Improved image reconstruction for partial Fourier gradient-echo echo-planar imaging (EPI).
The partial Fourier gradient-echo echo planar imaging (EPI) technique makes it possible to acquire high-resolution functional MRI (fMRI) data at an optimal echo time. This technique is especially important for fMRI studies at high magnetic fields, where the optimal echo time is short and may not be achieved with a full Fourier acquisition scheme. In addition, it has been shown that partial Fourier EPI provides better anatomic resolvability than full Fourier EPI. However, the partial Fourier gradient-echo EPI may be degraded by artifacts that are not usually seen in other types of imaging. Those unique artifacts in partial Fourier gradient-echo EPI, to our knowledge, have not yet been systematically evaluated. Here we use the k-space energy spectrum analysis method to understand and characterize two types of partial Fourier EPI artifacts. Our studies show that Type 1 artifact, originating from k-space energy loss, cannot be corrected with pure postprocessing, and Type 2 artifact can be eliminated with an improved reconstruction method. We propose a novel algorithm, that combines images obtained from two or more reconstruction schemes guided by k-space energy spectrum analysis, to generate partial Fourier EPI with greatly reduced Type 2 artifact. Quality control procedures for avoiding Type 1 artifact in partial Fourier EPI are also discussed.


2016 White Paper on recent issues in bioanalysis: focus on biomarker assay validation (BAV): (Part 3 - LBA, biomarkers and immunogenicity).
The 2016 10th Workshop on Recent Issues in Bioanalysis (10th WRIB) took place in Orlando, Florida with participation of close to 700 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. WRIB was once again a weeklong event - A Full Immersion Week of Bioanalysis for PK, Biomarkers and Immunogenicity. As usual, it is specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecules involving LCMS, hybrid LBA/LCMS, and LBA approaches, with the focus on PK, biomarkers and immunogenicity. This 2016 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. This White Paper is published in 3 parts due to length. This part (Part 3) discusses the recommendations for large molecule bioanalysis using LBA, biomarkers and immunogenicity. Parts 1 (small molecule bioanalysis using LCMS) and Part 2 (Hybrid LBA/LCMS and regulatory inputs from major global health authorities) have been published in the Bioanalysis journal, issues 22 and 23, respectively.


Rapid assessment of octocoral diversity and habitat on Saba Bank, Netherlands Antilles.
Saba Bank is a large submerged platform (approximately 2200 km(2)), average depth 30 m, located 4 km southwest of Saba Island in Netherlands Antilles, Caribbean Sea. Ships traveling to and from oil terminals on nearby St. Eustatius routinely anchor on the Bank, damaging benthic megafauna. Gorgonian octocorals are vulnerable to anchor damage, and they are common and conspicuous in shallow water (15-50 m) around the banks. This prompted a rapid assessment of octocoral habitat and diversity. The primary objectives were to estimate total species richness and to characterize habitats vis a vis gorgonians. Landsat imagery and multibeam bathymetry were employed to identify random sites for quantitative transects. A Seabotix LBV200L remotely operated vehicle (ROV) and SCUBA were used to collect and survey to 130 m. A total of 14 scuba dives and 3 ROV dives were completed in 10 days. During that time, 48 octocoral species were collected, including two likely undescribed species in the genera Pterogorgia and Lytreia. Gorgonian richness was exceptional, but not all species were collected, because the species accumulation curve remained steeply inclined after all surveys. Two shallow-water gorgonian habitat types were identified using multidimensional scaling and hierarchical cluster analyses: 1) a high diversity, high density fore-reef environment characterized by Eunicea spp., Gorgonia spp., and Pseudopterogorgia spp. and 2) a low diversity, low density plateau environment characterized by Pseudopterogorgia acerosa, Pterogorgia guadalupensis, and Gorgonia mariae. The analyses support hypotheses of broad (approximately 15 km) habitat homogeneity (ANOSIM, P>0.05), but a significant difference between fore-reef and plateau environments (ANOSIM, P<0.05). However, there was some indication of habitat heterogeneity along the 15 km study section of the 50 km platform edge along the southeast rim. Our results highlight the complexity and biodiversity of the Saba Bank, and emphasize the need for more scientific exploration.


Three modules of zebrafish Mind bomb work cooperatively to promote Delta ubiquitination and endocytosis.
Precise regulation of Notch signaling activity is critical for development of many different tissues. Here, we show that the zebrafish insertional mutation Hi904 attenuates Notch signaling, and is allelic to mind bomb. We show that Mind bomb protein displays E3 ubiquitin ligase activity in vitro and that it is associated with Delta and enhances its ubiquitination and internalization in transfected cells. Furthermore, by functional analysis of three conserved regions of Mind bomb, we show that the N-terminal half is required for Delta association, the ankyrin repeats are important for Delta internalization, and the ring fingers are required for Delta ubiquitination. Thus, the three functionally distinct modules of Mind bomb work cooperatively to regulate Notch signaling by associating with, ubiquitinating, and internalizing Delta.


Maintenance of granulocyte numbers during acute peritonitis is defective in galectin-3-null mutant mice.
Galectin-3, also known as the macrophage marker Mac-2, is a member of a family of structurally related animal lectins that exhibit specificity for beta-galactosides. In order to investigate the role of galectin-3 in acute inflammation, we have compared the number of leucocytes present in the peritoneal cavity of wild type and galectin-3 null mutant mice after intraperitoneal (i.p.) injection of thioglycolate broth. At day 1 after injection, we found no difference in the recruitment of mononuclear phagocytes and granulocytes to the peritoneal cavity. However, 4 days after thioglycolate injection, galectin-3 mutant mice exhibited a significantly reduced number of recoverable granulocytes compared to wild-type animals. As mutant granulocytes did not exhibit an accelerated rate of apoptosis and their uptake by macrophages appeared to be unaffected by the mutation, the phenotype described here suggests that galectin-3 participates in an additional level of control during the resolution of acute inflammation.


