients with Cerebral Palsy have reported on the adverse effects of less active daily activity programmes with resultant decreased functional mobility. While the negative effects of ageing have been reported in these clients, programmes have not been implemented to determine whether these adverse changes can be reversed or prevented. The efficacy of a work-station intervention programme to improve functional ability and flexibility in ageing clients with cerebral palsy was investigated. A clinical intervention study using repeated measures (pre/post-intervention and at follow-up) to evaluate efficacy was undertaken. Twenty-two clients with Cerebral Palsy participated in a twice-weekly work-station programme delivered over 8 weeks. The Physical Mobility Scale items, two upper limb function measures, range limitation of hip and knee extension and gleno-humeral movement were assessed. Results showed a significant improvement that was retained at follow-up in functional but not flexibility measures. The efficacy of a work-station exercise programme for ageing clients with Cerebral Palsy was demonstrated. Evidence was provided that the PMS is effective in showing level of dependency for these clients.


Dynamic outflow obstruction due to the transient extensive left ventricular wall motion abnormalities caused by acute myocarditis in a patient with hypertrophic cardiomyopathy: reduction in ventricular afterload by disopyramide.
A 65-year-old woman was admitted to the coronary care unit because of acute pulmonary edema. Immediate 2-dimensional and Doppler echocardiograms revealed extensive left ventricular wall motion abnormalities and left ventricular hypertrophy with extreme outflow obstruction. Although an ECG showed ST-segment elevation in the anterolateral leads, a coronary arteriogram revealed normal epicardial arteries. Heart failure was relieved after diminishing the dynamic outflow obstruction with disopyramide administration. An endomyocardial biopsy from the right ventricle on the 8th hospital day showed borderline myocarditis. Wall motion abnormalities gradually normalized within 2 weeks. It is speculated that her pulmonary edema would not have been relieved so readily without the immediate reduction in ventricular afterload by disopyramide. These clinical changes over time were observed with serial echo-Doppler examinations.


Urban Living Environment and Myopia in Children.
The global prevalence of myopia has shown a steady increase over recent decades, with urban areas seemingly experiencing a more significant impact. To assess the association between urbanization and the prevalence, incidence, progression, and severity of myopia. This cohort study included students in grades 1 to 6 in Tianjin, China, who underwent 3 vision examinations conducted over a 2-year period, from March 1, 2021, to March 31, 2023. Participants from grades 1 to 4 completed the 2-year follow-up. Urban living environment. The association of urbanization with the incidence, progression, prevalence, and severity of myopia. To quantify urbanization, an urban score was constructed using satellite data and an iterative exploratory factor analysis. Of 177 894 students (51.7% male; mean [SD] age, 10.27 [1.75] years) included in the study, 137 087 students (52.3% male; mean [SD] age, 8.97 [1.21] years) were followed up for 2 years. A positive association was identified between myopia incidence and urbanization. Specifically, each 1-unit increment in the urban score was associated with an increased risk of myopia over a 1-year period (odds ratio [OR], 1.09; 95% CI, 1.01-1.15; P = .02) and a 2-year period (OR, 1.53; 95% CI, 1.50-1.57; P < .001). Conversely, each 1-unit increase in the urban score was associated with a significant decrease in myopia progression at 1 year (OR, 0.84; 95% CI, 0.82-0.86; P < .001) and 2 years (OR, 0.73; 95% CI, 0.70-0.75, P < .001). In a cross-sectional data analysis, the urban score was positively associated with myopia prevalence (OR, 1.62; 95% CI, 1.08-2.42; P = .02) and negatively associated with myopia severity, as indicated by spherical equivalent refraction (OR, 1.46; 95% CI, 1.07-1.99; P = .02). This study exploring urban living environments and myopia revealed dual associations of urban living with both the incidence and the progression of myopia. The observed patterns emphasize the urgency of promptly implementing myopia control strategies in less urbanized regions, where myopia progression may be accentuated.


Magnetoencephalography in partial epilepsy: clinical yield and localization accuracy.
The goals of this study were to determine (1) the yield of magnetoencephalography (MEG) according to epilepsy type, (2) if MEG spike sources colocalize with focal epileptogenic pathology, and (3) if MEG can identify the epileptogenic zone when scalp ictal electroencephalogram (EEG) or magnetic resonance imaging (MRI) fail to localize it. Twenty-two patients with mesial temporal (10 patients), neocortical temporal (3 patients), and extratemporal lobe epilepsy (9 patients) were studied. A 37-channel biomagnetometer was used for simultaneously recording MEG with EEG. During the typical 2-3-hour MEG recording session, interictal epileptiform activity was observed in 16 of 22 patients. MEG localization yield was greater in patients with neocortical epilepsy (92%) than in those with mesial temporal lobe epilepsy (50%). In 5 of 6 patients with focal epileptogenic pathology, MEG spike sources were colocalized with the lesions. In 11 of 12 patients with nonlocalizing (ambiguous abnormalities or normal) MRI, MEG spike sources were localized in the region of the epileptogenic zone as ultimately defined by all clinical and EEG information (including intracranial EEG). In conclusion, MEG can reliably localize sources of spike discharges in patients with temporal and extratemporal lobe epilepsy. MEG sometimes provides noninvasive localization data that are not otherwise available with MRI or conventional scalp ictal EEG.


Dissecting the EGFR-PI3K-AKT pathway in oral cancer highlights the role of the EGFR variant III and its clinical relevance.
Dysregulated epidermal growth factor receptor (EGFR)-phosphoinositide-3-kinase (PI3K)-AKT signaling is considered pivotal for oral cancer, and the pathway is a potential candidate for therapeutic targeting. A total of 108 archival samples which were from surgically resected oral cancer were examined. Immunohistochemical staining showed the protein expression of membranous wild-type EGFR and cytoplasmic phosphorylated AKT was detected in 63.9% and 86.9% of the specimens, respectively. In 49.1% of the samples, no phosphatase and tensin homolog (PTEN) expression was detected. With regard to the EGFR variant III (EGFRvIII), 75.0% of the samples showed positive expression for moderate to severe staining, 31.5% of which had high expression levels. Real-time polymerase chain reaction assays for gene copy number assessment of PIK3CA revealed that 24.8% of the samples had alterations, and of EGFR showed that 49.0% had amplification. Direct sequencing of PIK3CA gene showed 2.3% of the samples had a hotspot point mutation. Statistical assessment showed the expression of the EGFRvIII correlated with the T classification and TNM stage. The Kaplan-Meier analyses for patient survival showed that the individual status of phosphorylated AKT and EGFRvIII led to significant differences in survival outcome. The multivariate analysis indicated that phosphorylated AKT, EGFRvIII expression and disease stage were patient survival determinants. Aberrations in the EGFR-PI3K-AKT pathway were frequently found in oral cancers. EGFRvIII and phosphorylated AKT were predictors for the patient survival and clinical outcome.


[Bone metastases treated with radiopharmaceuticals].
The administration of a radionuclide in unsealed source whose radiation will destroy cells that have selectively accumulated product is called radiometabolic therapy. The management of bone pain is a major problem, particularly in cases of breast or prostate where the presence of metastases can remain compatible with long-term survival of cancer patients. In this context, the radiometabolic therapy reduces the pain secondary to bone metastases, in association or not with analgesics. This technique is rarely prescribed as first-line. It can also be combined with external beam radiotherapy or chemotherapy, if clinical conditions permit (due to the increased risk of hematologic toxicity). In this setting, the currently used substances are Metastron® and Quadramet®. Recently, a new product, radium chloride (or Alpharadin®) has shown efficacy in bone metastases from prostate cancer, particularly in terms of bone pain palliation, but also of increased overall survival. In addition, this product has virtually no hematologic toxicity.


The Australian Genetics of Depression Study: New Risk Loci and Dissecting Heterogeneity Between Subtypes.
Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder, but little is known about the genetic characterization of this heterogeneity. Understanding the genetic etiology of MDD can be challenging because large sample sizes are needed for gene discovery-often achieved with a trade-off in the depth of phenotyping. The Australian Genetics of Depression Study is the largest stand-alone depression cohort with both genetic data and in-depth phenotyping and comprises a total of 15,792 participants of European ancestry, 92% of whom met diagnostic criteria for MDD. We leveraged the unique nature of this cohort to conduct a meta-analysis with the largest publicly available depression genome-wide association study to date and subsequently used polygenic scores to investigate genetic heterogeneity across various clinical subtypes of MDD. We increased the number of known genome-wide significant variants associated with depression from 103 to 126 and found evidence of association of novel genes implicated in neuronal development. We found that a polygenic score for depression explained 5.7% of variance in MDD liability in our sample. Finally, we found strong support for genetic heterogeneity in depression with differential associations of multiple psychiatric and comorbid traits with age of onset, longitudinal course, and various subtypes of MDD. Until now, this degree of detailed phenotyping in such a large sample of MDD cases has not been possible. Along with the discovery of novel loci, we provide support for differential pathways to illness models that recognize the overlap with other common psychiatric disorders as well as pathophysiological differences.


