Design of a SIMO Deep Learning-Based Chaos Shift Keying (DLCSK) Communication System.
This paper brings forward a Deep Learning (DL)-based Chaos Shift Keying (DLCSK) demodulation scheme to promote the capabilities of existing chaos-based wireless communication systems. In coherent Chaos Shift Keying (CSK) schemes, we need synchronization of chaotic sequences, which is still practically impossible in a disturbing environment. Moreover, the conventional Differential Chaos Shift Keying (DCSK) scheme has a drawback, that for each bit, half of the bit duration is spent sending non-information bearing reference samples. To deal with this drawback, a Long Short-Term Memory (LSTM)-based receiver is trained offline, using chaotic maps through a finite number of channel realizations, and then used for classifying online modulated signals. We presented that the proposed receiver can learn different chaotic maps and estimate channels implicitly, and then retrieves the transmitted messages without any need for chaos synchronization or reference signal transmissions. Simulation results for both the AWGN and Rayleigh fading channels show a remarkable BER performance improvement compared to the conventional DCSK scheme. The proposed DLCSK system will provide opportunities for a new class of receivers by leveraging the advantages of DL, such as effective serial and parallel connectivity. A Single Input Multiple Output (SIMO) architecture of the DLCSK receiver with excellent reliability is introduced to show its capabilities. The SIMO DLCSK benefits from a DL-based channel estimation approach, which makes this architecture simpler and more efficient for applications where channel estimation is problematic, such as massive MIMO, mmWave, and cloud-based communication systems.


Evaluation of per-operative cough stress test during transobturator mid-urethral sling surgery.
Currently, it is unclear how the mesh tension should be adjusted on the transobturator tape surgery (TOT) for improving continence. The aim of this study was to evaluate the effects of per-operative cough stress test on TOT. Between March 2007 and December 2011, 206 women with SUI were enrolled in this study. Patients were randomly categorized to treatment with TOT (96) or TOT with cough stress test (110). The IIQ-7 and the UDI-6 were used to identify satisfaction level. At the end of 1st year, two groups were compared patient characteristics, operation time, duration of hospital stay, cure and complication rates. The cure rate was 84.37% 81/96) versus 83.63% (92/110) in TOT and TOT with cough test groups, respectively. Postoperatively ten patient (10/110, 9.09%) suffered voiding difficulties (> 250 ml residual urine) in TOT with cough stress test group. Five patients were discharged with transurethral catheter, whereas, in traditional TOT group, two patients (2/96, 2.1%) had transient postoperative voiding difficulty and two patients were treated with repeated catheterization for 1 week (p < 0.05). Postoperative groin pain was present in 7/96 (8%) versus 24/110 (22%) in TOT and TOT with cough test groups, respectively (p < 0.05). TOT with cough stress test group had an higher rate of complications like, retention of urine, necessitating to cut the tape, mesh erosion and pain in groin or leg. No patient had resistant voiding difficulty or prolonged urinary retention (> 1 week) in traditional TOT group. We believe that per-operative cough stress test leads to overtreatment of stress urinary incontinence when the complication rates were considered.


Emerging concepts in the management of acute retinal necrosis.
Acute retinal necrosis (ARN), also known as Kirisawa-type uveitis, is an uncommon condition caused by infection of the retina by one of the herpes family of viruses, most typically varicella zoster virus or herpes simplex virus and less commonly cytomegalovirus. Clinical diagnosis can be challenging and is often aided by PCR-based analysis of ocular fluids. Treatment typically involves extended use of one or more antiviral agents. Long term retinal detachment risk is high. We review the literature on ARN and present an approach to the diagnosis and management of this serious condition.


DOT or SAT for Rifampicin-resistant tuberculosis? A non-randomized comparison in a high HIV-prevalence setting.
Daily directly-observed therapy (DOT) is recommended for rifampicin-resistant tuberculosis (RR-TB) patients throughout treatment. We assessed the impact of self-administered treatment (SAT) in a South African township with high rates of RR-TB and HIV. Community-supported SAT for patients who completed the intensive phase was piloted in five primary care clinics in Khayelitsha. We compared final treatment outcomes among RR-TB patients initiating treatment before (standard-of-care (SOC)-cohort, January 2010-July 2013) and after the implementation of the pilot (SAT-cohort, January 2012-December 2014). All patients with outcomes before January 1, 2017 were considered in the analysis of outcomes. One-hundred-eighteen patients in the SOC-cohort and 174 patients in the SAT-cohort had final RR-TB treatment outcomes; 70% and 73% were HIV-co-infected, respectively. The proportion of patients with a final outcome of loss to follow-up (LTFU) did not differ whether treated in the SOC (25/118, 21.2%) or SAT-cohort (31/174, 17.8%) (P = 0.47). There were no significant differences in the time to 24-month LTFU among HIV-infected and uninfected patients (HR 0.90, 95% CI: 0.51-1.6, P = 0.71), or among patients enrolled in the SOC-cohort versus the SAT-cohort (HR 0.83, 95% CI: 0.49-1.4, P = 0.50) who received at least 6-months of RR-TB treatment. The introduction of SAT during the continuation phase of RR-TB treatment does not adversely affect final RR-TB treatment outcomes in a high TB and HIV-burden setting. This differentiated, patient-centred model of care could be considered in RR-TB programmes to decrease the burden of DOT on patients and health facilities.


A model to predict level of adherence to prehabilitation in older adults with frailty having cancer surgery.
Preoperative exercise could improve postoperative outcomes for people with frailty; however, little is known about how to predict older people's adherence to exercise before surgery (i.e., prehabilitation) programs. Our objective was to derive and validate a model to predict prehabilitation adherence in older adults living with frailty before cancer surgery. This was a nested prospective cohort study of older adults with frailty having cancer surgery who participated in a randomized controlled trial of home-based prehabilitation compared with standard perioperative care. We constructed a multivariable ordinary least squares linear regression model to predict adherence. Covariates were selected a priori based on clinical expertise and systematic review. Optimism was estimated through internal validation using bootstrap resampling. The derivation cohort consisted of 95 participants in the intervention arm of the trial. Percent adherence ranged from 0% to 100%, with a mean (standard deviation) of 61 (34)%. Previous physical activity and age were the only predictors significant at the 5% level. A prespecified multivariable model may help to explain a modest degree of variation in prehabilitation adherence in older people with frailty. While this model is an important step toward personalizing prehabilitation support, this study was limited by a small sample size and future research is needed to better understand personalized prediction of prehabilitation adherence in older people with frailty.


Designing allosteric regulators of thrombin. Monosulfated benzofuran dimers selectively interact with Arg173 of exosite 2 to induce inhibition.
Earlier, we reported on the design of sulfated benzofuran dimers (SBDs) as allosteric inhibitors of thrombin (Sidhu et al. J. Med. Chem.201154 5522-5531). To identify the site of binding of SBDs, we studied thrombin inhibition in the presence of exosite 1 and 2 ligands. Whereas hirudin peptide and heparin octasaccharide did not affect the IC(50) of thrombin inhibition by a high affinity SBD, the presence of full-length heparin reduced inhibition potency by 4-fold. The presence of γ' fibrinogen peptide, which recognizes Arg93, Arg97, Arg173, Arg175, and other residues, resulted in a loss of affinity that correlated with the ideal Dixon-Webb competitive profile. Replacement of several arginines and lysines of exosite 2 with alanine did not affect thrombin inhibition potency, except for Arg173, which displayed a 22-fold reduction in IC(50). Docking studies suggested a hydrophobic patch around Arg173 as a plausible site of SBD binding to thrombin. The absence of the Arg173-like residue in factor Xa supported the observed selectivity of inhibition by SBDs. Cellular toxicity studies indicated that SBDs are essentially nontoxic to cells at concentrations as high as 250 mg/kg. Overall, the work presents the localization of the SBD binding site, which could lead to allosteric modulators of thrombin that are completely different from all clinically used anticoagulants.


Treatment of immunocompromised COVID-19 patients with convalescent plasma.
Immunosuppressed patients such as solid organ transplant and hematologic malignancy patients appear to be at increased risk for morbidity and mortality due to coronavirus disease 2019 (COVID-19) caused by SARS coronavirus 2 (SARS-CoV-2). Convalescent plasma, a method of passive immunization that has been applied to prior viral pandemics, holds promise as a potential treatment for COVID-19. Immunocompromised patients may experience more benefit from convalescent plasma given underlying deficits in B and T cell immunity as well as contraindications to antiviral and immunomodulatory therapy. We describe our institutional experience with four immunosuppressed patients (two kidney transplant recipients, one lung transplant recipient, and one chronic myelogenous leukemia patient) treated with COVID-19 convalescent plasma through the Expanded Access Program (NCT04338360). All patients clinically improved after administration (two fully recovered and two discharged to skilled nursing facilities) and none experienced a transfusion reaction. We also report the characteristics of convalescent plasma product from a local blood center including positive SARS-CoV-2 IgG and negative SARS-CoV-2 PCR in all samples tested. This preliminary evidence suggest that convalescent plasma may be safe among immunosuppressed patients with COVID-19 and emphasizes the need for further data on the efficacy of convalescent plasma as either primary or adjunctive therapy for COVID-19.


What factors affect the quality of life of patients with keloids?
To evaluate factors that affect the quality of life (QoL) of patients with keloids. A study was conducted on 102 patients of both genders between 15 and 70 years old. During initial evaluation, clinical factors, such as keloid visibility, duration and evolution of the disease, previous treatments, types of treatments and recurrence were recorded. Later, patients responded to the QualiFibro questionnaire, which is specific for evaluation of the QoL of patients with keloids and comprises the physical and psychological domains, and six visual numeric scales (VNS), of which three are related to psychological factors (satisfaction with appearance, shame of the disease, and suffering experienced), and the other three are related to physical factors (pruritus, pain and movement restriction). Patients with keloids on non-visible areas of the body (p<0.01) and more than 10 years of disease (p<0.049) reported higher scores on the physical domain of the QualiFibro questionnaire, indicating increased severity compared with patients with keloids on visible areas of the body and disease duration of less than 10 years. There was a positive correlation between psychological (satisfaction with appearance, feelings of embarrassment about the disease and suffering experienced) and physical factors (pruritus, pain and movement restriction) evaluated using the VNSs, and both domains of the QualiFibro questionnaire. Results indicate that the physical domain of the QualiFibro questionnaire was the most affected in patients with keloids on non-visible areas and in those with keloids for more than 10 years. Psychological and physical factors associated with keloids as assessed with the VNS affected both psychological and physical domains of QoL.