Pharmacokinetics and safety of famciclovir in children with herpes simplex or varicella-zoster virus infection.
Two multicenter, open-label, single-arm, two-phase studies evaluated single-dose pharmacokinetics and single- and multiple-dose safety of a pediatric oral famciclovir formulation (prodrug of penciclovir) in children aged 1 to 12 years with suspicion or evidence of herpes simplex virus (HSV) or varicella-zoster virus (VZV) infection. Pooled pharmacokinetic data were generated after single doses in 51 participants (approximately 12.5 mg/kg of body weight [BW] for children weighing < 40 kg and 500 mg for children weighing > or = 40 kg). The average systemic exposure to penciclovir was similar (6- to 12-year-olds) or slightly lower (1- to < 6-year-olds) than that in adults receiving a 500-mg dose of famciclovir (historical data). The apparent clearance of penciclovir increased with BW in a nonlinear manner, proportional to BW(0.696). An eight-step weight-based dosing regimen was developed to optimize exposure in smaller children and was used in the 7-day multiple-dose safety phases of both studies, which enrolled 100 patients with confirmed/suspected viral infections. Twenty-six of 47 (55.3%) HSV-infected patients who received famciclovir twice a day and 24 of 53 (45.3%) VZV-infected patients who received famciclovir three times a day experienced at least one adverse event. Most adverse events were gastrointestinal in nature. Exploratory analysis following 7-day famciclovir dosing regimen showed resolution of symptoms in most children with active HSV (19/21 [90.5%]) or VZV disease (49/53 [92.5%]). Famciclovir formulation (sprinkle capsules in OraSweet) was acceptable to participants/caregivers. In summary, we present a weight-adjusted dosing schedule for children that achieves systemic exposures similar to those for adults given the 500-mg dose.


Assertive case management versus enhanced usual care for people with mental health problems who had attempted suicide and were admitted to hospital emergency departments in Japan (ACTION-J): a multicentre, randomised controlled trial.
Non-fatal suicide attempt is the most important risk factor for later suicide. Emergency department visits for attempted suicide are increasingly recognised as opportunities for intervention. However, no strong evidence exists that any intervention is effective at preventing repeated suicide attempts. We aimed to investigate whether assertive case management can reduce repetition of suicide attempts in people with mental health problems who had attempted suicide and were admitted to emergency departments. In this multicentre, randomised controlled trial in 17 hospital emergency departments in Japan, we randomly assigned people aged 20 years and older with mental health problems who had attempted suicide to receive either assertive case management (based on psychiatric diagnoses, social risks, and needs of the patients) or enhanced usual care (control), using an internet-based randomisation system. Interventions were provided until the end of the follow-up period (ie, at least 18 months and up to 5 years). Outcome assessors were masked to group allocation, but patients and case managers who provided the interventions were not. The primary outcome was the incidence of first recurrent suicidal behaviour (attempted suicide or completed suicide); secondary outcomes included completed suicide and all-cause mortality. This study is registered at ClinicalTrials.gov (NCT00736918) and UMIN-CTR (C000000444). Between July 1, 2006, and Dec 31, 2009, 914 eligible participants were randomly assigned, 460 to the assertive case management group and 456 to the enhanced usual care group. We noted no significant difference in incidence of first recurrent suicidal behaviour between the assertive case management group and the enhanced usual care group over the full study period (log-rank p=0·258). Because the proportional hazards assumption did not hold, we did ad-hoc analyses for cumulative incidence of the primary outcome at months 1, 3, 6, 12, and 18 after randomisation, adjusting for multiplicity with the Bonferroni method. Assertive case management significantly reduced the incidence of first recurrent suicidal behaviour up to the 6-month timepoint (6-month risk ratio 0·50, 95% CI 0·32-0·80; p=0·003), but not at the later timepoints. Prespecified subgroup analyses showed that the intervention had a greater effect in women (up to 18 months), and in participants younger than 40 years and those with a history of previous suicide attempts (up to 6 months). We did not identify any differences between the intervention and control groups for completed suicide (27 [6%] of 460 vs 30 [7%] of 454, log-rank p=0·660) or all-cause mortality (46 [10%] of 460 vs 42 [9%] of 454, log-rank p=0·698). Our results suggest that assertive case management is feasible in real-world clinical settings. Although it was not effective at reducing the incidence of repetition of suicide attempts in the long term, the results of our ad-hoc analyses suggested that it was effective for up to 6 months. This finding should be investigated in future research. The Ministry of Health, Labour, and Welfare of Japan.


cDNA cloning of p42, a shared subunit of two proteasome regulatory proteins, reveals a novel member of the AAA protein family.
We have employed cDNA cloning to deduce the complete primary structure of p42, a protein previously identified as a common subunit of two proteasome regulatory proteins: PA700, a 700000-Da multisubunit complex that binds to the proteasome and promotes the ATP-dependent degradation of ubiquitinated proteins, and modulator, a 250000-Da PA700-dependent proteasome activator. Computer analysis reveals that p42 is a novel member of a large protein family characterized by a conserved 200 amino acid domain which contains a consensus sequence for ATP binding. Five other members of this family, termed AAA proteins (ATPases associated with a variety of cellular activities) are also subunits of PA700. Gel filtration chromatography was employed to determine the qualitative and quantitative distribution of p42 in crude soluble lysates of bovine red blood cells. These studies demonstrated that p42 was found in two multi-protein complexes: the 26S proteasome (formed from the 20S proteasome and PA700) and the modulator. These results establish the identity of a new protein involved in the regulation of proteasome function and indicate that this protein is found in at least two different protein complexes.


Reliability of a New Medicine Ball Throw Power Test.
The purpose of this study was to examine the reliability of a new upper body medicine ball push-press (MBP-P) test. Twenty-three strength trained volunteers performed a series of supine MBP-P throws using loads representing 5% and10% of their 5RM bench press (5 repetitions at each load). Throws were performed on a force platform (2000 Hz), with medicine ball kinematic data collected using a high-speed motion capture (500 Hz). Testing was repeated after 7-10 days to quantify intertest reliability. Maximal force (Fmax), impulse at Fmax, time to Fmax, and maximum rate of force development (RFDmax) were all calculated from the force platform outputs, with maximum ball velocity (Velmax) and maximum ball acceleration (Accelmax) developed from the kinematic data. Reliability was assessed using intraclass correlation (ICC), coefficient of variation (%CV), and typical error. Medicine ball kinematic variables were more reliable (CV% = 2.6-5.3, ICC = 0.87-0.95) than the various force platform derived power variables (CV% = 7.9-26.7, ICC = 0.51-0.90). The MBP-P test produces reliable data and can be used to quantify many standard power based measures, with the key findings have implications for athletic populations requiring high velocity, light load upper body pushing power.