Rationing, racism and justice: advancing the debate around 'colourblind' COVID-19 ventilator allocation.
Withholding or withdrawing life-saving ventilators can become necessary when resources are insufficient. In the USA, such rationing has unique social justice dimensions. Structural elements of dominant allocation frameworks simultaneously advantage white communities, and disadvantage Black communities-who already experience a disproportionate burden of COVID-19-related job losses, hospitalisations and mortality. Using the example of New Jersey's Crisis Standard of Care policy, we describe how dominant rationing guidance compounds for many Black patients prior unfair structural disadvantage, chiefly due to the way creatinine and life expectancy are typically considered.We outline six possible policy options towards a more just approach: improving diversity in decision processes, adjusting creatinine scores, replacing creatinine, dropping creatinine, finding alternative measures, adding equity weights and rejecting the dominant model altogether. We also contrast these options with making no changes, which is not a neutral default, but in separate need of justification, despite a prominent claim that it is simply based on 'objective medical knowledge'. In the regrettable absence of fair federal guidance, hospital and state-level policymakers should reflect on which of these, or further options, seem feasible and justifiable.Irrespective of which approach is taken, all guidance should be supplemented with a monitoring and reporting requirement on possible disparate impacts. The hope that we will be able to continue to avoid rationing ventilators must not stand in the way of revising guidance in a way that better promotes health equity and racial justice, both to be prepared, and given the significant expressive value of ventilator guidance.


Evaluation criteria for bioaerosol samplers.
Humans contract a variety of serious diseases through inhalation of infectious aerosols. Thus, the importance of monitoring air for microbial, toxic, or allergic content is recognized in clinical, occupational, and biodefense arenas. However, accurate monitoring of potentially contaminated environments can be hampered by selection of aerosol samplers with inadequate performance for the intended task. In this study, 29 aerosol samplers were evaluated based on their respective air flow, size, weight, power consumption, and efficiency in sampling particles in the respirable range. The resulting data demonstrates that sampling air flow and efficiency vary widely, and cannot be predicted from the physical characteristics of air samplers, and hence, that proper selection of air samplers should be more involved than shopping for a device based on the limited characteristics that are published by the manufacturers. The findings are summarized in an approach to rationally select bioaerosol samplers for use in infection control and environmental biomonitoring. The presented data demonstrates that inadequate selection of air samplers could result in a failure to collect particles of interest and thus, underestimate the risk and provide a false sense of security in contaminated health care settings and environments contaminated with infectious or toxic aerosols.


The University of Miami Infectious Disease Elimination Act Syringe Services Program: A Blueprint for Student Advocacy, Education, and Innovation.
After the closure of pill mills and implementation of Florida's Prescription Drug Monitoring Program in 2010, high demand for opioids was met with counterfeit pills, heroin, and fentanyl. In response, medical students at the University of Miami Miller School of Medicine embarked on a journey to bring syringe services programs (SSPs) to Florida through an innovative grassroots approach. Working with the Florida Medical Association, students learned patient advocacy, legislation writing, and negotiation within a complex political climate. Advocacy over 4 legislative sessions (2013-2016) included committee testimony and legislative visit days, resulting in the authorization of a 5-year SSP pilot. The University of Miami's Infectious Disease Elimination Act (IDEA) SSP opened on December 1, 2016. Students identified an urgent need for expanded health care for program participants and founded a weekly free clinic at the SSP. Students who rotate through the clinic learn medicine and harm reduction through the lens of social justice, with exposure to people who use drugs, sex workers, individuals experiencing homelessness, and other vulnerable populations. The earliest success of the IDEA SSP was the distribution of over 2,000 boxes of nasal naloxone, which the authors believe positively contributed to a decrease in the number of opioid-related deaths in Miami-Dade County for the first time since 2013. The second was the early identification of a cluster of acute human immunodeficiency virus infections among program participants. Inspired by these successes, students from across the state joined University of Miami students and met with legislators in their home districts, wrote op-eds, participated in media interviews, and traveled to the State Capitol to advocate for decisive action to mitigate the opioid crisis. The 2019 legislature passed legislation authorizing SSPs statewide. In states late to adopt SSPs, medical schools have a unique opportunity to address the opioid crisis using this evidence-based approach.


Use of superoxide as an electron shuttle for iron acquisition by the marine cyanobacterium Lyngbya majuscula.
Reduction of iron from the ferric state to the ferrous state is one strategy employed by microorganisms in nearneutral environments to increase its biological availability. In recent years, the existence of mobile reducing agents produced bymicroorganismsto promote iron reduction, known as electron shuttles, has been demonstrated. Production of electron shuttles has been shown for several organisms, employing a variety of mostly organic molecules as the electron carrier. Here we show that the coastal cyanobacterium Lyngbya majuscula produces iron-reducing superoxide radicals (02*-) and that this facilitates increased iron uptake. We suggest that superoxide is a useful electron shuttle because it reacts rapidly and almost indiscriminately with Fe(lll)-organic complexes and its precursor, dissolved oxygen, is ubiquitous in the photic zone. We further suggest that, for these reasons, the generation of superoxide by marine oxygenic photosynthetic microorganisms and its use in facilitating iron uptake may be a reasonably widespread process.


Repair of UV damaged DNA in systemic lupus erythematosus.
The NZB/NZW hybrid mouse is an animal model of human systemic lupus erythematosus (SLE). Two breeding schemes were devised using NZB, NZW, B/W, and CBA mice, which permit definitive decisions regarding genetic and/or viral origin of the disease. It is proposed that at least two factors must be involved: (1) a genetic abnormality producing hyper-responsiveness to nucleic acid antigens, and (2) a DNA repair defect which results in liberation of DNA and RNA when cells are lethally injured. Evidence is presented for a DNA repair deficit in human SLE lymphocytes following in vitro irradiation with ultraviolet (UV) light. Lymphocytes from adult New Zealand and control mice were found to lack normal amounts of endonuclease necessary for repairing UV damage.


Systematic review of studies comparing combined treatment with paracetamol and ibuprofen, with either drug alone.
To evaluate the evidence surrounding the use of combinations of paracetamol and ibuprofen in the treatment of fever. Systematic narrative review of randomised controlled trials using the UK Economic and Social Research Council guidance on the conduct of narrative synthesis. Inpatient, outpatient and home care. Children with fever. The effect of combination treatments of paracetamol and ibuprofen on fever and comfort, and identification of side effects. Seven studies were identified, six of which provided useful data for the evaluation of the effect of treatment on temperature. Overall these studies showed limited benefit from the combined treatment until around 4 h, after which there was a statistically but only marginally clinically significant benefit. Two studies contained data directly relating to comfort; these suggest a marginal benefit from the combined treatment, but the clinical significance of this was limited. There was no evidence of greater side effects or toxicities associated with the combined treatment. However, it is important to note that these studies were small, short term, and not conducted in the normal setting in which these treatments are given. There is little evidence of any benefit or harm from the combined treatment compared with the use of each drug alone. In the absence of such benefit, there is little to recommend the unnecessary use of polypharmaceutical methods to treat a symptom that does not require treatment, when effective monotherapies exist.


Ion pairing techniques: compatibility with on-line liquid chromatography--mass spectrometry.
The mass spectrometric properties of a series of model ion pairs were examined. In the cases studied it was possible to vaporize the ion pair consituents and to produce spectra corresponding to those of the unpaired materials. These findings offer a convenient means for derivatizing certain ionic compounds and demonstrate the feasibility of analyzing ionic species by on-line liquid chromatography-mass spectrometry.


WAVE2 Regulates Actin-Dependent Processes Induced by the B Cell Antigen Receptor and Integrins.
B cell antigen receptor (BCR) signaling induces actin cytoskeleton remodeling by stimulating actin severing, actin polymerization, and the nucleation of branched actin networks via the Arp2/3 complex. This enables B cells to spread on antigen-bearing surfaces in order to increase antigen encounters and to form an immune synapse (IS) when interacting with antigen-presenting cells (APCs). Although the WASp, N-WASp, and WAVE nucleation-promoting factors activate the Arp2/3 complex, the role of WAVE2 in B cells has not been directly assessed. We now show that both WAVE2 and the Arp2/3 complex localize to the peripheral ring of branched F-actin when B cells spread on immobilized anti-Ig antibodies. The siRNA-mediated depletion of WAVE2 reduced and delayed B cell spreading on immobilized anti-Ig, and this was associated with a thinner peripheral F-actin ring and reduced actin retrograde flow compared to control cells. Depleting WAVE2 also impaired integrin-mediated B cell spreading on fibronectin and the LFA-1-induced formation of actomyosin arcs. Actin retrograde flow amplifies BCR signaling at the IS, and we found that depleting WAVE2 reduced microcluster-based BCR signaling and signal amplification at the IS, as well as B cell activation in response to antigen-bearing cells. Hence, WAVE2 contributes to multiple actin-dependent processes in B lymphocytes.