Modeling the Leukemia Microenviroment In Vitro.
Over the last decade, the active role of the microenvironment in the pathogenesis, development and drug resistance of B cell malignancies has been clearly established. It is known that the tissue microenvironment promotes proliferation and drug resistance of leukemic cells suggesting that successful treatments of B cell malignancies must target the leukemic cells within these compartments. However, the cross-talk occurring between cancer cells and the tissue microenvironment still needs to be fully elucidated. In solid tumors, this lack of knowledge has led to the development of new and more complex in vitro models able to successfully mimic the in vivo settings, while only a few simplified models are available for haematological cancers, commonly relying only on the co-culture with stabilized stromal cells and/or the addition of limited cocktails of cytokines. Here, we will review the known cellular and molecular interactions occurring between monoclonal B lymphocytes and their tissue microenvironment and the current literature describing innovative in vitro models developed in particular to study chronic lymphocytic leukemia (CLL). We will also elaborate on the possibility to further improve such systems based on the current knowledge of the key molecules/signals present in the microenvironment. In particular, we think that future models should be developed as 3D culture systems with a higher level of cellular and molecular complexity, to replicate microenvironmental-induced signaling. We believe that innovative 3D-models may therefore improve the knowledge on pathogenic mechanisms leading to the dissemination and homing of leukemia cells and consequently the identification of therapeutic targets.


A Lowly Digestible-Starch Diet after Weaning Enhances Exogenous Glucose Oxidation Rate in Female, but Not in Male, Mice.
Starches of low digestibility are associated with improved glucose metabolism. We hypothesise that a lowly digestible-starch diet (LDD) versus a highly digestible-starch diet (HDD) improves the capacity to oxidise starch, and that this is sex-dependent. Mice were fed a LDD or a HDD for 3 weeks directly after weaning. Body weight (BW), body composition (BC), and digestible energy intake (dEI) were determined weekly. At the end of the intervention period, whole-body energy expenditure (EE), respiratory exchange ratio (RER), hydrogen production, and the oxidation of an oral 13C-labelled starch bolus were measured by extended indirect calorimetry. Pancreatic amylase activity and total 13C hepatic enrichment were determined in females immediately before and 4 h after administration of the starch bolus. For both sexes, BW, BC, and basal EE and RER were not affected by the type of starch, but dEI and hydrogen production were increased by the LDD. Only in females, total carbohydrate oxidation and starch-derived glucose oxidation in response to the starch bolus were higher in LDD versus HDD mice; this was not accompanied by differences in amylase activity or hepatic partitioning of the 13C label. These results show that starch digestibility impacts glucose metabolism differently in females versus males.


Wild type and tailless CD8 display similar interaction with microfilaments during capping.
We examined the influence of the intracytoplasmic region of CD8 alpha on capping and interaction with microfilaments. We used cell clones obtained by transfecting a CD4+ T-cell hybridoma with (a) T-cell receptor (TCR) alpha and beta chains from a cytolytic clone and (b) CD8 alpha genes that were either native or modified by extensive deletion of the intracytoplasmic region or replacement of the transmembrane and intracytoplasmic domains with those of a class I major histocompatibility complex gene (Letourneur et al. (1990). Proc. natn. Acad. Sci. U.S.A. 87, 2339-2343). Different cell surface structures were cross-linked with anti-T-cell receptor, anti-CD8 or anti-class I monoclonal antibodies and anti-immunoglobulin (Fab')2. Double labeling and quantitative image analysis were combined to monitor fluorescence anisotropy and correlation between different markers. Microfilaments displayed maximal polarization within two minutes. The correlation between these structures and surface markers was then maximal and started decreasing, whereas the redistribution of surface markers remained stable or continued. Furthermore, wild type and altered CD8 alpha exhibited similar ability to be capped and to induce co-capping of TCR and MHC (major histocompatibility complex) class I: the fraction of cell surface label redistributed into a localized cap ranged between 40% and 80%. Finally, cytochalasin D dramatically decreased CD8 capping in all tested clones. It is concluded that the transmembrane and/or intracellular domains of CD8 molecules are able to drive the extensive redistributions of membrane structures and cytoskeletal elements that are triggered by CD8 cross-linking.


The technique and cost of radiosurgery for the treatment of 1-3 brain metastases.
Radiosurgery can be delivered through a variety of modalities including robotic and fixed gantry Linac-based systems. They appear equally effective and safe. Thus, community need and costs remain the main determinants for choosing a given modality. We performed an economic evaluation to identify settings in which one modality could be preferred over the other. Using local estimates of resource volumes and unit prices, we computed the incremental cost/patient of robotic radiosurgery compared to fixed-gantry radiosurgery from a payer's perspective. By varying parameters of resource volumes, we performed a probabilistic analysis stratified by number of brain lesions. in addition, we performed sensitivity analyses to examine the effect of patient volume on cost/patient. The cost of robotic radiosurgery was $4,783/patient, and cost of fixed-gantry radiosurgery was $5,166/patient. The mean incremental cost was $-383 (95% interval: $-670, $110) for all lesions, $78 ($23, $123) for solitary lesions, and $-610 ($-679, $-534) for multiple lesions. The cost/patient of robotic radiosurgery varied from $5,656 (low volume setting) to $4,492 (high volume setting). in settings of moderate to high volume (6-10 hours of daily operation), and in multiple lesions, robotic radiosurgery is more cost effective than fixed-gantry radiosurgery. Technique utilisée et coût de la radiochirurgie pour le traitement de 1 à 3 métastases cérébrales.


Early oseltamivir treatment of influenza in children 1-3 years of age: a randomized controlled trial.
Oseltamivir provides modest clinical benefits to children with influenza when started within 48 hours of symptom onset. The effectiveness of oseltamivir could be substantially greater if the treatment were started earlier during the course of the illness. We carried out a randomized, double-blind, placebo-controlled trial of the efficacy of oseltamivir started within 24 hours of symptom onset in children 1-3 years of age with laboratory-confirmed influenza during the seasons of 2007-2008 and 2008-2009. Eligible children received either orally administered oseltamivir suspension or a matching placebo twice daily for 5 days. The children received clinical examinations, and the parents filled out detailed symptom diaries for 21 days. Of 408 randomized children who received the study drug (oseltamivir, 203, and placebo, 205), 98 had laboratory-confirmed influenza (influenza A, 79, and influenza B, 19). When started within 12 hours of the onset of symptoms, oseltamivir decreased the incidence of acute otitis media by 85% (95% confidence interval, 25%-97%), but no significant reduction was observed with treatment started within 24 hours. Among children with influenza A, oseltamivir treatment started within 24 hours shortened the median time to resolution of illness by 3.5 days (3.0 vs 6.5 days; P = .006) in all children and by 4.0 days (3.4 vs 7.3; P = .006) in unvaccinated children and reduced parental work absenteeism by 3.0 days. No efficacy was demonstrated against influenza B infections. Oseltamivir treatment started within 24 hours of symptom onset provides substantial benefits to children with influenza A infection. Clinical trials registration. ClinicalTrials.gov identifier: NCT00593502.


Presbyopia Treatments by Mechanism of Action: A New Classification System Based on a Review of the Literature.
Presbyopia, a loss of accommodative ability associated with aging, is a significant cause of vision impairment globally. At the clinical level, it is a frustrating and difficult issue that negatively impacts patients' quality of life. Less appreciated is the fact that loss of accommodative ability and its current treatments methods may present safety concerns, for example, increasing the risk of falls. Therefore, a more complete understanding of treatment options with respect to how they relate to the natural ability of the eye is needed to improve decision making and to aid clinicians in individualizing treatment options. This article reviews the options for expanding functional through focus-a term coined to describe the ability of the eye to see at all distances with minimal latency-by how they vary the refractive power over time, across the visual field, between eyes, or across a range of distances.


Parent and child experiences using a hydrophilic or reused PVC catheter for intermittent catheterisation.
To highlight the challenges faced in adjusting to intermittent catheterisation for families and children affected by spina bifida. Toileting is a particular issue for children with spina bifida resulting in difficulty emptying their bladder. Management of incomplete emptying is intermittent catheterisation, which is now part of routine clinical care. The physical benefits of intermittent catheterisation are critical to renal health, and significant attention has been paid to this; less attention has been given to the personal aspects for the family or older child. A descriptive study of satisfaction with two products for intermittent catheterisation: polyvinyl chloride and hydrophilic catheters based on data obtained from a randomised controlled trial on urinary tract infections in catheter users. At the end of each of the polyvinyl chloride and hydrophilic study arms, parents or older children completed a 'Satisfaction Questionnaire' and then participated in a follow-up interview. Data were analysed for emerging themes. Three themes emerged: adjustment, ease of use and self-reliance. Key findings include: increased independence and confidence of the child catheterising using the hydrophilic catheter, self-management strategies to successfully manipulate the slippery hydrophilic catheter and reasons for the lack of success, and identification of participants who preferred polyvinyl chloride catheters. Descriptive data revealed potential areas where a hydrophilic catheter could improve the lives of the family and child as well as noting the need for user choice in product selection. Listening to the stories of children and families increases the nurse's ability to act as a guide as families struggle to assist their children in reaching their potential. Incontinence has been demonstrated to be the cause of self-isolation potentially leading to a decreased sense of self-worth. Ambulatory care nurses play a large role in helping families find the routine and resources necessary to reduce the incidence of incontinence, in children with spina bifida.


Multiple path interference and differential modal delay reduction using spatial filters in a 4F system.
Multiple path interference (MPI) and differential modal delay (DMD) are two major impairments in fiber optic communication systems. MPI can be found in a few mode fibers in which a higher order mode propagates as a weak replica of the signal and interferes with the fundamental mode at the output of the fiber link. DMD in multimode fibers (MMF) leads to intersymbol interference, which limits the bit rate-distance product of the system. A simple method is proposed to reduce MPI and DMD effects using spatial filters in a 4F system. Higher order modes have higher spatial frequency components. Therefore by choosing a proper spatial filter with a suitable bandwidth, a fraction of the unwanted higher order modes can be suppressed, and therefore MPI and DMD effects can be reduced.