Neural mechanisms of selective attention in the somatosensory system.
Selective attention allows organisms to extract behaviorally relevant information while ignoring distracting stimuli that compete for the limited resources of their central nervous systems. Attention is highly flexible, and it can be harnessed to select information based on sensory modality, within-modality feature(s), spatial location, object identity, and/or temporal properties. In this review, we discuss the body of work devoted to understanding mechanisms of selective attention in the somatosensory system. In particular, we describe the effects of attention on tactile behavior and corresponding neural activity in somatosensory cortex. Our focus is on neural mechanisms that select tactile stimuli based on their location on the body (somatotopic-based attention) or their sensory feature (feature-based attention). We highlight parallels between selection mechanisms in touch and other sensory systems and discuss several putative neural coding schemes employed by cortical populations to signal the behavioral relevance of sensory inputs. Specifically, we contrast the advantages and disadvantages of using a gain vs. spike-spike correlation code for representing attended sensory stimuli. We favor a neural network model of tactile attention that is composed of frontal, parietal, and subcortical areas that controls somatosensory cells encoding the relevant stimulus features to enable preferential processing throughout the somatosensory hierarchy. Our review is based on data from noninvasive electrophysiological and imaging data in humans as well as single-unit recordings in nonhuman primates.


Disruption of contact lens-associated Pseudomonas aeruginosa biofilms formed in the presence of neutrophils.
To evaluate the capacity of neutrophils to enhance biofilm formation on contact lenses by an infectious Pseudomonas aeruginosa (PA) corneal isolate. Agents that target F-actin and DNA were tested as a therapeutic strategy for disrupting biofilms formed in the setting of neutrophils in vitro and for limiting the infectious bioburden in vivo. Biofilm formation by infectious PA strain 6294 was assessed in the presence of neutrophils on a static biofilm plate and on unworn etafilcon A soft contact lenses. A d-isomer of poly(aspartic acid) was used alone and with DNase to reduce biofilm formation on test contact lenses. The gentamicin survival assay was used to determine the effectiveness of the test compound in reducing subsequent intracellular bacterial load in the corneal epithelium in a contact lens infection model in the rabbit. In a static reactor and on hydrogel lenses, PA biofilm density was enhanced 30-fold at 24 hours in the presence of neutrophils (P < 0.0001). The combination of DNase and anionic poly(aspartic acid) reduced the PA biofilms formed in the presence of activated neutrophils by 79.2% on hydrogel contact lenses (P < 0.001). An identical treatment resulted in a 41% reduction in internalized PA in the rabbit corneal epithelium after 24 hours (P = 0.03). These results demonstrate that PA can exploit the presence of neutrophils to form biofilm on contact lenses within a short time. Incorporation of F-actin and DNA represent a mechanism for neutrophil-induced biofilm enhancement and are targets for available agents to disrupt pathogenic biofilms formed on contact lenses and as a treatment for established corneal infections.


Optimising health care for people living with chronic kidney disease: Health-professional perspectives.
People with chronic kidney disease are often multimorbid and have complex psychosocial needs. For health professionals to deliver holistic, person-centred care to individuals and their carers living with this multifaceted disease, they are required to communicate complex information and problem solve in a multifactorial health and disease context. To explore the perspectives and experiences of tertiary care multidisciplinary team members and primary care providers of health care to people with chronic kidney disease; identify opportunities to innovate and improve the coordinated delivery of health services. The qualitative study design used purposive sampling to recruit 39 health professionals, working in the primary and tertiary sector in a regional Australian health district. Participants included general practitioners, renal and general practice nurses, dietitians, nephrologists and social workers. The data were collected through semistructured interviews and analysed using a relativist ontological position and directed content analysis approach. Analysis of interviews was undertaken by three independent researchers and key themes were derived via consensus. A common goal to deliver person-centred individualised care was evident among health care professionals. However a deficit in shared understanding of the disease within and between disciplines was identified. The complex nature of chronic kidney disease requires up-skilling of health professionals to ensure patient education is targeted to individual health contexts and motivates self-management. Improved communication and comprehension might best be achieved across disciplines with an integrated approach to delivery of primary health care to individuals living with early-stage kidney disease.


[Dialysis withdrawal and shared end-of-life management between nephrology and palliative care: our three-year experience].
Most dialysis patients with end-stage kidney disease (ESKD) lack access to palliative care services. According to the data of the Dialysis Outcomes and Practice Study (DOPPS), Italy when compared to other countries included in the study, had the lowest rates of dialysis discontinuation. Indeed, there is a growing interest in the implementation of international and national programs for the co-management between nephrology and palliative care in end-of-life decision-making for patients with ESKD. On behalf of this, since 2017, we started in the nephrology outpatient clinic and hemodialysis facilities of the Provincia Autonoma of Trento a shared program between Nephrology and Palliative Care Units to improve the end-of-life quality of care in ESKD patients in conservative and dialytic therapy. Methods:A retrospective analysis, from the 1st of January 2019 to 31st December 2021, of dialysis withdrawal in a cohort of patients undergoing hemodialysis and peritoneal dialysis. Results:Dialysis withdrawal and subsequent death, according to the integrated protocol with the Palliative Care resources, were 24 in 2019, 20 in 2020, and 28 in 2021. The mean age was 75 years in 2019, 78 years in 2020, and in 2021. Most of the patients were male. Dialysis discontinuation was higher in chronic dialysis patients (80% in 2019 and 2020, and 79% in 2021), and considering the annual rates of death of all the dialysis patients, those who died because of dialysis withdrawal were 38% in 2019, 31% in 2020 and 40% in 2021. Survival after dialysis withdrawal was in most of the cases less than 7 days; only few patients lived more than 30 days. Furthermore, the data, in the 3 years considered, showed a reduction of hospitalization and an increase of the rate of death at home. Conclusions:As described in the present study, strategies to expand palliative care by a shared protocol among nephrology and palliative care staff improved the quality of care in the end of life and reduced the hospitalization rates of admission of patients after dialysis withdrawal.