Would people living with epilepsy benefit from palliative care?
Palliative care (PC) is an approach to the care of persons living with serious illness and their families that focuses on improving quality of life and reducing suffering by addressing complex medical symptoms, psychosocial needs, spiritual well-being, and advance care planning. While PC has traditionally been associated with hospice care for persons with cancer, there is now recognition that PC is relevant to many noncancer diagnoses, including neurologic illness, and at multiple points along the illness journey, not just end of life. Despite the recent growth of the field of neuropalliative care there has been scant attention paid to the relevance of PC principles in epilepsy or the potential for PC approaches to improve outcomes for persons living with epilepsy and their families. We believe this has been a significant oversight and that PC may provide a useful framework for addressing the many sources of suffering facing persons living with epilepsy, for engaging patients and families in challenging conversations, and to focus efforts to improve models of care for this population. In this manuscript we review areas of significant unmet needs where a PC approach may improve patient and family-centered outcomes, including complex symptom management, goals of care, advance care planning, psychosocial support for patient and family and spiritual well-being. When relevant we highlight areas where epilepsy patients may have unique PC needs compared to other patient populations and conclude with suggestions for future research, clinical, and educational efforts.


Results from a multicenter evaluation of the 4th generation Elecsys Troponin T assay.
Discrepancies between serum and heparin plasma samples have been described for many commercial troponin assays including the cardiac troponin T (cTnT) assay. Using the current 3rd generation Elecsys Troponin T immunoassay, heparin plasma cannot be recommended for the determination of cTnT due to systematic lower test results caused by a direct interference of the immunoassay by heparin. The purpose of the multicenter study was to evaluate the analytical performance of an improved 4th generation Elecsys Troponin T immunoassay with a special focus on the comparability of cTnT results determined in heparin plasma and serum. The multicenter evaluation was performed in 10 clinical laboratories according to a standardized protocol (Roche Diagnostics, Penzberg, Germany, Study No. B05P008). The Elecsys Troponin T immunoassay was performed on the Modular Analytics E170 and Elecsys 2010 systems. Intraassay imprecision (n = 21) and total imprecision (2 runs/d, 10 days, triplicate measurements) were evaluated using 2 commercial controls (Roche Diagnostics) and 6 different serum pools (cTnT: 0.0140 - 4.102 microg/L). Intraassay CVs ranged from 0.73 to 3.22%. Total imprecision CVs ranged from 3.61 to 35.45% (cTnT < 0.1 microg/L) and 1.82 to 9.09% (cTnT > 0.1 microg/L), respectively. The cut-off for myocardial necrosis was determined to be 0.03 microg/L using the 10% total imprecision CV criteria. Linearity was assessed by serial dilutions of 6 different serum samples using cTnT negative serum pools. Linearity was proven up to 21.3 microg/L (recoveries: 90% - 110%). Regression data of all comparison studies were calculated according to the method of Passing and Bablok. The method comparison between the 4th generation and the commercially available cTnT immunoassay showed highly similar results across the whole measuring range (0.01 - 25.0 microg/L): y = 1.024x -0.001, r = 0.998; n = 988. Using the commercially available cTnT reagent, the serum to heparin plasma comparison yielded a systematic bias to approximately 8% lower cTnT results in heparin plasma. However, suitable comparability was obtained using the 4th generation Elecsys cTnT assay. The regression analysis (serum vs. heparin plasma) across the studied measuring range (cTnT: 0.01 - 14 microg/L) yielded the following equation: y = 0.975x + 0.001; r = 0.986; n = 403. However, rare individual serum to matched heparin plasma samples still yielded poor comparability (deviation > 20%) using the 4th generation Elecsys Troponin T immunoassay. Our data confirm an excellent analytical performance of the improved troponin T immunoassay. Most importantly, no systematic bias between cTnT results determined in serum and heparin plasma was observed from data obtained in 7 evaluation sites. The performance of the 4th generation Elecsys Troponin T assay is therefore comparable to other commercially available troponin immunoassays. Further studies are necessary to investigate the cause of poor comparability of cTnT results in rare individual serum to matched heparin plasma samples.


Role of O2-hemoglobin affinity in the regulation of cerebral blood flow in fetal sheep.
Cerebral blood flow (CBF) and cerebral O2 transport (CBF X arterial O2 content) in the fetal sheep are nearly twice that in the adult, despite similar rates of cerebral O2 utilization. We tested the hypothesis that the difference depends on the increased oxyhemoglobin affinity in the fetus, using P50 (PO2 at which hemoglobin is 50% saturated) as the index of oxyhemoglobin affinity. We studied 18 unanesthetized fetal sheep in utero. In six animals the P50 was raised from 16.6 +/- 1.2 (SD) mmHg to 31.7 +/- 4.7 mmHg by exchange transfusing the fetus with adult sheep red blood cells. We measured CBF (with radioactive microspheres) and the PO2, PCO2, pH, and O2 content in carotid artery and sagittal sinus blood twice at the original P50 and twice after exchange transfusion. Arterial O2 content fell significantly at the higher P50. Since the fall in O2 content was not accompanied by a corresponding rise in CBF, O2 transport fell by 45%. Cerebral O2 consumption (CMRO2) did not change and cannot be implicated in the fall of O2 transport. E (the ratio CMRO2/O2 transport) rose by 77%. Sham exchange transfusions in six fetuses showed that the exchange transfusion procedure itself was not responsible for this alteration. To determine whether the fall in O2 transport and the rise in E was reproducible over a range of arterial O2 contents, a third group of six fetuses was studied. Fetal arterial O2 content varied from 4 to 12 vol%, first at P50 = 17 +/- 1.8 mmHg and again after exchange transfusion at P50 = 29.6 +/- 3.9 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)


Plasmid-encoded Tet B tetracycline resistance in Haemophilus parasuis.
The complete sequence of two plasmids, pHS-Tet (5.1 kb) and pHS-Rec (9.5 kb), isolated from Haemophilus parasuis strain HS1543 has been obtained. Plasmid pHS-Tet contains four open reading frames including a tet(B) tetracycline resistance gene which unusually did not have an associated tetR repressor gene. From a total of 45 H. parasuis isolates surveyed (15 international reference strains, 15 field isolates selected for their genetic diversity, and 15 recent Australian field isolates), 2 tetracycline-resistant field isolates (HS226 and HS1859) were identified. Analysis of three additional isolates from the same disease outbreak as strain HS1859 revealed a further tetracycline-resistant H. parasuis strain (HS1857, serovar 8) and a tetracycline-resistant Actinobacillus pleuropneumoniae strain (HS1861). An approximately 10.6-kb plasmid was identified in field isolate HS226 and outbreak strains HS1857, HS1859, and HS1861. Southern hybridization analysis of these plasmids showed that the Tet B determinant was present, and restriction digest comparisons suggest that these plasmids are related. This is believed to be the first report of native H. parasuis plasmids and Tet B-mediated tetracycline resistance in this microorganism.


Universal fluctuations around typicality for quantum ergodic systems.
For a quantum system in a macroscopically large volume V, prepared in a pure state and subject to maximally noisy or ergodic unitary dynamics, the reduced density matrix of any sub-system v≪V is almost surely totally mixed. We show that the fluctuations around this limiting value, evaluated according to the invariant measure of these unitary flows, are captured by the Gaussian unitary ensemble (GUE) of random matrix theory. An extension of this statement, applicable when the unitary transformations conserve the energy but are maximally noisy or ergodic on any energy shell, allows to decipher the fluctuations around canonical typicality. According to typicality, if the large system is prepared in a generic pure state in a given energy shell, the reduced density matrix of the sub-system is almost surely the canonical Gibbs state of that sub-system. We show that the fluctuations around the Gibbs state are encoded in a deformation of the GUE whose covariance is specified by the Gibbs state. Contact with the eigenstate thermalization hypothesis is discussed.


The benefit of adjuvant chemotherapy combined with postoperative radiotherapy for endometrial cancer: a meta-analysis.
The objective of our study was to determine whether adjuvant chemotherapy combined with postoperative radiotherapy would have benefits for the disease-free survival and overall survival in patients with high-risk endometrial cancer. Electronic searches for studies of adjuvant chemotherapy combined with postoperative radiotherapy in endometrial cancer patients between March 1971 and March 2012 were made on MEDLINE, SCOPUS, and the Cochrane library. Articles with more than 4 stars on the Newcastle-Ottawa scale or a score of more than 4 on the modified Jadad scale were included. A meta-analysis was performed, and pooled hazard ratios (HR) of progression-free survival (PFS) and overall survival (OS) between patients whose adjuvant chemotherapy was combined with radiotherapy (the CTx+RTx group) and patients with adjuvant radiotherapy only (the RTx group) were derived from the fixed effect model or random effect model. Three observational studies and 3 randomized clinical trials (RCTs) were included in the final analysis. Subgroup analysis for FIGO stage showed that the CTx+RTx group had a more significant survival benefit compared to that of the RTx group in advanced stage endometrial cancer (OS HR 0.53, 95% CI 0.36-0.80; PFS HR 0.54, 95% CI 0.37-0.77), but no significant benefit in early stage endometrial cancer (OS HR 0.96, 95% CI 0.70-1.32; PFS HR 1.00, 95% CI 0.39-2.58). This meta-analysis suggests that adjuvant chemotherapy combined with postoperative radiotherapy could probably reduce disease progression and overall death in patients with advanced-stage disease. In order to examine whether the multimodal treatment has benefit in high-risk endometrial cancer, we need further large-scale RCTs.