Learning by following a food source.
Hungry pigeons first learned to eat grain from the experimenter's hand. When the hand approached and "pecked" a small disk to produce grain in a food hopper, the pigeons followed the hand rapidly learned to peck the disk. Birds given operant conditioning training took significantly longer to learn the same response. Under natural conditions, young animals may learn to behave like their parents simply by following parental sources of food.


Conserved left-right asymmetry of nodal expression and alterations in murine situs inversus.
Vertebrates have characteristic and conserved left-right (L-R) visceral asymmetries, for example the left-sided heart. In humans, alterations of L-R development can have serious clinical implications, including cardiac defects. Although little is known about how the embryonic L-R axis is established, a recent study in the chick embryo revealed L-R asymmetric expression of several previously cloned genes, including Cnr-1 (for chicken nodal-related-1), and indicated how this L-R molecular asymmetry might be important for subsequent visceral morphogenesis. Here we show that nodal is asymmetrically expressed in mice at similar stages, as is Xnr-1 (for Xenopus nodal related-1) in frogs. We also examine nodal expression in two mouse mutations that perturb L-R development, namely situs inversus viscerum (iv), in which assignment of L-R asymmetry is apparently random and individuals develop either normally or are mirror-image-reversed (situs inversus), and inversion of embryonic turning (inv), in which all individuals develop with situs inversus. In both, nodal expression is strikingly affected, being reversed or converted to symmetry. These results further support a key role for nodal and nodal-related genes in interpreting and relaying L-R patterning information in vertebrates. To our knowledge, our results provide the first direct evidence that iv and inv normally function well before the appearance of morphological L-R asymmetry.


Transgenic mice carrying the human KRAS oncogene under the control of a thyroglobulin promoter: KRAS expression in thyroids analyzed by in situ hybridization.
We have previously generated transgenic mice bearing a molecular construct obtained by fusing the rat thyroglobulin promoter with the human Kirsten ras oncogene (KRAS). These mice showed thyroid abnormalities, although at very low incidence and after a long latency period. A six-month thyrotropin (TSH) stimulation of thyroid glands, followed by a two-month suspension, induced a significant increase in the number of lesions in transgenic mice as compared with a nontransgenic control group. Our goal was to follow the progression and the reversion of the tumorigenesis process in relationship with the levels of expression of the KRAS in this experimental model. In situ hybridization was used to detect expression of KRAS mRNA in sections of thyroids of the various groups of mice. A positive hybridization was observed in follicular cells of TSH-stimulated transgenic mice, whereas no expression could be appreciated in control nontransgenic mice. A positive signal was also observed in thyroid glands excised from transgenic mice after the 2-month suspension of treatment; however, the number of expressing cells was decreased compared with transgenic mice killed immediately after 6 months of a goitrogen regimen. Finally, every cell in the single thyroid carcinoma observed after the two-month suspension was positive for the transgene mRNA. This study further strengthens the role of the expression of mutated KRAS in the early stages of thyroid follicular cell transformation and indicates that when the expression of the mutated KRAS becomes independent of exogenous TSH stimulation, this event coincides with a further progression towards tumorigenesis.


Periventricular leukomalacia and placental histopathologic abnormalities.
To estimate whether there are placental histopathologic abnormalities associated with neonatal periventricular leukomalacia (PVL), a major precursor of cerebral palsy. This is a case-control study of 167 neonates born between 23 and 34 weeks of gestation diagnosed with PVL by head ultrasonography within 6 weeks of birth, and 167 control neonates without neurologic morbidity matched by gestational age. Placentas for both case neonates and control neonates were reviewed by two perinatal pathologists who were blinded to neonatal course. Neonates with PVL were significantly more likely to have positive neonatal blood (28.7%, 16.8%, P=.001) and cerebrospinal fluid (14.4%, 4.8%, P=.007) cultures. The ratio of placental weight to birth weight did not differ between groups, but neonates with PVL had significantly more chronic diffuse capsular deciduitis (20.4%, 10.8%, P=.02) and capsular decidual plasma cells (8.4%, 2.4%, P=.02). Conditional logistic regression adjusting for birth weight and the presence of multiple gestation in the identification of PVL showed a significant increase for diffuse capsular deciduitis (P=.02) and capsular decidual plasma cells (P=.03). Periventricular leukomalacia has a significant but weak association with chronic diffuse capsular deciduitis and the presence of capsular decidual plasma cells, evidence of chronic infection but not histologic acute chorioamnionitis. II.


Coevolution of Contrary Choices in Host-Parasitoid Systems.
We investigate patch selection strategies of hosts and parasitoids in heterogeneous environments. Previous theoretical work showed that when host traits vary among patches, coevolved populations of hosts and parasitoids make congruent choices (i.e., hosts and parasitoids preferentially select the same patches) and exhibit direct density dependence in the distribution of percent parasitism. However, host-parasitoid systems in the field show a range of patterns in percent parasitism, while behavioral studies indicate that hosts and parasitoids can exhibit contrary choices (i.e., hosts avoid patches favored by the parasitoid). We extend previous theory by permitting life-history traits of the parasitoid as well as the host to vary among patches. Our analysis implies that in coevolutionarily stable populations, hosts preferentially select patches that intrinsically support higher host equilibrium numbers (i.e., the equilibrium number achieved by hosts when both populations are confined to a single patch) and that parasitoids preferentially select patches that intrinsically support higher parasitoid equilibrium numbers (i.e., the equilibrium number achieved by the parasitoids when both populations are confined to a patch). Using this result, we show how variation in life-history traits among patches leads to contrary or congruent choices or leads to direct density dependence, inverse density dependence, or density independence in the distribution of percent parasitism. In addition, we determine when populations playing the coevolutionarily stable strategies are ecologically stable. Our analysis shows that heterogeneous environments containing patches where the intrinsic rate of growth of the host and the survivorship rate of the parasitoid are low result in the coevolved populations exhibiting contrary choices and, as a result, promote ecological stability.


[Pain and pain perception].
Pain is both sensual perception and sense of touch, and it leads to emotional change of health, which has an effect back to a pain perception. Experience of pain is modified by intern and extern influences, and it can appear very multiformly in the chronicity. A part of these factors are described.


Oil-assisted sample preparation: a simple method for analysis of solid samples using matrix-assisted laser desorption/ionization mass spectrometry.
Common mass spectrometric techniques, e.g., electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI), require samples to be soluble in suitable solvents. Samples with solubility problems have difficulties for their mass spectrometric characterization. In this paper, an oil-assisted sample preparation (OASP) method was introduced for the analysis of solid samples using MALDI-MS. The novel method involves the use of a droplet of oil (i.e., paraffin oil) as the mixing and loading media for solid analyte and solid matrix. Using this method, rapid on-target sample preparation can be easily achieved, and only a transferable minimal amount of analyte and matrix is required. This method was demonstrated to be applicable for a wide range of analytes, including poorly soluble organic compounds, polymers, organometallic compounds, membrane peptides, and biological solid samples. The novel method can also be used for the analysis of "wet" and solution samples. The limit of detection of the OASP MALDI-MS was determined to be 1 ng with reserpine.


Mate choice and the operational sex ratio: an experimental test with robotic crabs.
The operational sex ratio (OSR: sexually active males: receptive females) predicts the intensity of competition for mates. It is less clear, however, under what circumstances, the OSR predicts the strength of sexual selection - that is, the extent to which variation in mating success is attributable to traits that increase the bearer's attractiveness and/or fighting ability. To establish causality, experiments that manipulate the OSR are required. Furthermore, if it is possible to control for any OSR-dependent changes in the chosen sex (e.g. changes in male courtship), we can directly test whether the OSR affects the behaviour of the choosing sex (e.g. female choice decisions). We conducted female mate choice experiments in the field using robotic models of male fiddler crabs (Uca mjoebergi). We used a novel design with two females tested sequentially per trial. As in nature, the choice of the first female to mate therefore affected the mates available to the next female. In general, we detected significant sexual selection due to female choice for 'males' with larger claws. Importantly, the strength of sexual selection did not vary across five different OSR/density treatments. However, as the OSR decreased (hence the number of available males declined), females chose the 'males' with the largest claws available significantly more often than expected by chance. Possible reasons for this mismatch between the expected and observed effects of the OSR on the strength of sexual selection are discussed.


Tau seeding without tauopathy.
Neurodegenerative tauopathies such as Alzheimer's disease (AD) are caused by brain accumulation of tau assemblies. Evidence suggests tau functions as a prion, and cells and animals efficiently propagate unique, transmissible tau pathology. This suggests a dedicated cellular replication machinery, potentially with a normal physiologic function for tau seeds. Consequently, we hypothesized that healthy control brains would have seeding activity. We have recently developed a novel monoclonal antibody (MD3.1) specific for tau seeds. We used this antibody to immunopurify tau from the parietal and cerebellar cortices of 19 healthy subjects without any neuropathology, ranging 19-65 years. We detected seeding in lysates from the parietal cortex, but not in the cerebellum. We also detected no seeding in brain homogenates from wild-type or human tau knockin mice, suggesting that cellular/genetic context dictates development of seed-competent tau. Seeding did not correlate with subject age or brain tau levels. We confirmed our essential findings using an orthogonal assay, RTQuIC, which amplifies tau seeds in vitro. Dot blot analyses revealed no AT8 immunoreactivity above background levels in parietal and cerebellar extracts and ∼1/100 of that present in AD. Based on binding to a panel of antibodies, the conformational characteristics of control seeds differed from AD, suggesting a unique underlying assembly, or structural ensemble. Tau's ability to adopt self-replicating conformations under non-pathogenic conditions may reflect a normal function that goes awry in disease states.