Intravenous Versus Nonintravenous Benzodiazepines for the Cessation of Seizures: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
The acquisition of intravenous (IV) access in the actively convulsing patient is difficult. This often delays the administration of the IV benzodiazepine (BDZ) necessary for seizure cessation. Delays in seizure cessation are associated with increased pharmacoresistance, increased risk of neuronal injury, worse patient outcomes, and increased morbidity. The objective was to assess whether the delay imposed by IV access acquisition is justified by improved outcomes. We compared IV versus non-IV BDZ efficacy in the real world with regard to failure rates (primary outcome), interval to seizure control, and observed complications (secondary outcomes). A systematic review was performed using Medline, Embase, and the Cochrane Library. All studies published or in press from the inception of the respective database to July 2016 were included. Only randomized and quasi-randomized controlled trials directly comparing IV to non-IV (buccal, rectal, intranasal, or intramuscular) BDZ were included. Our search strategy retrieved 2,604 citations for review. A total of 11 studies were finally included in qualitative synthesis and 10 in quantitative analysis. Only one was of high quality. For treatment failure, non-IV BDZ was superior to IV BDZ (odd ratio [OR] = 0.72; 95% confidence interval [CI] = 0.56-0.92). However, no significant difference was found between the two treatments in the pediatric subgroup (OR = 1.16; 95% CI = 0.74-1.81). Non-IV BDZ was administered faster than IV BDZ and therefore controlled seizures faster (mean difference = 3.41 minutes; 95% CI = 1.69-5.13 minutes) despite a longer interval between drug administration and seizure cessation (mean difference = 0.74 minutes; 95% CI = 0.52-0.95 minutes). Respiratory complications requiring intervention were similar between non-IV BDZ and IV BDZ, regardless of administration route (risk difference = 0.00; 95% CI = -0.02 to 0.01). Non-IV BDZ, compared to IV BDZ, terminate seizures faster and have a superior efficacy and side effect profile. Higher-quality studies and further evaluation in different age groups are warranted.


Green chemistry for nanoparticle synthesis.
The application of the twelve principles of green chemistry in nanoparticle synthesis is a relatively new emerging issue concerning the sustainability. This field has received great attention in recent years due to its capability to design alternative, safer, energy efficient, and less toxic routes towards synthesis. These routes have been associated with the rational utilization of various substances in the nanoparticle preparations and synthetic methods, which have been broadly discussed in this tutorial review. This article is not meant to provide an exhaustive overview of green synthesis of nanoparticles, but to present several pivotal aspects of synthesis with environmental concerns, involving the selection and evaluation of nontoxic capping and reducing agents, the choice of innocuous solvents and the development of energy-efficient synthetic methods.


Dead or gone? Bayesian inference on mortality for the dispersing sex.
Estimates of age-specific mortality are regularly used in ecology, evolution, and conservation research. However, estimating mortality of the dispersing sex, in species where one sex undergoes natal dispersal, is difficult. This is because it is often unclear whether members of the dispersing sex that disappear from monitored areas have died or dispersed. Here, we develop an extension of a multievent model that imputes dispersal state (i.e., died or dispersed) for uncertain records of the dispersing sex as a latent state and estimates age-specific mortality and dispersal parameters in a Bayesian hierarchical framework. To check the performance of our model, we first conduct a simulation study. We then apply our model to a long-term data set of African lions. Using these data, we further study how well our model estimates mortality of the dispersing sex by incrementally reducing the level of uncertainty in the records of male lions. We achieve this by taking advantage of an expert's indication on the likely fate of each missing male (i.e., likely died or dispersed). We find that our model produces accurate mortality estimates for simulated data of varying sample sizes and proportions of uncertain male records. From the empirical study, we learned that our model provides similar mortality estimates for different levels of uncertainty in records. However, a sensitivity of the mortality estimates to varying uncertainty is, as can be expected, detectable. We conclude that our model provides a solution to the challenge of estimating mortality of the dispersing sex in species with data deficiency due to natal dispersal. Given the utility of sex-specific mortality estimates in biological and conservation research, and the virtual ubiquity of sex-biased dispersal, our model will be useful to a wide variety of applications.


The role of Cajal cells in chronic prostatitis.
Types of prostatitis can be defined as groups of syndromes in adult men associated with infectious and noninfectious causes characterized frequently by lower abdominal and perineal signs and diverse clinical symptoms and complications. Etiopathogenesis of chronic prostatitis is not well defined. Moreover, its treatment outcomes are not satisfactory. Presence of c-kit positive interstitial cells in human prostate is already known. It has been demonstrated that these cells can be pacemaker cells which trigger spontaneous slow-wave electrical activity in the prostate and can be responsible for the transport of glandular secretion from acinar cells into major and minor prostatic ducts and finally into urethra. In the light of all these data, when presence of a possible inflammatory pathology is thought to involve prostate that secretes and has a reservoir which drains its secretion (for prostate, prostatic urethra), two points are worth mentioning. Impairment of secretion mechanism and collection of secretion within the organ with reflux of the microbial material from its reservoir back into prostate gland. Both of these potential conditions can be explained by ductal neuromuscular mechanism, which induces secretion. We think that in this neuromuscular mechanism interstitial Cajal cells have an important role in chronic prostatitis. Our hypothesis is that curability of prostatitis is correlated with the number of Cajal cells not subjected to apoptosis.


Characterization of the structure, dynamics and allosteric pathways of human NPP1 in its free form and substrate-bound complex from molecular modeling.
The ectonucleotide phosphodiesterase/pyrophosphatase-1 (NPP1) is a type II transmembrane glycoprotein that regulates extracellular inorganic purine nucleotide and inorganic diphosphate levels through the hydrolysis of ATP into AMP and diphosphate. NPP1 is a promising drug target as it plays a role in several disorders. In the present work, we report the 3D structure modeling and extensive molecular dynamics simulations of NPP1-h, both in its free and ATP-bound forms. We identified the key residues involved in the binding of the ATP and the binding modes. The simulations suggest that NPP1-h is a rigid enzyme except for specific residues or segments, with the most mobile residues located in the unstructure "lasso loop" (LSO) domain. The binding of ATP significantly affected the dynamics of NPP1-h, with a rigidification of the phosphodiesterase (PDE) catalytic domain and an increase in mobility for the residues of the Nuclease-like (NUC) and the LSO domains. A dynamical network analysis identified that the most prevalent edges of the networks were located between the PDE and the NUC domains. In presence of ATP the networks became scattered through the PDE domain while the networks converged into a specific path that stretched from the PDE-NUC interdomain up to the middle of the LSO loop throughout the NUC domain. We suggest that these sections of the dynamical network may host potential allosteric inhibition sites. These results provide an improved understanding of the structure and dynamics of NPP1-h and will contribute to the rational design of NPP1-h inhibitors.