[Prevalence of recurrent respiratory tuberculosis in the tense epidemic situation].
The authors studied the rates of respiratory tuberculosis morbidity and recurrences in 6 towns of Kazakhstan, in half of them for 3 years. The study covered 4779 new cases of tuberculosis and 1150 patients with its recurrences; chemotherapy was performed in accordance with the DOTS strategy in 255 patients (Group I) and by the routine procedures in 895 (Group 2). The study has demonstrated that the rate of recurrences may be one of the criteria for assessing the tension of the tuberculosis epidemiological situation. The high rate of morbidity corresponds to that of recurrences. Recurrences are of fundamental value for forming a contingent of patients with tuberculosis. They are more significantly more frequently accompanied by bacterial isolation than new-onset tuberculosis. In Group 1, recurrences occur thrice less frequently than those in Group 2; however, the rate of the latter tends to decrease.


The role of data science in healthcare advancements: applications, benefits, and future prospects.
Data science is an interdisciplinary field that extracts knowledge and insights from many structural and unstructured data, using scientific methods, data mining techniques, machine-learning algorithms, and big data. The healthcare industry generates large datasets of useful information on patient demography, treatment plans, results of medical examinations, insurance, etc. The data collected from the Internet of Things (IoT) devices attract the attention of data scientists. Data science provides aid to process, manage, analyze, and assimilate the large quantities of fragmented, structured, and unstructured data created by healthcare systems. This data requires effective management and analysis to acquire factual results. The process of data cleansing, data mining, data preparation, and data analysis used in healthcare applications is reviewed and discussed in the article. The article provides an insight into the status and prospects of big data analytics in healthcare, highlights the advantages, describes the frameworks and techniques used, briefs about the challenges faced currently, and discusses viable solutions. Data science and big data analytics can provide practical insights and aid in the decision-making of strategic decisions concerning the health system. It helps build a comprehensive view of patients, consumers, and clinicians. Data-driven decision-making opens up new possibilities to boost healthcare quality.


[Electrosurgical technology of the closed type in the treatment of ulcer disease].
Based on experiments (n=36), studies on cadavers (n=17) and clinical studies (n=462) advantages of developed electrosurgical method of creation of one-row gastroduodenal anastomosis of a closed type are shown. It heals better compared with two-row sutures. Good conditions of tissues trophicity lead to a decrease of alteration and improvement of reparative processes. Clinical studies demonstrated reliability of anastomosis. It provides minimal postoperative complications, including potentially fatal ones. It is easy for surgeon, doesn't require large mobilization of duodenal stump even in difficult cases.


[Surfactant--treatment of complete lobar atelectasis after exacerbation of bronchial asthma by infection].
Dysfunction of airway surfactant is suggested as an important factor contributing to the pathogenesis of bronchoconstriction of patients with asthma. We report the case of a 59-year-old female who had an infect-exacerbation of her asthma complicated by a complete collapse of the left lower lung lobe. Only the local application of 150 mg of bovine surfactant resulted in a complete reexpansion of the lobe. Local therapy with replacement of surfactant may be a promising therapeutic approach in treatment of forms of atelectasis, which depend on a dysfunction or disturbed homeostasis of surfactant.


[Patterns of swimming of cercariae in some trematode species].
Swimming activity of cercariae in the trematode species Cryptocotyle lingua, Himasthla elongata, Maritrema subdolum, and Cercaria parvicaudata (Renicola sp.) is studied using video microfilming. The larvae of C. lingua demonstrate a typical intermittent swimming with regularly alternating periods of active movement and passive floating. The duration of both periods during the first 30 min of cercaria's life retains equal, and later the passive period becomes longer. In 15 h the duration of the active period is 0.5-1 s and the passive one--20-30 s. The cercariae of H. elongata during the first 10-15 min of their free life make short stops (1-2 s) in every 10-15 s of swimming. Later these stops become rare and their duration reduces to 0.5-1 s. The cercariae of M. subdolum and C. parvicaudata are continuous swimmers, having left the molluscan host they move persistently. If stops take place they are very rare (one case in 5-15 min) and very short (0.5-1 s). The movements of cercariae body and their tail during swimming are similar in all species studied. The proximal part of the tail undulates in lateral plane, and the middle and distal parts of this organ in the top view circumscribe a figure of eight. In the side view the middle and distal parts of the tail being rotate form a figure like a screw. The cercariae move along the screw axis. The linear swimming rate in the beginning of cercariae's life is 4.8 mm/s for C. lingua, 2.4 mm/s for H. elongata, and 0.35 mm/s for M. subdolum and C. parvicaudata. By the aging the cercariae swimming rate decreases down to the full cease of swimming activity, and the larvae sediment onto the bottom. The age dynamics of swimming rate is different in cercariae of different species and is determined by the morphological functional features of the larvae.


[Personality disorders and aging].
Personality disorder can be defined as an enduring pattern of inner experience and behavior that markedly deviates from the expectations of the individual's culture. With aging, personality disorders may improve or worsen. Their prevalence in the elderly is slightly lower than the prevalence in young adult. Furthermore, their comorbidity and co-occurrence are the rule with an increased risk of late decompensation. Categorical approach used in the current international classifications (ICD-10 and DSM-5) is not adapted to the specificities of the elderly with consequent overrepresentation of "unspecified personality disorder". However, a pathological personality tends to complicate all interventions for somatic or psychological care in the elderly. Thus, this review describes changes in personality disorders related to aging in order to help the clinician to better identify these disorders. Indeed, recognizing a pathological personality in the elderly improves its management both in the field of mental health and in somatic disorders in which the role of personality must be evaluated. Personality and its disorders should therefore be taken into account in all geriatric practices, in particular in the context of cognitive disorders.


Directionality Between Tolerance of Deviance and Deviant Behavior is Age-Moderated in Chronically Stressed Youth.
Problem behavior theory posits that tolerance of deviance is an antecedent to antisocial behavior and substance use. In contrast, cognitive dissonance theory implies that acceptability of a behavior may increase after experiencing the behavior. Using structural equation modeling, this investigation tested whether changes in tolerance of deviance precede changes in conduct disorder criteria or substance use or vice versa, or if they change concomitantly. Two-year longitudinal data from 246 8- to 16-year-olds suggested that tolerance of deviance increases after conduct disorder criteria or substance use in 8-to-10- and 11-to-12-year-olds. These results were consistent with cognitive dissonance theory. In 13-to-16- year-olds, no directionality was suggested, consistent with neither theory. These results were replicated in boys and girls and for different types of conduct disorder criteria aggression (covert behavior), deceitfulness and vandalism (overt behavior), and serious rule-breaking (authority conflict). The age-specific directionality between tolerance of deviance and conduct disorder criteria or substance use is consistent with unique etiologies between early onset versus adolescent-onset subtypes of behavior problems.


Wnt/β-catenin activation promotes prostate tumor progression in a mouse model.
Our previous studies have found that activation of Wnt/β-catenin signaling resulted in mouse prostatic intraepithelial neoplasia (mPIN). In the large probasin promoter directed SV40-large T-antigen (LPB-Tag) expressing mouse prostate, mPIN forms with rare areas of adenocarcinoma. Combining expression of both Wnt-signaling and Tag expression in the mouse prostate, we have studied the role of Wnt/β-catenin signaling in the progression from mPIN to adenocarcinoma. Our results show that the prostates of mice expressing Tag alone or nuclear β-catenin alone developed mPIN, whereas the activation of both Tag and the Wnt/β-catenin pathway resulted in invasive prostate adenocarcinoma. Furthermore, Foxa2, a forkhead transcription factor, was induced by active Wnt/β-catenin signaling, and the expression of Foxa2 was associated with the invasive phenotype in the primary prostate cancer. In the LPB-Tag/dominant active (DA) β-catenin prostates, MMP7, a Wnt/β-catenin target gene, was upregulated. Furthermore, we also assessed AR and AR signaling pathway in these LPB-Tag/DA β-catenin mice. Although β-catenin is a well-known AR co-activator in vitro, our study provides strong in vivo evidences indicating that both AR protein and the AR pathway were downregulated in the prostate of LPB-Tag/DA β-catenin mice. Histological analysis shows that prostate sections derived from the LPB-Tag/DA β-catenin mice display neuroendocrine differentiation (NED), but NE cancer does not develop. Together, our findings indicate that Wnt/β-catenin signaling has an important role in the progression of mPIN to prostate adenocarcinoma.