Biophysical evidence to support and extend the vitamin D-folate hypothesis as a paradigm for the evolution of human skin pigmentation.
To test the "vitamin D-folate hypothesis for the evolution of human skin pigmentation." Total ozone mapping spectrometer (TOMS) satellite data were used to examine surface UV-irradiance in a large (n = 649) Australian cross-sectional study population. Genetic analysis was used to score vitamin D- and folate-related gene polymorphisms (n = 22), along with two pigmentation gene variants (IRF4-rs12203592/HERC2-rs12913832). Red cell folate and vitamin D3 were measured by immunoassay and HPLC, respectively. Ultraviolet radiation (UVR) and pigmentation genes interact to modify blood vitamin levels; Light skin IRF4-TT genotype has greatest folate loss while light skin HERC2-GG genotype has greatest vitamin D3 synthesis (reflected in both TOMS and seasonal data). UV-wavelength exhibits a dose-response relationship in folate loss within light skin IRF4-TT genotype (305 > 310 > 324 > 380 nm). Significant vitamin D3 photosynthesis only occurs within light skin HERC2-GG genotype, and is maximal at 305 nm. Three dietary antioxidants (vitamins C, E, and β-carotene) interact with UVR and pigmentation genes preventing oxidative loss of labile reduced folate vitamers, with greatest benefit in light skin IRF4-TT subjects. The putative photosensitiser, riboflavin, did not sensitize red cell folate to UVR and actually afforded protection. Four genes (5xSNPs) influenced blood vitamin levels when stratified by pigmentation genotype; MTHFR-rs1801133/rs1801131, TS-rs34489327, CYP24A-rs17216707, and VDR-ApaI-rs7975232. Lightest IRF4-TT/darkest HERC2-AA genotype combination (greatest folate loss/lowest vitamin D3 synthesis) has 0% occurrence. The opposing, commonest (39%) compound genotype (darkest IRF4-CC/lightest HERC2-GG) permits least folate loss and greatest synthesis of vitamin D3 . New biophysical evidence supports the vitamin D-folate hypothesis for evolution of skin pigmentation.


Development and psychometric evaluation of a three-dimensional Gambling Motives Questionnaire.
This study was designed to develop and evaluate a self-report measure of gambling motives. Participants A community-recruited sample of 193 gamblers (70% male; mean age = 35.5 years) were selected to fill two groups according to scores on the South Oaks Gambling Screen: probable pathological gamblers (PPG; n = 154) and non-pathological gamblers (NPG; n = 39). Participants completed a novel 15-item measure of gambling motives called the Gambling Motives Questionnaire (GMQ), which was modeled after the original Drinking Motives Questionnaire, as well as a variety of gambling behavior and problem criterion measures. An exploratory principal components analysis revealed three intercorrelated factors tapping enhancement (ENH), coping (COP), and social (SOC) motives, respectively. Each GMQ subscale showed good internal consistency (alphas > 0.80). The PPG group scored higher on all three scales than the NPG group, with larger differences for ENH and COP. In line with the clinical literature, PPG women scored higher than PPG men on the COP subscale but also, unexpectedly, on the SOC subscale. In concurrent validity analyses, ENH consistently predicted greater gambling behavior, and COP and ENH consistently predicted more severe gambling problems. With gambling behavior levels controlled, only COP remained a significant predictor of gambling problem severity. Finally, gender interacted with gambling motives in predicting gambling problem severity: COP predicted gambling problems more strongly in women, whereas ENH predicted gambling problems more strongly in men. The GMQ appears to be a promising tool for both research and clinical applications with problem gamblers.


Elevations of plasma glucose do not support taste-to-postingestive consequence learning.
We examined whether elevations in plasma glucose are a sufficient postingestive consequence to support taste-to-postingestive consequence learning. Because real, but not sham, feeding supports taste-to-postingestive consequence learning, we recorded changes in plasma glucose during sham and real feeding. For the 1st 15 min of the meal, both sham and real feeding produced similar elevations in plasma glucose. Thereafter, real feeding produced sustained elevations in plasma glucose, whereas sham feeding did not. However, mimicking the plasma glucose profile of real feeding in the sham feeding rat by infusing glucose intravenously did not produce taste-to-postingestive consequence learning. Using radiolabeled sucrose, we determined that the rise in plasma glucose during sham feeding results from absorption of nutrient. We conclude that elevations in plasma glucose in isolation are not a sufficient consequence to support taste-to-postingestive consequence learning.


Jóge Kankei: a key concept for an understanding of Japanese-American achievement.
Jóge Kankei, or an emphasis on superior-inferior relationships, refers to the pervasive concern with ranking in Japanese society. This concept is associated with achievement motivation in that it is related to socialization practices that create in the individual a heightened sensitivity to the opinions of significant others. In this paper, the pervasive concern with ranking and the sensitivity to the opinions of others is first used as a conceptual tool to explain the alleged paradoxical behavior of the Japanese at various times in their history, and is then used as the basis of a study aimed at understanding the rapid acculturation of the Japanese Americans. The study is based upon interviews with 234 Issei (first generation, born in Japan), 241 Nisei (second generation, born of Issei parents), and 372 Sansei (third generation, born of Nisei parents). Additionally, these three groups were administered several tests and questionnaires designed to measure acculturation and the retention of Japanese values.


Intrahepatic Cholangiolocellular and Cholangiocellular Carcinoma - Differences in the 18F-FDG PET/CT Findings.
Cholangiolocellular carcinoma is a minor primary cancerous tumor of the liver and its coexistence with intrahepatic cholangiocarcinoma in the liver is rare. We herein report a case of concurrent cholangiolocellular carcinoma and intrahepatic cholangiocarcinoma in the liver, in addition to a rectal G1 neuroendocrine tumor, a so-called carcinoid. The intrahepatic tumors showed a different uptake in the 18F-fluoro-2-deoxyglucose (FDG) positron-emission tomography (PET)/computed tomography (CT) findings. In addition to conventional dynamic contrast-enhanced CT, we concluded that FDG PET/CT could therefore be a helpful modality to identify the properties of both cholangiolocellular carcinoma and intrahepatic cholangiocarcinoma.


Experimental coevolution: rapid local adaptation by parasites depends on host mating system.
Host-parasite interactions can drive rapid, reciprocal genetic changes (coevolution), provided both hosts and parasites have high heritabilities for resistance/infectivity. Similarly, the host's mating system should also affect the rate of coevolutionary change in host-parasite interactions. Using experimental coevolution, we determined the effect of obligate outcrossing verses partial self-fertilization (mixed mating) on the rate of evolutionary change in a nematode host (Caenorhabditis elegans) and its bacterial parasite (Serratia marcescens). Bacterial populations were derived from a common ancestor. We measured the effects of host mating system on host adaptation to the parasite. We then determined the extent of parasite adaptation to their local host populations. Obligately outcrossing hosts exhibited more rapid adaptation to parasites than did mixed mating hosts. In addition, most of the parasites became adapted to infecting their local hosts, but parasites from obligately outcrossing hosts showed a greater level of local adaptation. These results suggest that host populations evolved along separate trajectories and that outcrossing host populations diverged further than partially selfing populations. Finally, parasites tracking outcrossing host populations diverged further than parasites tracking the partially selfing host populations. These results show that the evolutionary trajectories of both hosts and parasites can be shaped by the host's mating system.


Treatment of vascular lesions with balloon catheters.
During a 4 year period, 48 patients were treated with balloon catheters. There were 39 fistulas and nine aneurysms. Detachable balloons with a modified Debrun technique were used in 37 patients. Different kinds of technical problems were encountered. The arterial axis remained patent in 29 of the 37 fistulas; in the two mixed internal and external carotid-cavernous sinus fistulas, combined embolization with dura, isobutyl cyanoacrylate, and detachable balloon was used. In six of the nine aneurysms the arterial axis was occluded with a detachable balloon. In three of 48 patients, severe neurologic complications resulted in death.


It's my party and I eat if I want to. Reasons for unhealthy snacking.
Investigating the reasons that people give for unhealthy snacking behavior is important for developing effective health interventions. Little research, however, has identified reasons that apply to a large audience and most studies do not integrate multiple factors, precluding any conclusions regarding their relative importance. The present study explored reasons for unhealthy snacking among a representative community sample. Participants (N = 1544) filled out the newly developed Reasons to Snack inventory assessing an elaborate range of motives at baseline and 1-month follow-up. Exploratory and replication factor analyses identified six categories: opportunity induced eating, coping with negative emotions, enjoying a special occasion, rewarding oneself, social pressure, and gaining energy. The highest mean scores were obtained for enjoying a special occasion and opportunity induced eating. Regression analyses with participant characteristics as independent variables and each category of reasons as dependent variables showed differences for age. For all reasons except to enjoy a special occasion, younger people reported a higher score. Women indicated a higher score than men on coping with negative emotions, enjoying a special occasion and gaining energy. People who diet to a stronger extent reported a higher score for snacking because of social pressure, to reward oneself and to cope with negative emotions, with the latter also being related to a higher BMI. Finally, a higher education was associated with enjoying a special occasion. Future health interventions could allocate more attention to diminishing unhealthy snacking with regard to the six identified categories, specifically focusing on enjoying a special occasion and opportunity induced eating.


Elaborations on Mössbauer rotor experiments with synchrotron radiation and with usual resonant sources.
A comparative analysis of Mössbauer experiments in a rotating system between a recent application using synchrotron radiation [Friedman et al. (2016). Eur. Phys. Lett. 114, 50010; Friedman et al. (2017). J. Synchrotron Rad. 24, 661-666] and usual sources of resonant radiation is carried out. The principal methodological difference between these experiments can be related to the fact that in the former set of experiments the source of the resonant radiation rests in a laboratory frame whereas for the latter set of experiments the source is attached to a rotating system. It is concluded that the utilization of ordinary Mössbauer sources remains the most promising path for further research appertaining to the Mössbauer effect in rotating systems.