Sorafenib Inhibits Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) in Hepatocellular Carcinoma Cells.
The main curative treatments for hepatocellular carcinoma (HCC) are surgical resection and liver transplantation, which only benefits 15% to 25% of patients. In addition, HCC is highly refractory and resistant to cytotoxic chemotherapy. Although several multi-kinase inhibitors, such as sorafenib, regorafenib, and lenvatinib, have been approved for treating advanced HCC, only a short increase of median overall survival in HCC patients was achieved. Therefore, there is an urgent need to design more effective strategies for advanced HCC patients. Human ribonucleotide reductase is responsible for the conversion of ribonucleoside diphosphate to 2'-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools. In this study, mining the cancer genomics and proteomics data revealed that ribonucleotide reductase regulatory subunit M2 (RRM2) serves as a prognosis biomarker and a therapeutic target for HCC. The RNA sequencing (RNA-Seq) analysis and public microarray data mining found that RRM2 was a novel molecular target of sorafenib in HCC cells. In vitro experiments validated that sorafenib inhibits RRM2 expression in HCC cells, which is positively associated with the anticancer activity of sorafenib. Although both RRM2 knockdown and sorafenib induced autophagy in HCC cells, restoration of RRM2 expression did not rescue HCC cells from sorafenib-induced autophagy and growth inhibition. However, long-term colony formation assay indicated that RRM2 overexpression partially rescues HCC cells from the cytotoxicity of sorafenib. Therefore, this study identifies that RRM2 is a novel target of sorafenib, partially contributing to its anticancer activity in HCC cells.


Embroidered electrode with silver/titanium coating for long-term ECG monitoring.
For the long-time monitoring of electrocardiograms, electrodes must be skin-friendly and non-irritating, but in addition they must deliver leads without artifacts even if the skin is dry and the body is moving. Today's adhesive conducting gel electrodes are not suitable for such applications. We have developed an embroidered textile electrode from polyethylene terephthalate yarn which is plasma-coated with silver for electrical conductivity and with an ultra-thin titanium layer on top for passivation. Two of these electrodes are embedded into a breast belt. They are moisturized with a very low amount of water vapor from an integrated reservoir. The combination of silver, titanium and water vapor results in an excellent electrode chemistry. With this belt the long-time monitoring of electrocardiography (ECG) is possible at rest as well as when the patient is moving.


DQB1*0602 and DQA1*0102 (DQ1) are better markers than DR2 for narcolepsy in Caucasian and black Americans.
In the present study, we tested 19 Caucasian and 28 Black American narcoleptics for the presence of the human leucocyte antigen (HLA) DQB1*0602 and DQA1*0102 (DQ1) genes using a specific polymerase chain reaction (PCR)-oligotyping technique. A similar technique was also used to identify DRB1*1501 and DRB1*1503 (DR2). Results indicate that all but one Caucasian patient (previously identified) were DRB1*1501 (DR2) and DQB1*0602/DQA1*102 (DQ1) positive. In Black Americans, however, DRB1*1501 (DR2) was a poor marker for narcolepsy. Only 75% of patients were DR2 positive, most of them being DRB1*1503, but not DRB1*1501 positive. DQB1*0602 was found in all but one Black narcoleptic patient. The clinical and polygraphic results for this patient were typical, thus confirming the existence of a rare, but genuine form of DQB1*0602 negative narcolepsy. These results demonstrate that DQB1*0602/DQA1*0102 is the best marker for narcolepsy across all ethnic groups.


On a quasi-wavelet model of refractive index fluctuations due to atmospheric turbulence.
When studying light propagation through the atmosphere, it is usual to rely on widely used spectra such as the modified von Kármán or Andrews-Hill. These are relatively tractable models for the fluctuations of the refractive index, and are primarily used because of their mathematical convenience. They correctly describe the fluctuations behaviour at the inertial range yet lack any physical basis outside this range. In recent years, deviations from the Obukhov-Kolmogorov theory (e. g. interminttency, partially developed turbulence, etc.) have been built upon these models through the introduction of arbitrary spectral power laws. Here we introduce a quasi-wavelet model for the refractive index fluctuations which is based on a phenomenological representation of the Richardson cascade. Under this model, the atmospheric refractive index has a correct spectral representation for the inertial range, behaves as expected outside it, and even accounts for non-Kolmogorov behaviour; moreover, it has non-Gaussian statistics. Finally, we are able to produce second order moments under the Rytov approximation for the complex phase; we estimate the angle-of-arrival as an example of application.


Apoptosis of endothelial progenitor cells in a metabolic syndrome experimental model.
This study tests the hypothesis postulating that metabolic syndrome induced by chronic administration of fructose to spontaneously hypertensive rats (FFHR) generates impairment in vascular repair by endothelial progenitor cells (EPC). TO CHARACTERIZE THE VASCULAR ADVERSE ENVIRONMENT PRESENT IN THIS EXPERIMENTAL MODEL WE MEASURED: NAD(P)H oxidase activity, eNOS activity, presence of apoptosis in the arterial wall, all these parameters were most affected in the FFHR group. Also, we found decreased level and proliferative capacity of EPC measured by flow cytometry and colonies forming units assay in cultured cells, respectively, in both groups treated with fructose; FFHR (SHR fructose fed rats) and FFR (WKY fructose fed rats) compared with their controls; SHR and WKY. The fructose-fed groups FFR and SHR also showed an incremented number of apoptotic (annexinV+/7AADdim) EPC measured by flow cytometry that returns to almost normal values after eliminating fructose administration. Our findings suggest that increased apoptosis levels of EPC generated in this experimental model could bein part the underlying cause for the impaired vascular repair by in EPC.


Laser performance of highly neodymium-doped yttrium aluminum garnet crystals.
The laser performance of highly neodymium-doped yttrium aluminum garnet (YAG) crystals is reported. In cw laser-diode pumping, a slope efficiency of 54% was achieved for a 2-at. %-doped sample, which was comparable with the slope efficiency of 55% of YVO(4) . The crystal also exhibited a slope efficiency of 64% under pulsed Ti:sapphire pumping. Such a high efficiency suggests a total cavity loss of ~1% , which is as low as that of commercially available 1-at. % YAG crystal. The excellent performance of the neodymium-doped YAG crystals indicates their high optical quality.


Biostatistics and study design for evidence-based practice.
The hallmark of an evidence-based practitioner is one who reflects on their clinical decision making and uses research evidence to reduce clinical uncertainty and guide their practice. Understanding how the results of empirical research can be appropriately integrated into clinical practice requires a basic understanding of study design and statistical analysis. This article provides an overview of some of the key concepts related to study design and statistical inference that are important to accurately measure clinical outcomes and to appropriately interpret the results of studies within the context of evidence-based decision making.