Increased endocytic activity in monocyte-derived dendritic cells in patients with psoriasis vulgaris.
The understanding of the pathogenesis of psoriasis vulgaris has focused on T cell mediated immune disorder for many years. Recent studies provide evidence that dendritic cells may be of major importance as regulatory cells driving the psoriasis tissue reaction, and they are one of the therapeutic targets. In order to further characterize the role of dendritic cells in psoriasis, this study was designed to assess the differentiation of dendritic cells from monocytes (MoDC), the expression of phagocytosis related receptors by MoDC, their endocytic activity for fluorescent beads and lucifer yellow as well as their superoxide generation in patients with psoriasis. Twenty eight patients with psoriasis vulgaris and 12 healthy controls were included in the study. MoDC were obtained by culturing monocytes with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4) for 5 days. Cell surface expression of CD1a, CD14, CD40, CD80, CD83, CD86, HLA-DR, mannose receptor (MR) and Fcg receptors by MoDC and their endocytosis of dextran and lucifer yellow were analyzed by flow cytometry. Zymosan ingestion was measured to access the phagocytosis of MoDC. Differentiation of monocytes to dendritic cells was upregulated in patients manifested as significantly increased expression of CD40, CD80, CD86 and HLA-DR compared with that in healthy controls (P<0.01). Expression of MR and Fcg receptor II (CD32) by MoDC was significantly increased in patients with psoriasis as well (P<0.01). Endocytosis of dextran but not lucifer yellow in patients was significantly higher than controls (P<0.01), and significantly enhanced phagocytosis by increasing zymosan ingestion was also observed (P<0.01) in patients. Taken together, endocytic and phagocytic activity of MoDC in psoriasis was increased than normal persons. Enhanced activity of dendritic cells binding and capturing foreign antigens for subsequent antigen presentation and the initiation of immune responses in psoriasis may contribute to the pathogenesis of the disease. The upregulated expression of MR and the enhanced endocytic activity of DC might be an explanation for the absence of skin infection observed in psoriasis.


A nomogram to predict the progression-free survival of clival chordoma.
Chordoma shows poor patient prognosis because of its high recurrence rate. Even though many clinical factors and biomarkers are reported to be associated with prognosis, no prediction model has been applied clinically. Thus, the authors aim to derive and validate a prognostic nomogram to predict progression-free survival (PFS) of chordoma. A total of 201 patients were randomly divided into a derivation group (151 cases) and a validation group (50 cases). The expression levels of biomarkers were quantified using tissue microarray analysis. A nomogram was established via univariate and multivariate Cox regression analysis in the derivation group. The predictive performance of the nomogram was then tested in the validation group. The mean follow-up interval was 57 months (range 26-107 months). One clinical factor and 3 biomarkers were confirmed to be associated with PFS, including degree of resection, E-cadherin, Ki-67, and VEGFA. The nomogram with these prognostic factors had areas under the receiver operating characteristic curve of 0.87 and 0.95 in the derivation group at 3 years and 5 years, respectively, compared with 0.87 and 0.84 in the validation group. Calibration and score-stratified survival curve were good in the derivation group and validation group, respectively. The established nomogram performs well for predicting the PFS of chordoma and for risk stratification, which could facilitate prognostic evaluation and follow-up.


Characterization of a novel CDC gene (ORC1) partly homologous to CDC6 of Saccharomyces cerevisiae.
A novel cell cycle gene was identified by a computer search for genes partly homologous to known CDC genes, CDC6 of Saccharomyces cerevisiae and CDC18 of Schizosaccharomyces pombe, using the nucleotide sequence data base for S. cerevisiae produced by the Yeast Sequencing Project. The protein sequence coded by the cloned gene was found to be identical to that of purified ORC1 protein. Disruption of the gene and subsequent tetrad analysis revealed that the gene was essential for growth. The function of the gene product was analyzed by depleting the protein from the cell using a mutant haploid strain containing the disrupted ORC1 gene on the chromosome and a galactose-inducible gene coding for HA-tagged ORC1 protein on a single copy plasmid. The HA-tagged protein was expressed during growth in the presence of galactose but began to decrease rapidly upon depletion of galactose. Analysis of the cell cycle progression of the mutant cells by FACS after the removal of galactose from the medium, and microscope observations of cells and their nuclei revealed that the normal progression of 2N cells was immediately impeded as the ORC1 protein started to decrease. This was blocked completely in the cells that had progressed to the S phase under conditions deficient in ORC1 protein followed by cell death. Two-dimensional gel analysis of the replication intermediates after the galactose removal revealed that the depletion of ORC1 protein caused a decrease in the frequency of initiation of chromosomal replication, eventually resulting in the inhibition of replication as a whole. The function of the ORC1 protein in the cell cycle progression of S. cerevisiae is discussed in light of current information on ORC.


Calibration of ultrawide fisheye lens cameras by eigenvalue minimization.
We present a new technique for calibrating ultrawide fisheye lens cameras by imposing the constraint that collinear points be rectified to be collinear, parallel lines to be parallel, and orthogonal lines to be orthogonal. Exploiting the fact that line fitting reduces to an eigenvalue problem in 3D, we do a rigorous perturbation analysis to obtain a practical calibration procedure. Doing experiments, we point out that spurious solutions exist if collinearity and parallelism alone are imposed. Our technique has many desirable properties. For example, no metric information is required about the reference pattern or the camera position, and separate stripe patterns can be displayed on a video screen to generate a virtual grid, eliminating the grid point extraction processing.


Thrombotic risk in paroxysmal nocturnal hemoglobinuria-like (PNH-like) phenotype.
The complement system is an essential component of the innate immune defence that, if overly activated, may damage organs and tissues. For this reason, there is a fine complement regulatory system. The complement modulation system includes two proteins with important regulatory activity, CD55 or decay accelerating factor (DAF) and CD59 or membrane inhibitor of reactive lysis (MIRL).The paroxysmal nocturnal hemoglobinuria (PNH) is a clonal and non-neoplastic disease characterized by intravascular haemolysis, occurrence of thrombosis and bone marrow failure.In clinical practice, in opposition to PNH, a variety of pathological conditions have been observed with an acquired and non-genetic deficiency of the regulatory proteins CD55 and CD59. This abnormal, non-clonal, reduced expression of complement regulatory proteins configures what we may define as PNH-like phenotype.Similarly to PNH, even in the PNH-like phenotype diseases there has been a greater exposure to the mediated complement cellular lysis and, a likely increased risk of thromboembolic events.Therefore, the knowledge of the potential roles of the complement system becomes necessary for a deeper understanding of several pathological conditions and for an improved clinical management of the patients.


Reduced soluble CD14 levels in amniotic fluid and breast milk are associated with the subsequent development of atopy, eczema, or both.
Exposure to various microbial products in early life reduces the risk of atopy. Such exposure induces downregulation of T(H)2 allergy-biased responses by means of pattern recognition molecules, such as CD14, an LPS receptor. We sought to determine whether infant and maternal levels of soluble CD14 (sCD14) are associated with the atopic outcomes of infants. Levels of sCD14 in plasma, amniotic fluid, and breast milk were measured with a specific ELISA in different cohorts. Expression of toll-like receptors in the fetal gut was examined by using RT-PCR. Soluble CD14 levels increased during fetal development and postnatally, attaining adult levels by around 4 months of age, with an overshoot of adult levels from 6 months of age. There was no difference in plasma sCD14 levels at birth of children with a high compared with those with a low risk of development of atopy. Amniotic fluid sCD14 levels at midgestation (16-17 weeks) were significantly lower when the child was subsequently atopic (P <.05). Soluble CD14 levels in breast milk collected 3 months postpartum were significantly lower in children with eczema at 6 months of age, irrespective of whether they were atopic (P =.003). Transcripts for toll-like receptor 4, which would enable transmembrane signaling for LPS/sCD14 complexes, were expressed within fetal gut and skin. Exposure to reduced levels of sCD14 in the fetal and neonatal gastrointestinal tract is associated with the development of atopy, eczema, or both. Thus the exogenous supply of sCD14 might influence immunologic reactivity both locally and systemically in early life and thereby influence disease outcome.


Imbalance in gut microbes from babies born to obese mothers increases gut permeability and myeloid cell adaptations that provoke obesity and NAFLD.
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease affecting nearly 40% of obese youth and up to 10% of the general pediatric population. A key aspect of NAFLD pathogenesis is proinflammatory hepatic macrophage activation and hepatic recruitment of circulating monocytes, which originate from the bone marrow. In neonates, the activation and polarization of myeloid immune cells are normally shaped in part by systemic factors derived from intestinal microbiota during the first 1000 days of life. Perturbations of the gut microbiome, and in turn the metabolites and bacterial products released systemically, can affect the functional phenotype of these immune cells. Evidence in germ-free mice has shown that fecal microbial transfer from obese mice or obese human donors promotes obesity and inflammation in the recipients, suggesting a direct role for the gut microbiome in promoting obesity and possibly NAFLD. Indeed, patients suffering from NAFLD show evidence for dysbiosis, increased gut permeability, and changes in bile acids that drive the progression of hepatic inflammation toward non-alcoholic steatohepatitis (NASH), the more severe form of the disease. Compared with infants born to normal-weight mothers, we previously showed that the gut microbiome from neonates born to obese mothers is compositionally distinct. However, whether this alteration in early gut microbiota in infants born to obese mothers can cause inflammatory processes that initiate development of NAFLD or obesity is unknown. How these alterations contribute to long-term immune cell mediated liver inflammation and progression of NAFLD needs to be determined. Our recently published work (Soderborg et al., Nat Commun 9:4462) demonstrates a causative role of early life microbiome dysbiosis in infants born to mothers with obesity in novel pathways that promote developmental programming of NAFLD.