Pediatric neuroenhancement: ethical, legal, social, and neurodevelopmental implications.
The use of prescription medication to augment cognitive or affective function in healthy persons-or neuroenhancement-is increasing in adult and pediatric populations. In children and adolescents, neuroenhancement appears to be increasing in parallel to the rising rates of attention-deficit disorder diagnoses and stimulant medication prescriptions, and the opportunities for medication diversion. Pediatric neuroenhancement remains a particularly unsettled and value-laden practice, often without appropriate goals or justification. Pediatric neuroenhancement presents its own ethical, social, legal, and developmental issues, including the fiduciary responsibility of physicians caring for children, the special integrity of the doctor-child-parent relationship, the vulnerability of children to various forms of coercion, distributive justice in school settings, and the moral obligation of physicians to prevent misuse of medication. Neurodevelopmental issues include the importance of evolving personal authenticity during childhood and adolescence, the emergence of individual decision-making capacities, and the process of developing autonomy. This Ethics, Law, and Humanities Committee position paper, endorsed by the American Academy of Neurology, Child Neurology Society, and American Neurological Association, focuses on various implications of pediatric neuroenhancement and outlines discussion points in responding to neuroenhancement requests from parents or adolescents. Based on currently available data and the balance of ethics issues reviewed in this position paper, neuroenhancement in legally and developmentally nonautonomous children and adolescents without a diagnosis of a neurologic disorder is not justifiable. In nearly autonomous adolescents, the fiduciary obligation of the physician may be weaker, but the prescription of neuroenhancements is inadvisable because of numerous social, developmental, and professional integrity issues.


Monitoring aerobic sludge digestion by online scanning fluorometry.
With sludge samples from two wastewater treatment plants, batch experiments of aerobic sludge digestion were conducted under different dissolved oxygen (DO) and solids concentrations. A fluorometer capable of online excitation and emission scanning was used to monitor the digestion process. Three major fluorescence peaks were observed. The peak at excitation/emission maxima of 290/350 nm was attributed to the fluorescence of proteinaceous materials in the sludge, with tryptophan residues being the primary contributor. The sources for the other two peaks (at 370/430 nm and 430/510 nm) remain unknown. The well-known biological fluorescence from reduced nicotinamide adenine dinucleotides (NADH and NADPH), at excitation/emission maxima of 340/460 nm, was found very weak in the aerobic digestion systems studied. It was buried under the broad peak at 370/430 nm and was detectable only in the early stage of the experiment that had the highest solids loading (at 4.8%) and was operated under low DO (0.2-1.0mg/L) conditions. On the other hand, the profile of the protein fluorescence (PF) correlated well with that of the volatile solids (VS) reduction in all the experiments. A semi-empirical exponential decay function was developed, which described well the profiles of both normalized VS and normalized PF. The feasibility of following the real-time performance of aerobic sludge digestion by monitoring PF was clearly demonstrated.


Complication rate after scoliosis surgery in children with cerebral palsy.
Scoliosis is an important problem in children with cerebral palsy (CP). However, the choice for a spinal fusion has to be weighed against the risks of major surgery in this vulnerable population. Paediatricians are frequently consulted preoperatively to assess the (respiratory) risk involved, but data on this question specific for CP are rare. Therefore, we investigated the complication rate after scoliosis surgery in children with CP, compared to idiopathic scoliosis (IS), and we searched for risk factors for the most common complications. In a retrospective monocenter study we analyzed the medical records from all children with CP and IS undergoing scoliosis surgery from 2010 until 2014. Duration of hospitalization and postoperative complications were compared within a 6-month follow-up. Univariate and multivariate logistic regression models were used to identify risk factors. The study included 44 patients with CP (mean age 15y0mo) and 78 patients with IS (mean age 14y6mo). Children with CP experience a higher rate of complications : respiratory and cardiovascular, as well as wound infections and decubitus ulcers (p<0.05). Postoperative pneumonia was the most frequent complication in both patient groups (43% and 18% in CP and IS respectively), with epilepsy being a significant risk factor (OR 3.85, p= 0.037) in children with CP. Intensive care unit and total hospital stay were longer in the CP group (p<0.001). These results may add information on perioperative care and surgical decision making.


A resource allocation model describing consequences of artificial selection under metabolic stress.
Long-term selection on production results in increased environmental sensitivity. This often is expressed through decreased fertility and increased health problems. The phenomenon has been described in all common farm animal species. One theory is that potential resource intake is insufficient to express production potential. Additional resources are drawn away from fitness-related traits, such as fertility and health, to further increase observed production. In addition, resources for maintaining fitness depend on the demands by the environment. In a harsh environment, more resources are required for fitness-related traits than in an optimal environment. Literature results show that selection in an optimal environment will increase sensitivity to less optimal environments. The objectives of this paper were to increase understanding of the underlying mechanism behind the development of environmental sensitivity and to gain insight into correlated response(s) when selection is on observed production. A resource allocation model was defined where observed production depended on production potential, resource intake potential, and the allocation of resources to production or fitness, including maintenance, health, and reproduction. Penalties for reproductive performance and probability of survival were included when the proportion of resources assigned to fitness dropped below a certain, environment-related, threshold. Mass selection was practiced on observed production during 40 generations using stochastic simulation. Depending on the heritabilities of the underlying components and on the environment, selection on observed production resulted in a decrease in reproductive rate and in the development of environmental sensitivity when resource intake becomes limiting. Correlations of observed production with underlying components changed across generations, following a nonlinear pattern. The proposed model is simple, but increases the understanding of underlying mechanisms and consequences of selection for production when resources are limiting.


Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy for early breast cancer.
The incidence of new primary cancers was evaluated in 3538 postmenopausal patients who had received surgical treatment for primary breast cancer. Of these patients, 1828 with a low risk of recurrence received no further treatment. High-risk patients were randomly assigned to one of two groups. The first group (n = 846) received postoperative radiotherapy, while the second group (n = 864) received radiotherapy plus tamoxifen at a dose of 30 mg given daily for 48 weeks. The median observation time was 7.9 years. In comparison with the number of new cancers in the general population, the number of new cancers in the three groups was elevated mostly due to a high number of cancers of the contralateral breast and of colorectal cancers in the high-risk groups. The cumulative risk of nonlymphatic leukemia was increased among patients who received postoperative radiotherapy (P = .04). Cancer incidence in the high-risk tamoxifen-treated group relative to that in the high-risk group not treated with tamoxifen was not significant (1.3). No protective effect of tamoxifen on the opposite breast was seen (rate ratio for breast cancer = 1.1), but a tendency to an elevated risk of endometrial cancer was observed (rate ratio = 3.3; 95% confidence interval = 0.6-32.4). Continued and careful follow-up of women treated with tamoxifen is necessary to clarify the potential cancer-suppressive or cancer-promoting effects of this drug.


Nanoscale Pulling of Type IV Pili Reveals Their Flexibility and Adhesion to Surfaces over Extended Lengths of the Pili.
Type IV pili (T4P) are very thin protein filaments that extend from and retract into bacterial cells, allowing them to interact with and colonize a broad array of chemically diverse surfaces. The physical aspects that allow T4P to mediate adherence to many different surfaces remain unclear. Atomic force microscopy (AFM) nanoscale pulling experiments were used to measure the mechanical properties of T4P of a mutant strain of Pseudomonas aeruginosa PAO1 unable to retract its T4P. After adhering bacteria to the end of an AFM cantilever and approaching surfaces of mica, gold, or polystyrene, we observed adhesion of the T4P to all of the surfaces. Pulling of single and multiple T4P on retraction of the cantilever from the surfaces could be described using the worm-like chain (WLC) model. Distinct peaks in the measured distributions of the best-fit values of the persistence length Lp on two different surfaces provide strong evidence for close-packed bundling of very flexible T4P. In addition, we observed force plateaus indicating that adhesion of the T4P to both hydrophilic and hydrophobic surfaces occurs along extended lengths of the T4P. These data shed new light, to our knowledge, on T4P flexibility and support a low-affinity, high-avidity adhesion mechanism that mediates bacteria-surface interactions.


The adaptation of the plaque reduction assay for measuring specific cytotoxic cells in limiting dilution cultures.
The use of the original haemolytic plaque reduction technique to measure cytotoxic T lymphocytes (CTL) has been developed further as a rapid screening assay, particularly suitable for limiting dilution analyses. Using hybridoma cells as targets, the cytotoxicity has been measured by the loss of haemolytic plaque formation and by the reduction of the amount of haemolytic monoclonal antibody secreted from viable target cells into the assay supernatants. The assessment of large numbers of cytotoxic samples has been greatly facilitated by quantitating the amount of haemoglobin released in the assay with an automated microELISA multiscanner and by scoring visually using a modification of the spot test. Using these new techniques, relatively high frequency estimates of cytotoxic cell precursors in an allogeneic response (1 in 462 spleen cells) and an anti-fluorescein response (1 in 3970 spleen cells) were obtained.


Duration of breastfeeding, age at introduction of complementary foods and allergy-related diseases: a prospective cohort study.
The influences of breastfeeding and infant diet in the prevention of allergy-related diseases are uncertain and many of the studies conducted on the topic are limited by methodological challenges. Our aim was to assess whether the duration of breastfeeding and age at complementary food introduction affected the prevalence of asthma, wheeze, allergic rhinoconjunctivitis (ARC) and eczema at two and six years of age. We used information gathered between 2000 and 2014 through questionnaires in the Prevention of Allergy among Children in Trondheim (PACT) study, a prospective cohort study in Trondheim, Norway. The current study includes 6802 children who submitted questionnaires detailing breastfeeding duration and or age at introduction to complementary foods, as well as at least one of the child health questionnaires completed at two and six years of age. Adjusted odds ratios (aORs) were calculated for each combination of exposure and outcomes and sensitivity analyses were performed to assess the possible influence of recall bias and reverse causality. The mean duration of breastfeeding was 11 months (SD 5.6) in this study population and 5695 of 6796 (84%) infants had been breastfed for at least 6 months. We did not find any conclusive preventative effect of longer breastfeeding on parental reported doctor-diagnosed asthma, aOR 0.79 (95% CI 0.51, 1.21). However, at 6 years of age we observed a reduction in the less strictly defined outcome wheeze, aOR 0.71 (95% CI 0.53, 0.95). Longer breastfeeding was associated with a reduced risk of ARC at 2 years, aOR 0.65 (95% CI 0.49, 0.86), with a continued protective trend at 6 years, aOR 0.77 (95% CI 0.58, 1.04). Longer breastfeeding resulted in a reduced risk of wheeze and a trend towards a protective effect on ARC up until school age. No conclusive associations were seen between the duration of breastfeeding or age at introduction to complementary foods and prevention of asthma, wheeze, ARC and eczema. The trial is registered in Current Controlled Trials as ISRCTN28090297 .