Principal component analysis of early immune cell dynamics during pembrolizumab treatment of advanced urothelial carcinoma.
Immune checkpoint inhibitors have been approved as second-line therapy for patients with advanced urothelial carcinoma (UC). However, which patients will obtain clinical benefit remains to be determined. To identify predictive biomarkers for the pembrolizumab (PEM) response early during treatment, the present study investigated 31 patients with chemotherapy-resistant recurrent or metastatic UC who received 200 mg PEM intravenously every 3 weeks. Blood was taken just before the first dose and again before the second dose, and the peripheral blood mononuclear cells of all 31 pairs of blood samples were immune phenotyped by flow cytometry. Data were assessed by principal component analysis (PCA), correlation analysis and Cox proportional hazards modeling in order to comprehensively determine the effects of PEM on peripheral mononuclear immune cells. Absolute counts of CD45RA+CD27-CCR7- terminally differentiated CD8+ T cells and KLRG1+CD57+ senescent CD8+ T cells were significantly increased after PEM administration (P=0.042 and P=0.043, respectively). Senescent and exhausted CD4+ and CD8+ T cell dynamics were strongly associated with each other. By contrast, counts of monocytic myeloid-derived suppressor cells (mMDSCs) were not associated with other immune cell phenotypes. The results of PCA and non-hierarchical clustering of patients suggested that excessive T cell senescence and differentiation early during treatment were not necessarily associated with a survival benefit. However, decreased mMDSC counts after PEM were associated with improved overall survival. In conclusion, early on-treatment peripheral T cell status was associated with response to PEM; however, it was not associated with clinical benefit. By contrast, decreased peripheral mMDSC counts did predict improved overall survival.


Limb salvage for malignant tumors of bone.
With the use of preoperative therapy of chemotherapy and radiation, limb salvage has been possible in more than 95% of patients with highly malignant bone tumors. Without preoperative treatment, limb salvage is possible in only 40% of the patients. In our experience, improved limb salvage is a direct result of the preoperative therapy. We are not sure this preoperative therapy is the ideal one, or whether the intraarterial Adriamycin is superior to intravenous administration, or whether the dose of radiation is the proper one, or even whether radiation is necessary at all. These questions remain unanswered at this time. However, the pathologist's evaluation of the excised specimens shows that the preoperative treatment has definite beneficial effect for more than 80% of the patients on this program. Local control is equal with either amputation or limb salvage. Additionally, the overall survival rate is identical for either limb salvage or primary amputation. The major factor for patient survival appears to be the systemic adjuvant chemotherapy. Limb salvage as practiced at UCLA is as effective as amputation for control of malignant bone tumors. The selection of patients for our limb salvage program has not adversely affected the rate of disease progression or ultimate survival. The cosmetic and functional results of limb-salvage surgery is at least comparable to if not better than external prostheses. Finally, the only factor that appears to influence long-term survival in a positive manner is participation in a polydrug postoperative adjuvant chemotherapy program.


Atypical subtrochanteric femoral shaft fractures: role for mechanics and bone quality.
Bisphosphonates are highly effective agents for reducing osteoporotic fractures in women and men, decreasing fracture incidence at the hip and spine up to 50%. In a small subset of patients, however, these agents have recently been associated with 'atypical femoral fractures' (AFFs) in the subtrochanteric region or the diaphysis. These fractures have several atypical characteristics, including occurrence with minimal trauma; younger age than typical osteoporotic fractures; occurrence at cortical, rather than cancellous sites; early radiographic appearance similar to that of a stress fracture; transverse fracture pattern rather than the familiar spiral or transverse-oblique morphologies; initiation on the lateral cortex; and high risk of fracture on the contralateral side, at the same location as the initial fracture. Fracture is a mechanical phenomenon that occurs when the loads applied to a structure such as a long bone exceed its load-bearing capacity, either due to a single catastrophic overload (traumatic failure) or as a result of accumulated damage and crack propagation at sub-failure loads (fatigue failure). The association of AFFs with no or minimal trauma suggests a fatigue-based mechanism that depends on cortical cross-sectional geometry and tissue material properties. In the case of AFFs, bisphosphonate treatment may alter cortical tissue properties, as these agents are known to alter bone remodeling. This review discusses the use of bisphosphonates, their effects on bone remodeling, mechanics and tissue composition, their significance as an effective therapy for osteoporosis, and why these agents may increase fracture risk in a small population of patients.


Improving support for parents of children with hearing loss: provider training on use of targeted communication strategies.
When proper protocols are followed, children who are identified with a permanent hearing loss early in life have opportunities to develop language on par with their typical hearing peers. Young children with hearing loss are dependent on their parents to manage intervention during early years critical to their development, and parents' ability to effectively integrate recommendations in daily life is foundational for intervention success. Audiologists and early intervention professionals not only need to provide current evidence-based services, but also must address parents' emotional and learning needs related to their child's hearing loss. This study explored practice patterns related to education and support provided to parents of children with hearing loss and the influence of an in-service training on provider attitudes. This study used a prepost design with a self-report questionnaire to identify practice patterns related to communication skills and support used by providers when working with parents of children with hearing loss. A total of 45 participants (21 professionals and 24 graduate students) currently working with children completed the pretraining questionnaire, and 29 participants (13 professionals and 16 graduate students) completed the postquestionnaire. Data were collected using an online questionnaire before the training and 1 mo after training. Descriptive analyses were done to identify trends, and paired-samples t-tests were used to determine changes pretraining to posttraining. Findings revealed that professionals most frequently teach skills to mothers (91%) and infrequently teach skills to fathers (19%) and other caregivers (10%). Professionals reported frequently collaborating with other intervention providers (76%) and infrequently collaborating with primary care physicians (19%). One-third of the professionals reported addressing symptoms of depression and anxiety as an interfering factor with the ability to implement management recommendations. For providers who completed both the prequestionnaires and postquestionnaires, an increase in confidence was reported for several areas of communication; however, as expected, practices remained similar, and all of the practicing professionals and 94% of the graduate students indicated a desire for more training on how to be effective in supporting parents with implementing intervention recommendations. Providers do not necessarily use effective methods of communication, needed to adequately help parents, requiring additional focused training to change how providers interact with parents and how support is provided.