Performance of the cerebral state index during increasing levels of propofol anesthesia: a comparison with the bispectral index.
The cerebral state monitor is a new device to measure depth of anesthesia. In this study we compared the cerebral state monitor with the bispectral index (BIS) monitor during propofol anesthesia. Fifteen healthy patients received a continuous infusion of propofol (300 mL/h). The cerebral state index (CSI) and the BIS values were recorded until burst suppression ratio > or =60%. Baseline variability, prediction probability, and agreement analysis between indices were evaluated. Clinical markers of loss of consciousness were also assessed. Mean awake BIS and CSI values were 95.6 and 91.6, respectively (P = 0.01). BIS and CSI prediction probability values (mean +/- sd) were estimated to be 0.87 +/- 0.08 and 0.86 +/- 0.08, respectively (NS). The CSI tended to stabilize at values of 60-40 when estimated propofol concentrations at the effect site increased from 5 to 8 mug/mL. The BIS stabilized at values of 40-20 when the propofol concentrations at the effect site increased from 7 to 10 mug/mL. The mean BIS-CSI difference was -7.4 with 95% limits of agreement of 22.2 and -36.9. The BIS and CSI correlation with the burst suppression ratio was -0.60 and -0.97, respectively (P < 0.01). Predicted BIS and CSI values for loss of eyelash reflex in 50% and 95% of the patients were different (P < 0.05). The overall performance of both monitors during propofol induction was similar. However, the different dynamic profiles of these monitors indicate that BIS may be a more useful index for evaluating intermediate anesthetic levels, whereas CSI may be better for evaluating deeper anesthetic levels.


Identification and characterization of two distinct intracellular GLUT4 pools in rat skeletal muscle: evidence for an endosomal and an insulin-sensitive GLUT4 compartment.
In skeletal muscle, acute insulin treatment results in the recruitment of the GLUT4 glucose transporter from intracellular vesicular structures to the plasma membrane. The precise nature of these intracellular GLUT4 stores has, however, remained poorly defined. Using an established skeletal-muscle fractionation procedure we present evidence for the existence of two distinct intracellular GLUT4 compartments. We have shown that after fractionation of crude muscle membranes on a discontinuous sucrose gradient the majority of the GLUT4 immunoreactivity was largely present in two sucrose fractions (30 and 35%, w/w, sucrose; denoted F30 and F35 respectively) containing intracellular membranes of different buoyant densities. Here we show that these fractions contained 44+/-6 and 49+/-7% of the crude membrane GLUT4 reactivity respectively, and could be further discriminated on the basis of their immunoreactivity against specific subcellular antigen markers. Membranes from the F30 fraction were highly enriched in transferrin receptor (TfR) and annexin II, two markers of the early endosome compartment, whereas they were significantly depleted of both GLUT1 and the alpha1-subunit of (Na++K+)-ATPase, two cell-surface markers. Insulin treatment resulted in a significant reduction in GLUT4 content in membranes from the F35 fraction, whereas the amount of GLUT4 in the less dense (F30) fraction remained unaffected by insulin. Immunoprecipitation of GLUT4-containing vesicles from both intracellular fractions revealed that TfR was present in GLUT4 vesicles isolated from membranes from the F30 fraction. In contrast, GLUT4 vesicles from the F35 fraction were devoid of TfR. The aminopeptidase, vp165, was present in GLUT4 vesicles from both F30 and F35; however, vesicles isolated from F30 contained over twice as much vp165 per unit of GLUT4 than those isolated from F35. The biochemical co-localization of vp165/GLUT4 was further substantiated by double-immunogold labelling of ultrathin muscle sections. Overall, our data indicate the presence of at least two internal GLUT4 pools: one possibly derived from an endosomal recycling compartment, and the other representing a specialized insulin-sensitive GLUT4 storage pool. Both pools contain vp165.


Isolation and biochemical characterization of the PilA protein of Neisseria meningitidis.
PilA is the response regulator of a two-component regulatory system that controls a number of genes in the pathogenic Neisseria. Previous work has shown that Neisseria gonorrhoeae (GC) PilA binds DNA and also hydrolyzes GTP. Here, we report the cloning, sequencing, purification, and biochemical characterization of PilA from N. meningitidis (MC) strain 8013. MC pilA is 94% identical to GC pilA at the nucleotide level. Of the 78 nucleotide changes, 52 are silent, while 26 result in a total of 20 amino acid changes. Additionally, the MC homolog has a 4-amino acid insertion between the putative DNA-binding and GTP-binding domains. Purified MC PilA binds to the same DNA fragment we have previously shown to be bound by GC PilA specifically and also hydrolyzes GTP. The K(m) of MC PilA for GTP is 8.6 microM, similar to that determined for the GC protein. However, the maximum velocity (Vmax) is approximately 35-fold greater than the GC PilA activity. Additionally, the nucleotide specificity of MC PilA differs from that of GC PilA. While GC PilA hydrolyzes only GTP, MC PilA hydrolyzes GTP and ATP equally well, and CTP and UTP also compete for this activity.


Update of the Preventive Antibiotics in Stroke Study (PASS): statistical analysis plan.
Infections occur in 30% of stroke patients and are associated with unfavorable outcomes. Preventive antibiotic therapy lowers the infection rate after stroke, but the effect of preventive antibiotic treatment on functional outcome in patients with stroke is unknown. The PASS is a multicenter, prospective, phase three, randomized, open-label, blinded end-point (PROBE) trial of preventive antibiotic therapy in acute stroke. Patients are randomly assigned to either ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to standard stroke-unit care, or standard stroke-unit care without preventive antibiotic therapy. The aim of this study is to assess whether preventive antibiotic treatment improves functional outcome at 3 months by preventing infections. This paper presents in detail the statistical analysis plan (SAP) of the Preventive Antibiotics in Stroke Study (PASS) and was submitted while the investigators were still blinded for all outcomes. The primary outcome is the score on the modified Rankin Scale (mRS), assessed by ordinal logistic regression analysis according to a proportional odds model. Secondary analysis of the primary outcome is the score on the mRS dichotomized as a favorable outcome (mRS 0 to 2) versus unfavorable outcome (mRS 3 to 6). Secondary outcome measures are death rate at discharge and 3 months, infection rate during hospital admission, length of hospital admission, volume of post-stroke care, use of antibiotics during hospital stay, quality-adjusted life years and costs. Complications of treatment, serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs) are reported as safety outcomes. The data from PASS will establish whether preventive antibiotic therapy in acute stroke improves functional outcome by preventing infection and will be analyzed according to this pre-specified SAP. Current controlled trials; ISRCTN66140176. Date of registration: 6 April 2010.


Differential expression of the insulin gene transcriptional repressor CCAAT/enhancer-binding protein beta and transactivator islet duodenum homeobox-1 in rat pancreatic beta cells during the development of diabetes mellitus.
Impairment of insulin secretion due to prolonged hyperglycemia is believed to contribute to the manifestation of diabetes mellitus, often referred to as glucose toxicity of pancreatic beta cells. In addition, impaired beta cell function has been associated with elevated islet triglyceride content (lipotoxicity). Impaired functions of the transactivating factors islet duodenum homeobox-1 (IDX-1) and RIPE3b-binding proteins have been implicated in the pathological downregulation of insulin gene transcription by high glucose levels in pancreatic beta cell lines in vitro, and, similarly, the exposure of pancreatic islets to fatty acids decreases IDX-1 expression. Previously, we identified the basic leucine zipper transcription factor CCAAT/enhancer-binding protein beta (C/ EBPbeta) as an inhibitor of insulin gene transcription in pancreatic beta cells and showed that the expression of C/EBPbeta is upregulated in insulinoma-derived beta cell lines by sustained high glucose concentrations. Here we describe the regulation of the expression of IDX-1, C/EBPbeta, and insulin at the mRNA and protein levels in pancreatic islets in animal models of diabetes mellitus. Concomitant with a downregulation of IDX-1 and insulin expression, C/EBPbeta is upregulated in association with the manifestation of hyperglycemia during the development of diabetes in the Zucker diabetic fatty (fa/fa) rat and in the 90% pancreatectomy rat model of diabetes. This regulation is demonstrated to influence both the amount of cellular protein and the level of steady state messenger RNA. Our findings indicate that the differential dysregulation of both IDX-1 and C/EBPbeta, in response to sustained hyperglycemia or hyperlipidemia, may be involved in the impairment of insulin gene expression during the manifestation of diabetes mellitus.


[Bone tuberculosis: when consider this diagnosis?].
The most common presentation of bone tuberculosis (TB) is called spondylodiscitis, or "Pott's disease", which is a difficult diagnosis due to its low prevalence in Switzerland. It should be considered in patients with persistent back pain, who are at high risk, such as migrant population and immunocompromised patients. Diagnosis is based on imaging and the detection of M. tuberculosis in biopsy of affected vertebra orparaspinal abscess, or even if active tuberculosis is proven in any other site. It's essential to initiate appropriate treatment as quickly as possible in order to avoid neurological complications and spinal deformity and to identify cases that will require a surgical therapy.