Programming of neural progenitors of the adult subependymal zone towards a glutamatergic neuron lineage by neurogenin 2.
Although adult subependymal zone (SEZ) neural stem cells mostly generate GABAergic interneurons, a small progenitor population expresses the proneural gene Neurog2 and produces glutamatergic neurons. Here, we determined whether Neurog2 could respecify SEZ neural stem cells and their progeny toward a glutamatergic fate. Retrovirus-mediated expression of Neurog2 induced the glutamatergic lineage markers TBR2 and TBR1 in cultured SEZ progenitors, which differentiated into functional glutamatergic neurons. Likewise, Neurog2-transduced SEZ progenitors acquired glutamatergic neuron hallmarks in vivo. Intriguingly, they failed to migrate toward the olfactory bulb and instead differentiated within the SEZ or the adjacent striatum, where they received connections from local neurons, as indicated by rabies virus-mediated monosynaptic tracing. In contrast, lentivirus-mediated expression of Neurog2 failed to reprogram early SEZ neurons, which maintained GABAergic identity and migrated to the olfactory bulb. Our data show that NEUROG2 can program SEZ progenitors toward a glutamatergic identity but fails to reprogram their neuronal progeny.


Evaluation of novel protease enzymes on growth performance and apparent ileal digestibility of amino acids in poultry: enzyme screening.
Three experiments were conducted to evaluate eight neutral and six acid proteases on growth performance and apparent ileal amino acid digestibility (AID) of poults (Experiment 1) or chicks (Experiments 2 and 3). Two basal diets were formulated: a nutrient adequate positive control (PC), which met or exceeded the nutrient requirements for poults (Experiment 1) or chicks (Experiments 2 and 3) and a negative control (NC) formulated to achieve 85% (Experiments 1 and 2) or 80% (Experiments 3) of the requirement for protein and amino acids. Phytase was included in all diets to provide 500 phytase units (FTU)/kg and xylanase was included in all diets to provide 10,000 (Experiments 1 and 2) or 16,000 (Experiments 3) xylanase units (BXU)/kg. Proteases were supplemented in the NC diet at an equivalent amount of enzyme protein to create 16 experimental diets. There were five birds/pen and 10 replicate pens per treatment in each experiment. In experiment 1, birds fed the PC diet gained more (P < 0.05) than birds fed the NC. There were no differences in growth performance in birds fed the PC or NC in experiments 2 or 3. In all three experiments, birds fed the NC supplemented with neutral protease 1 had reduced (P < 0.05) feed intake (FI) or body weight gain (BWG) and increased (P < 0.05) feed conversion ratio (FCR) compared with birds fed the NC. Birds fed the NC diet supplemented with neutral protease 3, 7 (Experiment 1), or acid protease 4 (Experiment 3) had increased (P < 0.05) FCR and birds fed neutral protease 6 (Experiment 2) had reduced (P < 0.05) BWG compared with birds fed the NC. Apparent ileal amino acid digestibility was improved (P < 0.05) with protease supplementation to the NC diets (Experiment 1 or 3), but this was dependent on the protease and the amino acid. In conclusion, novel protease supplementation improved AID of amino acids but this was not reflected in improvements in growth performance of poults or chicks.


Pathogenesis underlying hexanucleotide repeat expansions in C9orf72 gene in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder. Mutations in C9orf72 and the resulting hexanucleotide repeat (GGGGCC) expansion (HRE) has been identified as a major cause of familial ALS, accounting for about 40 % of familial and 6 % of sporadic cases of ALS in Western patients. The pathological outcomes of HRE expansion in ALS have been recognized as the results of two mechanisms that include both the toxic gain-of-function and loss-of-function of C9ORF72. The gain of toxicity results from RNA and dipeptide repeats (DPRs). The HRE can be bidirectionally transcribed into RNA foci, which can bind to and disrupt RNA splicing, transport, and translation. The DPRs that include poly-glycine-alanine, poly-glycine-proline, poly-glycine- arginine, poly-proline-alanine, and poly-proline-arginine can induce toxicity by direct binding and sequestrating other proteins to interfere rRNA synthesis, ribosome biogenesis, translation, and nucleocytoplasmic transport. The C9ORF72 functions through binding to its partners-Smith-Magenis chromosome regions 8 (SMCR8) and WD repeat-containing protein (WDR41). Loss of C9ORF72 function results in impairment of autophagy, deregulation of autoimmunity, increased stress, and disruption of nucleocytoplasmic transport. Further insight into the mechanism in C9ORF72 HRE pathogenesis will facilitate identifying novel and effective therapeutic targets for ALS.


Prognostic value of dobutamine stress echocardiography in patients with diabetes.
The aim of this study was to assess the incremental value of dobutamine stress echocardiography (DSE) for the risk stratification of diabetic patients who are unable to perform an adequate exercise stress test. Exercise capacity is frequently impaired in patients with diabetes. The role of pharmacologic stress echocardiography in the risk stratification of diabetic patients has not been well defined. We studied 396 diabetic patients (mean age 61 +/- 11 years, 252 men [64%]) with limited exercise capacity who underwent DSE for evaluation of known or suspected coronary artery disease (CAD). End points were hard cardiac events (cardiac death and nonfatal myocardial infarction) and all causes of mortality. During a median follow-up of 3 years, 97 patients (24%) died (55 cardiac deaths), and 27 patients had nonfatal myocardial infarction. In an incremental multivariate analysis model, clinical predictors of hard cardiac events were history of congestive heart failure, previous myocardial infarction, hypercholesterolemia, and ejection fraction at rest. The percentage of ischemic segments was incremental to the clinical model in the prediction of hard cardiac events (chi(2) = 37 vs. 18, P < 0.05). Clinical predictors of all causes of mortality were history of congestive heart failure, age, hypercholesterolemia, and ejection fraction at rest. Wall motion score index at peak stress was incremental to the clinical model in the prediction of mortality (chi(2) = 52 vs. 43, P < 0.05). DSE provides incremental data for the prediction of mortality and hard cardiac events in patients with diabetes who are unable to perform an adequate exercise stress test.


Standard anterior peritomy versus a small posterior incision for the implantation of the PRESERFLO microshunt.
To compare two approaches for the implantation of the PRESERFLO microshunt: an anterior approach (A) with a 6-8-mm peritomy and a posterior approach (P) with a 3-mm incision. We retrospectively analyzed 126 patients who received a PRESERFLO microshunt. We compared intraocular pressure (IOP), surgical time, medication count, and postoperative complications over nine months. The baseline IOP was similar in A (21.8 ± 8.5 mm Hg) and P (23.9 ± 8.1 mm Hg) (p = 0.08). Surgical duration was significantly shorter in P (10 ± 0.4 min) than in A (26 ± 0.8 min) (p < 0.001). Postoperative IOP levels were comparable in A (10.8 ± 5.9 mm Hg) and P (10.6 ± 4.5 mm Hg) at 30 days (p = 0.62) and throughout the study (all intra-group p-values > 0.08). The preoperative medication count was 3.2 ± 1.3 drops in A and 3.3 ± 1.0 drops in P (p = 0.4). Postoperative values were 0.2 ± 0.6 in A and 0.3 ± 0.7 in P at nine months. There were no significant differences in complications and surgical revisions between groups (p-values > 0.05). Both techniques achieved satisfactory IOP and medication count reductions and had similar safety profiles, but the posterior incision technique was 2.6 times faster than the anterior incision technique.


War exposure, 5-HTTLPR genotype and lifetime risk of depression.
In 1962 approximately 1.5 million French people living in Algeria were repatriated to France in very poor and often life-threatening conditions. These people constitute a cohort for the study of the long-term impact of gene-environment interaction on depression. To examine the interaction between a highly stressful life event and subsequent depression, and its modulation by a length polymorphism of the serotonin transporter gene (5-HTTLPR). A community sample of people aged 65 years and over residing in the Montpellier region of the south of France was randomly recruited from electoral rolls. Genotyping was performed on 248 repatriated persons and 632 controls. Current and lifetime major and minor depressive disorders were assessed according to DSM-IV criteria. A significant relationship was observed between exposure to repatriation and subsequent depression (P<0.002), but there was no significant effect of gene alone (P = 0.62). After controlling for age, gender, education, disability, recent life events and cognitive function, the gene-environment interaction (repatriation × 5-HTTLPR) was globally significant (P<0.002; OR = 3.21, 95% CI 2.48-5.12). Individuals carrying the two short (s) alleles of 5-HTTLPR were observed to be at higher risk (P<0.005; OR = 2.34, 95% CI 1.24-4.32), particularly when repatriation occurred before age 35 years (P<0.002; OR = 2.91, 95% CI 1.44-5.88), but this did not reach significance in those who were older at the time of the event (P = 0.067). The association between depression and war repatriation was significantly modulated by 5-HTTLPR genotype but this appeared to occur only in people who were younger at the time of exposure.


Selenoprotein Gpx3 knockdown induces myocardial damage through Ca2+ leaks in chickens.
Glutathione peroxidase 3 (Gpx3) is a pivotal selenoprotein that acts as an antioxidant. However, the role of Gpx3 in maintaining the normal metabolism of cardiomyocytes remains to be elucidated in more detail. Herein, we employed a model of Gpx3 interference in chicken embryos in vivo and Gpx3 knockdown chicken cardiomyocytes in vitro. Real-time PCR, western blotting and fluorescent staining were performed to detect reactive oxygen species (ROS), the calcium (Ca2+) concentration, endoplasmic reticulum (ER) stress, myocardial contraction, inflammation and heat shock proteins (HSPs). Our results revealed that Gpx3 suppression increased the level of ROS, which induced Ca2+ leakage in the cytoplasm by blocking the expression of Ca2+ channels. The imbalance of Ca2+ homeostasis triggered ER stress and blocked myocardial contraction. Furthermore, we found that Ca2+ imbalance in the cytoplasm induced severe inflammation, and HSPs might play a protective role throughout these processes. In conclusion, Gpx3 suppression induces myocardial damage through the activation of Ca2+-dependent ER stress.