The comparative effects of spinal and peripheral thrust manipulation and exercise on pain sensitivity and the relation to clinical outcome: a mechanistic trial using a shoulder pain model.
Single-blind randomized trial. To compare the effects of cervical and shoulder thrust manipulation (TM) and exercise on pain sensitivity, and to explore associations with clinical outcomes in patients with shoulder pain. Experimental studies indicate that spinal TM has an influence on central pain processes, supporting its application for treatment of extremity conditions. Direct comparison of spinal and peripheral TM on pain sensitivity has not been widely examined. Seventy-eight participants with shoulder pain (36 female; mean ± SD age, 39.0 ± 14.5 years) were randomized to receive 3 treatments of cervical TM (n = 26), shoulder TM (n = 27), or shoulder exercise (n = 25) over 2 weeks. Twenty-five healthy participants (13 female; mean ± SD age, 35.2 ± 11.1 years) were assessed to compare pain sensitivity with that in clinical participants at baseline. Primary outcomes were changes in local (eg, shoulder) and remote (eg, tibialis anterior) pressure pain threshold and heat pain threshold occurring over 2 weeks. Secondary outcomes were shoulder pain intensity and patient-rated function at 4, 8, and 12 weeks. Analysis-of-variance models and partial-correlation analyses were conducted to examine comparative effects and the relationship between measures. At baseline, clinical participants demonstrated lower local (mean difference, - 1.63 kg; 95% confidence interval [CI]: -2.40, -0.86) and remote pressure pain threshold (mean difference, -1.96 kg; 95% CI: -3.09, -0.82) and heat pain threshold (mean difference, -1.15°C; 95% CI: -2.06, -0.24) compared to controls, suggesting enhanced pain sensitivity. Following intervention, there were no between-group differences in pain sensitivity or clinical outcome (P>.05). However, improvements were noted, regardless of intervention, for pressure pain threshold (range of mean differences, 0.22-0.32 kg; 95% CI: 0.03, 0.43), heat pain threshold (range of mean differences, 0.30-0.58; 95% CI: 0.06, 0.96), pain intensity (range of mean differences, -1.79 to -1.45; 95% CI: -2.34, -0.94), and function (range of mean differences, 3.15-3.82; 95% CI: 0.69, 6.20) at all time points. We did not find an association between pain sensitivity changes and clinical outcome (P>.05). Conclusion Clinical participants showed enhanced pain sensitivity, but did not respond differently to cervical or peripheral TM. In fact, in this sample, cervical TM, shoulder TM, and shoulder exercise had similar pain sensitivity and clinical effects. The lack of association between pain sensitivity and clinical pain and function outcomes suggests different (eg, nonspecific) pain pathways for clinical benefit following TM or exercise. Therapy, level 1b.


End-of-life care considerations for gay, lesbian, bisexual, and transgender individuals.
Negative social attitudes, discrimination, and homophobia affect gay, lesbian, bisexual, and transgender (GLBT) individuals during their lifetimes. These experiences can affect how these individuals access health services and interact with health professionals, resulting in adverse outcomes compared with their heterosexual counterparts. End-of-life experiences can also be shaped by these factors. There are implications for health professionals in terms of equity of access to targeted health care, preventive screening, and visibility in policy, as well as in principles of inclusiveness, dignity and respect, and competence in care. This article takes a brief look at some of the issues specific to the end-of-life care of GLBT individuals, using a case study as an illustrative example. Holistic care at the end of life is a familiar concept to palliative care nurses, but it is important to place greater emphasis on considering competence in aspects of care relating to sexuality.


The Euplotes telomerase subunit p43 stimulates enzymatic activity and processivity in vitro.
Telomerase is a reverse transcriptase that synthesizes telomeric DNA repeats at the ends of eukaryotic chromosomes. Although it is minimally composed of a conserved catalytic protein subunit (TERT) and an RNA component, additional accessory factors present in the holoenzyme play crucial roles in the biogenesis and function of the enzyme complex. Telomerase from the ciliate Tetrahymena can be reconstituted in active form in vitro. Using this system, we show that p43, a telomerase-specific La-motif protein from the ciliate Euplotes, stimulates activity and increases repeat addition processivity of telomerase. Activity enhancement by p43 requires its incorporation into a TERT.RNA.p43 ternary complex but is independent of other dissociable protein factors functioning in telomerase complex assembly. Stimulation is enhanced at elevated temperatures, supporting a role for p43 in structural stabilization of a critical region of the RNA subunit. To our knowledge, this represents the first demonstration that an authentic telomerase accessory protein can directly affect the enzymatic activity of the core enzyme in vitro.


Super-resolution optical microscopy for studying membrane structure and dynamics.
Investigation of cell membrane structure and dynamics requires high spatial and temporal resolution. The spatial resolution of conventional light microscopy is limited due to the diffraction of light. However, recent developments in microscopy enabled us to access the nano-scale regime spatially, thus to elucidate the nanoscopic structures in the cellular membranes. In this review, we will explain the resolution limit, address the working principles of the most commonly used super-resolution microscopy techniques and summarise their recent applications in the biomembrane field.


Advances in modulating thermosensory TRP channels.
Thermosensory channels are a subfamily of the transient receptor potential (TRP) channel family that are activated by changes in the environmental temperature. These channels, known as thermoTRPs, cover the entire spectrum of temperatures, from noxious cold (< 15°C) to injurious heat (> 42°C). In addition, dysfunction of these channels contributes to the thermal hypersensitivity that accompanies painful conditions. Moreover, because of their wide tissue and cellular distribution, thermoTRPs are also involved in the pathophysiology of several diseases, from inflammation to cancer. Although the number of thermoTRPs is increasing with the identification of novel members such as TRPM3, we will cover the recent advances in the pharmacology of the classical thermosensory channels, namely TRPV1, TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1. This review will focus on the therapeutic progress carried out for all these channels and will highlight the tenet that TRPV1, TRPM8 and TRPA1 are the most exploited channels, and that the interest on TRPV3 and TRPV4 is growing with the first TRPV3 antagonist that moves into Phase-II clinical trials. In contrast, the pharmacology of TRPV2 is yet in its infancy. Despite the tremendous academic and industrial investment to develop therapeutic modulators of thermoTRPs, it apparently seems that we are still far from the first successful product, although hope is maintained high for all compounds currently in clinical trials. A major concern has been the appearance of side effects. A better knowledge of the thermosensory protein networks (signal-plexes), along with the application of system biology approaches may provide novel strategies to modulate thermoTRPs activity with improved therapeutic index. A case in point is TRPV1, where acting on interacting proteins is providing new therapeutic opportunities.