Dundee Ready Education Environment Measure: psychometric testing with Chinese nursing students.
This paper is a report of the psychometric testing of the Dundee Ready Education Environment Measure with Chinese nursing students. Although the Dundee Ready Education Environment Measure has been widely used to measure educational environments in the healthcare professions, no psychometric evaluation of the measure with Chinese nursing students has been reported. Data from 214 nursing students were collected during a 2-month period between December, 2004 and January, 2005. Exploratory factor analysis, internal consistency reliability and Cronbach's alpha were examined. Five factors were found by principal components analysis with Oblimin with Kaiser Normalization rotation. The original factor names were maintained, but items in each factor changed. These five factors all achieved eigenvalues >1, and in total accounted for 52.186% of the variance. Cronbach's alpha ranged from 0.623 to 0.9 across factors, with an overall alpha of 0.949. The Chinese version of the Dundee Ready Education Environment Measure could be a valuable measurement for nursing educators in professional development programmes and nursing curriculum design. Further studies need in different Chinese nursing schools and larger sample sizes to be conducted to validate its stability and factor structure.


Troglitazone or metformin in combination with sulfonylureas for patients with type 2 diabetes?
Combination oral therapy is often used to control the hyperglycemia of patients with type 2 diabetes. We compared the effectiveness of metformin and troglitazone when added to sulfonylurea therapy for patients with type 2 diabetes who had suboptimal blood glucose control. We used a randomized 2-group design to compare the efficacy, safety, and tolerability of troglitazone and metformin for patients with type 2 diabetes mellitus that was inadequately controlled with diet and oral sulfonylureas. Thirty-two subjects were randomized to receive either troglitazone or metformin for 14 weeks, including a 2-week drug-titration period. The primary outcome variable was mean change in the level of glycosylated hemoglobin (Hb A1c) from baseline. Secondary outcomes included mean changes from baseline in fasting plasma glucose and C-peptide levels, renal or metabolic side effects, and symptomatic tolerability. The addition of either troglitazone or metformin to oral sulfonylurea therapy significantly decreased Hb A1c levels. Both treatment regimens also significantly reduced fasting plasma glucose and C-peptide levels. We found no significant differences between the treatment arms in efficacy, metabolic side effects, or tolerability. Our results demonstrate that troglitazone and metformin each significantly improved Hb A1c, fasting plasma glucose, and C-peptide levels when added to oral sulfonylurea therapy for patients with type 2 diabetes who had inadequate glucose control.


Cross-linked polymers with fluorinated bridges for efficient gene delivery.
A new strategy for the construction of fluorinated cationic polymers for gene delivery was introduced. The fluorinated polymers were synthesized by crosslinking low molecular weight PEI with diols containing various lengths of perfluoroalkyl chains via epoxide ring-opening polymerization. Such a study presents the first example of polymeric gene vectors with fluorination on the polymer backbone but not on the side chains. These materials showed good DNA condensation and protection ability and could condense DNA into nanoparticles with appropriate sizes and zeta-potentials. The fluorine atoms might strengthen the interaction toward DNA, leading to more stable polyplexes. In vitro transfection results showed that the fluorinated polymers could mediate efficient gene delivery toward both 2D and 3D cell cultures at low weight ratios, and their transfection efficiency was higher than that of PEI 25 kDa and their non-fluorinated counterparts. Several assays including DLS, TEM, luciferase reporter gene transfection and flow cytometry revealed that fluorination improved the serum resistance of these polymeric vectors, and more fluorine atoms might lead to better serum tolerance. These fluorinated materials exhibited very low cytotoxicity at transfection dosage. A cellular uptake study with uptake inhibitors indicated that macro-pinocytosis and microtubule-mediated endocytosis were the major endocytosis pathways for these polyplexes.


CIPK6, a CBL-interacting protein kinase is required for development and salt tolerance in plants.
Calcineurin B-like proteins (CBL) and CBL-interacting protein kinases (CIPK) mediate plant responses to a variety of external stresses. Here we report that Arabidopsis CIPK6 is also required for the growth and development of plants. Phenotype of tobacco plants ectopically expressing a homologous gene (CaCIPK6) from the leguminous plant chickpea (Cicer arietinum) indicated its functional conservation. A lesion inAtCIPK6 significantly reduced shoot-to-root and root basipetal auxin transport, and the plants exhibited developmental defects such as fused cotyledons, swollen hypocotyls and compromised lateral root formation, in conjunction with reduced expression of a number of genes involved in auxin transport and abiotic stress response. The Arabidopsis mutant was more sensitive to salt stress compared to wild-type, while overexpression of a constitutively active mutant of CaCIPK6 promoted salt tolerance in transgenic tobacco. Furthermore, tobacco seedlings expressing the constitutively active mutant of CaCIPK6 showed a developed root system, increased basipetal auxin transport and hypersensitivity to auxin. Our results provide evidence for involvement of a CIPK in auxin transport and consequently in root development, as well as in the salt-stress response, by regulating the expression of genes.


Activation of RARα, RARγ, or RXRα Increases Barrier Tightness in Human Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells.
The blood-brain barrier (BBB) is critical to central nervous system (CNS) health. Brain microvascular endothelial cells (BMECs) are often used as in vitro BBB models for studying BBB dysfunction and therapeutic screening applications. Human pluripotent stem cells (hPSCs) can be differentiated to cells having key BMEC barrier and transporter properties, offering a renewable, scalable source of human BMECs. hPSC-derived BMECs have previously been shown to respond to all-trans retinoic acid (RA), and the goal of this study was to identify the stages at which differentiating human induced pluripotent stem cells (iPSCs) respond to activation of RA receptors (RARs) to impart BBB phenotypes. Here the authors identified that RA application to iPSC-derived BMECs at days 6-8 of differentiation led to a substantial elevation in transendothelial electrical resistance and induction of VE-cadherin expression. Specific RAR agonists identified RARα, RARγ, and RXRα as receptors capable of inducing barrier phenotypes. Moreover, RAR/RXRα costimulation elevated VE-cadherin expression and improved barrier fidelity to levels that recapitulated the effects of RA. This study elucidates the roles of RA signaling in iPSC-derived BMEC differentiation, and identifies directed agonist approaches that can improve BMEC fidelity for drug screening studies while also distinguishing potential nuclear receptor targets to explore in BBB dysfunction and therapy.


Process evaluation of a tailored multifaceted feedback program to improve the quality of intensive care by using quality indicators.
In multisite trials evaluating a complex quality improvement (QI) strategy the 'same' intervention may be implemented and adopted in different ways. Therefore, in this study we investigated the exposure to and experiences with a multifaceted intervention aimed at improving the quality of intensive care, and explore potential explanations for why the intervention was effective or not. We conducted a process evaluation investigating the effect of a multifaceted improvement intervention including establishment of a local multidisciplinary QI team, educational outreach visits and periodical indicator feedback on performance measures such as intensive care unit length of stay, mechanical ventilation duration and glucose regulation. Data were collected among participants receiving the intervention. We used standardised forms to record time investment and a questionnaire and focus group to collect data on perceived barriers and satisfaction. The monthly time invested per QI team member ranged from 0.6 to 8.1 h. Persistent problems were: not sharing feedback with other staff; lack of normative standards and benchmarks; inadequate case-mix adjustment; lack of knowledge on how to apply the intervention for QI; and insufficient allocated time and staff. The intervention effectively targeted the lack of trust in data quality, and was reported to motivate participants to use indicators for QI activities. Time and resource constraints, difficulties to translate feedback into effective actions and insufficient involvement of other staff members hampered the impact of the intervention. However, our study suggests that a multifaceted feedback program stimulates clinicians to use indicators as input for QI, and is a promising first step to integrating systematic QI in daily care.