Periacetabular osteotomy after failed hip arthroscopy for labral tears in patients with acetabular dysplasia.
Chronic mechanical overload of the acetabular rim may lead to acetabular labral disease in patients with hip dysplasia. Although arthroscopic debridement of the labrum may provide symptomatic relief, the underlying mechanical abnormality remains. There is little information regarding how the results of periacetabular osteotomy are affected by a prior primary treatment for labral disease in the presence of acetabular dysplasia. In a retrospective matched-cohort study, seventeen patients who had arthroscopic labral debridement prior to periacetabular osteotomy (the arthroscopy group) were compared with a control group of thirty-four patients who did not undergo arthroscopic labral debridement prior to periacetabular osteotomy (the non-arthroscopy group). Two control patients were randomly matched to each experimental patient from a pool of controls. Functional outcomes were assessed with use of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Failure of periacetabular osteotomy was defined as conversion to a total hip replacement. Changes in the preoperative and postoperative WOMAC scores of arthroscopy and non-arthroscopy patients were comparable, and the differences between the two treatment groups were not significant. We were unable to show a significant difference between the seventeen arthroscopy and thirty-four non-arthroscopy patients with regard to the risk of having to undergo a total hip replacement. When arthroscopic labral debridement fails to improve symptoms in patients with labral disease secondary to acetabular dysplasia, periacetabular osteotomy may still be considered as a joint-preserving procedure that can achieve good functional results.


Necropsy study of the association between sudden cardiac death, cardiac isoenzymes and contraction band necrosis.
To assess whether a quantitative analysis of myocardial contraction bands could aid the postmortem identification of early myocardial infarction, especially if used in conjunction with cardiac isoenzyme activities. Sixty four coroner's necropsies were grouped by gross and histological findings into 26 cases of definite non-cardiac death, 12 cases of definite myocardial infarction and 26 cases in which there was occlusive coronary artery atheroma, but no demonstrable evidence of infarction. Using multiple sections of left ventricular myocardium stained with Heidenhain's iron haematoxylin, the number of myocardial cells containing contraction bands per unit area was quantified. The results were analysed statistically using logistic regression, and were then compared and combined with results from the statistical analysis of postmortem cardiac isoenzymes that had recently been undertaken on the same cases. The number of cells containing contraction bands per unit area was higher in cases of definite myocardial infarction compared with those of non-cardiac deaths. In addition, cases of occlusive coronary artery atheroma only could be identified, indicating the presence of early myocardial infarction. The accuracy of this identification could be improved by combining these results with the results from the statistical analysis of postmortem cardiac isoenzymes. The quantitative assessment of myocardial contraction band necrosis can provide useful additional information in cases of sudden death, where myocardial infarction is suspected but not identified on routine histological staining. The value of the information obtained is increased when used in conjunction with the postmortem measurement of cardiac isoenzyme activities.


Production, properties, and some new applications of chitin and its derivatives.
Chitin is a polysaccharide composed from N-acetyl-D-glucosamine units. It is the second most abundant biopolymer on Earth and found mainly in invertebrates, insects, marine diatoms, algae, fungi, and yeasts. Recent investigations confirm the suitability of chitin and its derivatives in chemistry, biotechnology, medicine, veterinary, dentistry, agriculture, food processing, environmental protection, and textile production. The development of technologies based on the utilization of chitin derivatives is caused by their polyelectrolite properties, the presence of reactive functional groups, gel-forming ability, high adsorption capacity, biodegradability and bacteriostatic, and fungistatic and antitumour influence. Resources of chitin for industrial processing are crustacean shells and fungal mycelia. Fungi contain also chitosan, the product of N-deacetylation of chitin. Traditionally, chitin is isolated from crustacean shells by demineralization with diluted acid and deproteinization in a hot base solution. Furthermore, chitin is converted to chitosan by deacetylation in concentrated NaOH solution. It causes changes in molecular weight and a degree of deacetylation of the product and degradation of nutritionally valuable proteins. Thus, enzymatic procedures for deproteinization of the shells or mold mycelia and for chitin deacetylation were investigated. These studies show that chitin is resistant to enzymatic deacetylation. However, chitin deacetylated partially by chemical treatment can be processed further by deacetylase. Efficiency of enzymatic deproteinization depends on the source of crustacean offal and the process conditions. Mild enzymatic treatment removes about 90% of the protein and carotenoids from shrimp-processing waste, and the carotenoprotein produced is useful for feed supplementation. In contrast, deproteinization of shrimp shells by Alcalase led to the isolation of chitin containing about 4.5% of protein impurities and recovery of protein hydrolysate.


Mortality studies in systemic lupus erythematosus. Results from a single center. III. Improved survival over 24 years.
Prognosis studies have indicated that survival of patients with systemic lupus erythematosus (SLE) has improved significantly. We investigate whether the apparent improvement in the survival of patients with SLE is associated with a reduction in the risk of death compared with the general population, or with changes over time in the distribution of various prognostic factors. The University of Toronto cohort of 720 patients with SLE followed between 1970 and 1994 was divided into 3 groups based on year of entry into study: Group A 1970-77, Group B 1978-85, Group C 1986-1994. Standardized mortality ratios (SMR) were calculated for each cohort. Prognostic factors for death occurring in the first 8 yr period after entry into the study were examined in each of the 3 cohorts. Analysis involved chi-squared tests for categorical values and unpaired t tests for continuous variables. Group A comprised 183 patients, Group B 332 patients, and Group C 205 patients. An examination of the first 8 years of evaluation for each group revealed that the SMR decrease over time ranged from 10.1-fold greater than the general population in Group A, to 4.8-fold in Group B, to 3.3-fold in Group C. Prognostic factors for death varied over time, with vasculitis decreasing and hyperlipidemia increasing. Survival in SLE has improved over 24 yrs in the University of Toronto cohort more than the health of the general population has improved. This improved survival was not related to changing demographics, severity of lupus at presentation, major change in disease patterns, or new modalities of treatment.


Electrostatic Architecture of the Infectious Salmon Anemia Virus (ISAV) Core Fusion Protein Illustrates a Carboxyl-Carboxylate pH Sensor.
Segment 5, ORF 1 of the infectious salmon anemia virus (ISAV) genome, encodes for the ISAV F protein, which is responsible for viral-host endosomal membrane fusion during a productive ISAV infection. The entry machinery of ISAV is composed of a complex of the ISAV F and ISAV hemagglutinin esterase (HE) proteins in an unknown stoichiometry prior to receptor engagement by ISAV HE. Following binding of the receptor to ISAV HE, dissociation of the ISAV F protein from HE, and subsequent endocytosis, the ISAV F protein resolves into a fusion-competent oligomeric state. Here, we present a 2.1 Å crystal structure of the fusion core of the ISAV F protein determined at low pH. This structure has allowed us to unambiguously demonstrate that the ISAV entry machinery exhibits typical class I viral fusion protein architecture. Furthermore, we have determined stabilizing factors that accommodate the pH-dependent mode of ISAV transmission, and our structure has allowed the identification of a central coil that is conserved across numerous and varied post-fusion viral glycoprotein structures. We then discuss a mechanistic model of ISAV fusion that parallels the paramyxoviral class I fusion strategy wherein attachment and fusion are relegated to separate proteins in a similar fashion to ISAV fusion.


Multivariate statistics to investigate metal contamination in surface soil.
The modification of soil composition in the urbanized area of Ankara due to wet-dry deposition and pollution-derived particles from the atmosphere is investigated by analyzing 120 surface soil samples, collected from the urbanized area and its un-urbanized surrounding, for major, minor and trace elements. Concentrations of elements from human activity (e.g. Cd, Pb, Cr, Zn, Cu and Ca) in the urbanized area were higher than their corresponding concentrations in global average soil and soil in un-urbanized areas outside the urbanized area. Metal contents in soil were very high in densely populated districts and around some industrial facilities. The only exception was Pb distribution, which was more dispersed, due to the nature of motor vehicle emissions. Alteration of the Cd, Zn, Cu and Cr content of soil was confined to the inhabited and industrial areas, whereas enrichment factors of these elements were close to unity in the remaining study area. Factor analysis identified two polluted soil factor associations. One factor includes elements, such as Zn and Cd, which had high factor scores in inhabited areas and the other factor (high loading of Pb) represents soil polluted by motor vehicle emissions.


PI-3 kinase-PTEN signaling node: an intercept point for the control of angiogenesis.
Angiogenesis is tightly regulated by opposing mechanisms in mammalian cells and is controlled by the angiogenic switch. Other review articles have described a central role for the PTEN/PI-3 kinase/AKT signaling node in the coordinate control of cell division, tumor growth, apoptosis, invasion and cellular metabolism [1, 2]. In this review, we focus on literature that supports the PTEN/PI-3 kinase/AKT signaling node as a major control point for the angiogenic switch in both the on and off positions. We also discuss the rationale for designing small molecule drugs that target the PTEN/PI-3 kinase/AKT signaling node for therapeutic intervention. Our hypothesis is that, instead of inhibiting one cell surface receptor, such as VEGFR2 with bevacizumab (Avastin), thereby leaving a significant number of receptors free to pulse angiogenic signals, a more effective strategy may be to regulate signaling through an intercept node where redundant cell surface receptor signals converge to transmit important signaling events within the cell. This therapeutic configuration brings coordinate control over multiple cell surface receptors in concert with a physiologic response which may combine arrest of cell cycle progression with growth inhibition and the induction of genes involved in specialized functions such as movement, which are all required for the complex process of angiogenesis to occur in a temporal-spatial paradigm.


DNA base flipping analytical pipeline.
DNA base modifications and mutations are observed in all genomes throughout the kingdoms of life. Proteins involved in their establishment and removal were shown to use a base flipping mechanism to access their substrates. To better understand how proteins flip DNA bases to modify or remove them, we optimized and developed a pipeline of methods to step-by-step detect the process starting with protein-DNA interaction, base flipping itself and the ensuing DNA base modification or excision. As methylcytosine is the best-studied DNA modification, here we focus on the process of writing, modifying and reading this DNA base. Using multicolor electrophoretic mobility shift assays, we show that the methylcytosine modifier Tet1 exhibits little DNA sequence specificity with only a slight preference for methylated CpG containing DNA. A combination of chloroacetaldehyde treatment and high-resolution melting temperature analysis allowed us to detect base flipping induced by the methylcytosine modifier Tet1 as well as the methylcytosine writer M.HpaII. Finally, we show that high-resolution melting temperature analysis can be used to detect the activity of glycosylases, methyltransferases and dioxigenases on DNA substrates. Taken together, this DNA base flipping analytical pipeline (BaFAP) provide a complete toolbox for the fast and sensitive analysis of proteins that bind, flip and modify or excise DNA bases.


A preliminary assessment of professional footballers' awareness of injury prevention strategies.
Players from five English professional football clubs completed a questionnaire containing 52 items relating to injury prevention practices and advice received on these issues. Responses were received from 55 players, which represents a mean response of 11 (4) and a response rate of 38 (14)% from each club (means (SD)). The main deficiencies in awareness of injury prevention strategies for players were identified as: use of shin pads during training, carbohydrate intake before and after training and after matches, cool downs after training and matches, and flexibility work. These deficiencies indicate a need for wider education of players in current injury prevention strategies.


Three dimensional computed tomography lung modeling is useful in simulation and navigation of lung cancer surgery.
The number of minimally invasive operations, such as video-assisted thoracoscopic surgery (VATS) lobectomy or segmentectomy, has enormously increased in recent years. These operations require extreme knowledge of the anatomy of pulmonary vessels and bronchi in each patient, and surgeons must carefully dissect the branches of pulmonary vessels during operation. Thus, foreknowledge of the anatomy of each patient would greatly contribute to the safety and accuracy of the operation. The development of multi-detector computed tomography (MDCT) has promoted three dimensional (3D) images of lung structures. It is possible to see the vascular and bronchial structures from the view of the operator; therefore, it is employed for preoperative simulation as well as navigation during operation. Due to advances in software, even small vessels can be accurately imaged, which is useful in performing segmentectomy. Surgical simulation and navigation systems based on high quality 3D lung modeling, including vascular and bronchial structures, can be used routinely to enhance the safety operation, education of junior staff, as well as providing a greater sense of security to the operators.


Functional MR imaging study of language-related differences in bilingual cerebellar activation.
Reports in the monolingual literature suggest that the cerebellum has an important role in language processing. The purpose of this study was to determine whether bilingual cerebellar functional MR imaging (fMRI) activation differs during the performance of comparable tasks in subjects' primary and secondary languages. Eight bilingual, right-handed individuals underwent echo-planar fMRI at 1.5 T. They performed semantic (noun-verb association) and phonological (rhyming) tasks in Spanish (primary language) and English (secondary language). Individual and group functional datasets were analyzed using Statistical Parametric Mapping software (SPM99; P <.001 with a 10-voxel spatial extent threshold) and overlaid on T1-weighted anatomic images normalized to a standard (Montreal Neurologic Institute) space. Analysis of variance was performed on laterality indices derived from voxel counts in cerebellar regions of interest (ROIs). Subtraction of group-averaged normalized results from the combined Spanish tasks from the combined English tasks was also performed within SPM99 (P <.001 activation threshold). Significantly greater lateralilty indices were noted in the English tasks than in the Spanish tasks (mean Spanish LI, 0.3286; mean English LI, 0.5141 [P =.0143]). Overall, more robust activation was seen in the English tasks than in the Spanish tasks. Areas of significantly greater activation existed in the English tasks as compared with the Spanish tasks; these areas were more prominent in the left cerebellar hemisphere. Although both English and Spanish language tasks demonstrate left cerebellar dominance, English tasks demonstrate greater left hemispheric lateralization.


A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer.
Inhibition of mammalian target of rapamycin with everolimus may improve the efficacy of taxanes. Everolimus and docetaxel are both metabolized by CYP3A4, which could result in a pharmacokinetic (PK) interaction. Fifteen patients with metastatic breast cancer were treated with docetaxel (doses of 40-75 mg/m(2) intravenously on day 1 of a 21-day cycle) in combination with everolimus (doses ranging from 20 to 50 mg orally on days 1 and 8 of a 21-day cycle) in a phase 1 trial using the continuous reassessment method to determine maximum tolerated dose. The first 2 patients developed a dose-limiting toxicity (neutropenic infection), prompting a mandatory dose reduction and PK evaluation of both everolimus and docetaxel for patients enrolled in subsequent dosing cohorts. Fifteen patients were treated. Dose-limiting toxicity included grade 3 mucositis (n = 1), prolonged grade 4 neutropenia (n = 1), and grade 3 infection/febrile neutropenia (n = 3). Day 8 of everolimus was commonly held for neutropenia despite a dose reduction in docetaxel to 40 mg/m(2). Eleven patients underwent complete PK evaluation for everolimus, and 9 patients underwent complete PK evaluation for both everolimus and docetaxel. Widely variable changes in clearance were seen for both drugs, and the study was terminated because of lack of efficacy and concerns regarding toxicity seen with the combination. Weekly everolimus in combination with docetaxel every 3 weeks was associated with excessive neutropenia and variable clearance of both drugs, making combination therapy unpredictable, even at low doses of both drugs.


Short- and long-term outcome in elderly patients after out-of-hospital cardiac arrest: a cohort study.
Determinants of outcome and long-term survival are unknown in elderly patients successfully resuscitated after out-of-hospital cardiac arrest. Our aim was to identify factors associated with short- and long-term neurologic outcome in such patients. Retrospective cohort study. Tertiary hospital in Paris, France. Patients aged over 75 admitted in our ICU after an out-of-hospital cardiac arrest between 2000 and 2009. None. Two hundred twenty-five patients were included in the study. Fifty-seven patients (25.3%) had a good neurologic outcome at ICU discharge (Cerebral Performance Category 1-2). By multivariate logistic regression analysis, factors associated with good short-term outcome were time from collapse to cardiopulmonary resuscitation less than or equal to 3 minutes (odds ratio = 4.06; 95% CI, 1.49-11.09, p = 0.006) and blood lactate level less than or equal to 5.1 mmol/L (odds ratio = 3.30; 95% CI, 1.05-10.39, p = 0.04), but age less than or equal to 79.5 years and use of induced hypothermia were not. Long-term survivors were assessed for cognitive and functional status (using Cerebral Performance Category and Overall Performance Category scales), and their survival was compared with a large community-based cohort of participants over 75 years. The 1-year survival of ICU survivors (mean follow-up, 28.4 mo) was 69.3% (95% CI, 55.8-79.5) as compared with 95.3% (95% CI, 93.3-97.3) in the control community-based cohort (p< 0.001), resulting in a standardized mortality ratio of 3.49 (95% CI, 2.42-4.85). By multivariate Cox proportional hazard model, factors associated with long-term survival were initial shockable rhythm (hazard ratio = 1.41; 95% CI, 1.01-1.96; p = 0.04), epinephrine cumulate dose less than or equal to 3 mg (hazard ratio = 1.48; 95% CI, 1.06-2.08; p = 0.02), and blood lactate level less than or equal to 5.1 mmol/L (hazard ratio = 2.11; 95% CI, 1.5-2.96; p < 0.001). When available at end of follow-up, 91% and 74% of the patients were classified Cerebral Performance Category 1 and Overall Performance Category 1, respectively. Neurologic outcome in successfully resuscitated elderly patients depends on cardiac arrest characteristics rather than age. Short-term survival is 25% with acceptable long-term outcome among survivors.


Promoter CAG is more efficient than hepatocyte‑targeting TBG for transgene expression via rAAV8 in liver tissues.
The recombinant adeno‑associated virus 8 (rAAV8) vector is a widely used tool in basic research and clinical trials. The cytomegalovirus immediate‑early enhancer/chicken β‑actin (CAG) promoter is a synthetic promoter used in adenoviral constructs with a wide spectrum and notable efficiency. The thyroxine binding globulin (TBG) promoter is a liver‑specific promoter, which directs transgene expression in hepatocytes. However, the transduction efficiency of the rAAV vector is dependent on both the administration routes and the promoter elements. In the present study, the transduction efficiency in the liver following intraperitoneal (IP) and intravenous (IV) injections of rAAV8 with the CAG, TBG669 and TBG410 promoters was compared. Enhanced green fluorescent protein (EGFP) expression was used as the biomarker to indicate efficiency. Among the three different promoters, CAG exhibited the highest efficiency from both IV and IP injections. Following IV administration, EGFP expression, induced by the CAG promoter, was 67‑fold higher compared with that in the TBG410 promoter group and 26‑fold higher compared with that in the TBG669 promoter group. EGFP protein expression was higher with IV injection compared with that for IP injection for both the CAG and TBG669 promoters (P<0.05). With the CAG promoter, EGFP protein expression was 1.5‑fold higher with the use of IV injection than with IP injection. With the TBG410 promoter, no differences were observed between the two administrations. In conclusion, these findings demonstrated that the CAG promoter was much more efficient at driving gene expression in the liver compared with that for the TBG promoters in rAAV8. In addition, IP administration produced comparable efficiency for gene delivery via the rAAV8 vector, particularly with the promoter TBG410.


Statistical methods for analysis of time course gene expression data.
Since many biological systems or regulatory networks are dynamic systems, gene expression levels measured over different time points during a given biological process can often provide more insights about the underlying system. These gene expression data measured over time are often called the time-course gene expression data. One unique feature of such data is the time dependency of the gene expression levels for a given gene at different times or between two different genes. Statistical analysis needs to account for such dependency in order to make valid inferences. This paper presents several statistical methods for analyzing such time-course gene expression data, including the time-lagged correlation coefficient for analyzing the relationship between genes, a mixed-effects model with splines for clustering genes and for estimating missing gene expression data, and a new method for aligning gene expression profiles obtained under two experimental conditions and for identifying gene clusters that show significant changes between two experimental conditions. We used the yeast cell cycle gene expression data sets to illustrate these methods and obtained the biologically meaningful conclusions from these analyses.


Weight changes in teens on psychotropic medication combinations at Austin State Hospital.
Psychiatrists commonly treat adolescents with multiple psychotropic medications simultaneously. We studied the effects of psychotropic medications on the weight of adolescent patients at Austin State Hospital between June 1997 and December 2001. The medication combinations that caused the largest weight increases were olanzapine with valproic acid, and olanzapine with venlafaxine. The biggest weight loss combinations were valproic acid with bupropion, and valproic acid with venlafaxine. Medications drove a substantial portion of the changes in weight, not other variables. The specific medication prescribed, rather than the total number of medications, predicted weight gain. As current inpatient adolescents are receiving multiple medications and their weight is subsequently being affected, more study is needed to better understand these effects.