Prophage-Mediated Disruption of Genetic Competence in Staphylococcus pseudintermedius.
Methicillin-resistant Staphylococcus pseudintermedius (MRSP) is a major cause of soft tissue infections in dogs and occasionally infects humans. Hypervirulent multidrug-resistant (MDR) MRSP clones have emerged globally. The sequence types ST71 and ST68, the major epidemic clones of Europe and North America, respectively, have spread to other regions. The genetic factors underlying the success of these clones have not been investigated thoroughly. Here, we performed a comprehensive genomic analysis of 371 S. pseudintermedius isolates to dissect the differences between major clonal lineages. We show that the prevalence of genes associated with antibiotic resistance, virulence, prophages, restriction-modification (RM), and CRISPR/Cas systems differs significantly among MRSP clones. The isolates with GyrA+GrlA mutations, conferring fluoroquinolone resistance, carry more of these genes than those without GyrA+GrlA mutations. ST71 and ST68 clones carry lineage-specific prophages with genes that are likely associated with their increased fitness and virulence. We have discovered that a prophage, SpST71A, is inserted within the comGA gene of the late competence operon comG in the ST71 lineage. A functional comG is essential for natural genetic competence, which is one of the major modes of horizontal gene transfer (HGT) in bacteria. The RM and CRISPR/Cas systems, both major genetic barriers to HGT, are also lineage specific. Clones harboring CRISPR/Cas or a prophage-disrupted comG exhibited less genetic diversity and lower rates of recombination than clones lacking these systems. After Listeria monocytogenes, this is the second example of prophage-mediated competence disruption reported in any bacteria. These findings are important for understanding the evolution and clonal expansion of MDR MRSP clones.IMPORTANCE Staphylococcus pseudintermedius is a bacterium responsible for clinically important infections in dogs and can infect humans. In this study, we performed genomic analysis of 371 S. pseudintermedius isolates to understand the evolution of antibiotic resistance and virulence in this organism. The analysis covered significant reported clones, including ST71 and ST68, the major epidemic clones of Europe and North America, respectively. We show that the prevalence of genes associated with antibiotic resistance, virulence, prophages, and horizontal gene transfer differs among clones. ST71 and ST68 carry prophages with novel virulence and antibiotic resistance genes. Importantly, site-specific integration of a prophage, SpST71A, has led to the disruption of the genetic competence operon comG in ST71 clone. A functional comG is essential for the natural uptake of foreign DNA and thus plays an important role in the evolution of bacteria. This study provides insight into the emergence and evolution of antibiotic resistance and virulence in S. pseudintermedius, which may help in efforts to combat this pathogen.


Adolescent smoking: research and health policy.
A great deal is now known about the prevalence and natural history of adolescent smoking. The literature on smoking intervention, drawn from theoretically based experiments, shows that most programs are unlikely to become widely disseminated because of the extensive resources required. More thoughtful strategies for research and targeting of interventions are examined. They may yield coordinated and comprehensive approaches to moving more quickly and effectively from the behavioral laboratory into the field.


Characterization of quantitative trait loci for growth and meat quality in a cross between commercial breeds of swine.
A three-generation resource family was created by crossing two Berkshire grandsires with nine Yorkshire granddams to identify QTL affecting growth, body composition, and meat quality. A total of 512 F2 offspring were evaluated for 11 traits related to growth and body composition and 28 traits related to meat quality. All animals were initially genotyped for 125 markers across the genome. The objectives of this advanced phase of the project were to further identify and characterize QTL after genotyping for another 33 markers in special regions of interest, and to develop and apply methods for detecting QTL with parent-of-origin effects. New marker linkage maps were derived and used in QTL analysis based on line-cross least squares regression-interval mapping. A decision tree for identifying QTL with parent-of-origin effects was developed based on tests against the Mendelian mode of expression. Empirical significance thresholds were derived at chromosomewise and genomewise levels using specialized permutation strategies to create data under the null hypothesis appropriate for each test. Significance thresholds derived by the permutation tests were validated based on simulation of a pedigree and data structure similar to the Berkshire-Yorkshire population. The addition of 33 markers resulted in the discovery of 29 new QTL at the 5% chromosomewise level using the Mendelian model of analysis. Thirteen of the original QTL were no longer significant at the 5% chromosomewise level. A total of 33 QTL with parent-of-origin effects were identified, including QTL with paternal expression for backfat and loin muscle area on chromosome 2, near IGF2, and QTL with maternal expression for drip loss and reflectance on chromosome 9. Tests for imprinting against Mendelian expression identified much fewer QTL with parent-of-origin effects than tests based on significance of paternal and maternal alleles, which have been used in other studies. The detected QTL and their identified mode of expression will allow further research in these QTL regions and their utilization in marker-assisted improvement of meat quality.


Statistical mechanics of beam self-cleaning in GRIN multimode optical fibers.
Since its first demonstration in graded-index multimode fibers, spatial beam self-cleaning has attracted a growing research interest. It allows for the propagation of beams with a bell-shaped spatial profile, thus enabling the use of multimode fibers for several applications, from biomedical imaging to high-power beam delivery. So far, beam self-cleaning has been experimentally studied under several different experimental conditions. Whereas it has been theoretically described as the irreversible energy transfer from high-order modes towards the fundamental mode, in analogy with a beam condensation mechanism. Here, we provide a comprehensive theoretical description of beam self-cleaning, by means of a semi-classical statistical mechanics model of wave thermalization. This approach is confirmed by an extensive experimental characterization, based on a holographic mode decomposition technique, employing laser pulses with temporal durations ranging from femtoseconds up to nanoseconds. An excellent agreement between theory and experiments is found, which demonstrates that beam self-cleaning can be fully described in terms of the basic conservation laws of statistical mechanics.


Mesalamine Enemas for Induction of Remission in Oral Mesalamine-refractory Pediatric Ulcerative Colitis: A Prospective Cohort Study.
Paediatric ulcerative colitis [UC] is more extensive than adult disease, and more often refractory to mesalamine. However, no prospective trials have evaluated mesalamine enemas for inducing remission in children. Our goal was to evaluate the ability of mesalamine enemas to induce remission in mild to moderate paediatric UC refractory to oral mesalamine. This was an open-label arm of a previously reported randomised controlled trial of once-daily mesalamine in active paediatric UC [MUPPIT trial]. Children aged 4-18 years, with a Paediatric Ulcerative Colitis Activity Index [PUCAI] score of 10-55, were enrolled after failing at least 3 weeks of full-dose oral mesalamine. Patients treated with steroids or enemas in the previous month and those with isolated proctitis were excluded. Children received Pentasa® enemas 25 mg/kg [up to 1g] daily for 3 weeks with the previous oral dose. The primary endpoint was clinical remission by Week 3. A total of 38 children were enrolled (mean age 14.6 ± 2.3 years; 17/38 [45%] with extensive colitis). Clinical remission was obtained in 16 [42%] and response was obtained in 27 [71%] at Week 3. Eight children deteriorated and required steroids. There were no differences in baseline parameters between those who entered or failed to enter remission, including disease extent [43% in left-sided and 41% in extensive colitis] and disease activity [44% in mild and 41% in moderate activity]. Clinical remission can be markedly increased in children who are refractory to oral mesalamaine by adding mesalamine enemas for 3 weeks, before commencing steroids.


Approaches to refractory hypoxemia in acute respiratory distress syndrome: current understanding, evidence, and debate.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) cause substantial morbidity and mortality despite our improved understanding of lung injury, advancements in the application of lung-protective ventilation, and strategies to prevent ventilator-induced lung injury. Severe refractory hypoxemia may develop in a subset of patients with severe ARDS. We review several approaches referred to as "rescue" therapies for severe hypoxemia, including lung-recruitment maneuvers, ventilation modes, prone positioning, inhaled vasodilator therapy, and the use of extracorporeal membrane oxygenation. Each shows evidence for improving oxygenation, though each has associated risks, and no single therapy has proven superior in the management of severe hypoxemia. Importantly, increased survival with these strategies has not been clearly established.


Symptom burden and performance status in a population-based cohort of ambulatory cancer patients.
For ambulatory cancer patients, Ontario has standardized symptom and performance status assessment population-wide, using the Edmonton Symptom Assessment System (ESAS) and Palliative Performance Scale (PPS). In a broad cross-section of cancer outpatients, the authors describe the ESAS and PPS scores and their relation to patient characteristics. This is a descriptive study using administrative healthcare data. The cohort included 45,118 and 23,802 patients' first ESAS and PPS, respectively. Fatigue was most prevalent (75%), and nausea least prevalent (25%) in the cohort. More than half of patients reported pain or shortness of breath; about half of those reported moderate to severe scores. Seventy-eight percent had stable performance status scores. On multivariate analysis, worse ESAS outcomes were consistently seen for women, those with comorbidity, and those with shorter survivals from assessment. Lung cancer patients had the worst burden of symptoms. This is the first study to report ESAS and PPS scores in a large, geographically based cohort with a full scope of cancer diagnoses, including patients seen earlier in the cancer trajectory (ie, treated for cure). In this ambulatory cancer population, the high prevalence of numerous symptoms parallels those reported in palliative populations and represents a target for improved clinical care. Differences in outcomes for subgroups require further investigation. This research sets the groundwork for future research on patient and provider outcomes using linked administrative healthcare data.


Glucocorticoid receptors in normal leukocytes: effects of age, gender, season, and plasma cortisol concentrations.
We measured glucocorticoid receptors (GR) in mononuclear leukocytes (MNL) isolated from peripheral blood of 145 apparently healthy volunteers (86 men and 59 women). An age-related decrease in the number of GR was suggested between subjects younger than 20 years and elderly subjects; there was no apparent seasonal variation in GR. Gender difference in the number of GR was not significant, although women showed slightly fewer GR. Eight patients with dermatomyositis/polymyositis were examined to determine whether the number of GR in MNL could be down-regulated by their cognate ligands. The number of GR in MNL from these patients was significantly decreased one month after the initiation of prednisolone therapy. However, in normal subjects, the GR in MNL did not demonstrate circadian variation, in contrast to concentrations of plasma cortisol.