Running out of time: the decline of channel activity and nucleotide activation in adenosine triphosphate-sensitive K-channels.
KATP channels act as key regulators of electrical excitability by coupling metabolic cues-mainly intracellular adenine nucleotide concentrations-to cellular potassium ion efflux. However, their study has been hindered by their rapid loss of activity in excised membrane patches (rundown), and by a second phenomenon, the decline of activation by Mg-nucleotides (DAMN). Degradation of PI(4,5)P2 and other phosphoinositides is the strongest candidate for the molecular cause of rundown. Broad evidence indicates that most other determinants of rundown (e.g. phosphorylation, intracellular calcium, channel mutations that affect rundown) also act by influencing KATP channel regulation by phosphoinositides. Unfortunately, experimental conditions that reproducibly prevent rundown have remained elusive, necessitating post hoc data compensation. Rundown is clearly distinct from DAMN. While the former is associated with pore-forming Kir6.2 subunits, DAMN is generally a slower process involving the regulatory sulfonylurea receptor (SUR) subunits. We speculate that it arises when SUR subunits enter non-physiological conformational states associated with the loss of SUR nucleotide-binding domain dimerization following prolonged exposure to nucleotide-free conditions. This review presents new information on both rundown and DAMN, summarizes our current understanding of these processes and considers their physiological roles.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'.


The effect of daily Hassles of humoral immunity: an interaction moderated by locus of control.
Research has shown that stress is associated with depressed cellular immune functioning. Controversy exists as to whether humoral immunity shows a similar depression under stress. Several psychological variables have been found to moderate responses to stress. In particular, an internal locus of control has been correlated with better health. The present study examined the level of salivary immunoglobulin A (IgA) and health locus of control in subjects with high and low stress levels. The Hassles scale was administered to identify two subject groups differing significantly in reported stress levels. Results showed no significant differences between the two groups on salivary IgA. There was a significant negative correlation between IgA and internal locus of control. The direction of this correlation is in contrast with previous findings on internality. The evidence suggests that high internal individuals may be especially vulnerable to high levels of stress, particularly stress that they cannot control. Also, there was a significant difference in IgA levels between females depending on whether they were in the first or the second half of their menstrual cycle. Those in the premenstrual phase had lower IgA levels.


Membrane foulants and fouling mechanisms in microfiltration and ultrafiltration of an activated sludge effluent.
Membrane fouling in microfiltration (MF) and ultrafiltration (UF) of an activated sludge (AS) effluent was investigated. It was found that the major membrane foulants were polysaccharides, proteins, polysaccharide-like and protein-like materials and humic substances. MF fouling by the raw effluent was governed by pore adsorption of particles smaller than the pores during the first 30 minutes of filtration and then followed the cake filtration model. UF fouling could be described by the cake filtration model throughout the course of filtration. Coagulation with alum and (poly)aluminium chlorohydrate (ACH) altered the MF fouling mechanism to follow the cake filtration model from the beginning of filtration. The MF and UF flux improvement by coagulation was due to the removal of some of the foulants in the raw AS effluent by the coagulants. The MF flux improvement was greater for alum than for ACH whereas the two coagulants performed equally well in UF. Coagulation also reduced hydraulically irreversible fouling on the membranes and this effect was more prominent in MF than in UF. The unified membrane fouling index (UMFI) was used to quantitatively evaluate the effectiveness of coagulation on membrane flux enhancement.


[Medication leaflets used by elderly with hypertension: adequacy of information for sanitary regulation and possible implications for health].
The medication leaflets represent the main source of written information supplied to the patients, in special to the elderly. This study aimed to analyze the content of the leaflets of drugs often prescribed for elderly people with hypertension, as well as their adequacy to the sanitary regulations and possible health implications. A descriptive study was conducted in two stages: A, in July 2002, and B, in July 2007. In each stage were analyzed 34 medication leaflets of seven antihypertensive drugs of the National Essential Drugs List (2006). Among the 68 leaflets analyzed, most did not contain all the information required by Portaria nº 110/1997 (89.5%) in the stage A and the RDC nº 140/2003 (100%) in B. In 100% of the leaflets, the legislation had not been fulfilled. Some important topics as way of administration, how to use and overdose had been absent in 76% of the leaflets, the lack of this information has an impact in the security of the antihypertensive users. Based on these data, it was possible to evidence inadequate contents of the medication leaflets. So, it is necessary greater surveillance by Anvisa, to ensure the rational use of medicines and the reduction of the risks to the elderly health.


Strategy for selection of soybean genotypes tolerant to drought during germination.
Water deficit is the main reason for instability in the context of soybean culture. The development of strategies for the selection of more tolerant genotypes is necessary. These strategies include the use of polyethylene glycol 6000 solutions (PEG-6000) for conducting the germination test under conditions of water restriction. Thus, the objective of this study was to determine the osmotic potential and the main characteristics that promote the discrimination of soybean genotypes with regard to water stress tolerance during germination and the vigor test. Thirteen soybean cultivars were used. The seeds were allowed to germinate on sheets of germitest paper moistened in solution with PEG-6000, simulating different levels of water availability, which is expressed as osmotic potential (0.0, -0.2, -0.4, and -0.6 MPa). We assessed germination, length, and dry mass for seedlings and seeds, as well as reserve dynamics. Germination and variables related to the dynamics of reservation have great influence on the expression of variability in environments under stress. Among the different osmotic potentials, the -0.2 MPa was the most efficient for the expression of genetic variability among the cultivars. Conducting the germination test with PEG-6000 solution to -0.2 MPa was efficient for selecting soybean cultivars tolerant to water stress. This was accomplished by evaluating the percentage of germination, along with variables related to the dynamics of reservation.


Ultrasound of selected pathologies of the small intestine.
Intestines, especially the small bowel, are rarely subject to US assessment due to the presence of gases and chyme. The aim of this paper was to analyze ultrasound images in selected pathologies of the small intestine in adults, including the aspects of differential diagnosis. In 2001-2012, abdominal ultrasound examinations were conducted in 176 patients with the following small bowel diseases: Crohn's disease (n=35), small bowel obstruction (n=35), yersiniosis (n=28), infectious diarrhea (n=26), bacterial overgrowth syndrome (n=25), coeliac disease (n=15) and small bowel ischemia (n=12). During examinations patients were fasting and no other particular preparations were needed. Convex transducers of 3.5-6 MHz and linear ones of 7-12 MHz were used. The assessment of the small intestine in four abdominal quadrants constituted an integral element of the examination. The following features of the small bowel ultrasound presentation were subject to analysis: thickness and perfusion of the walls, presence of thickened folds in the jejunum, reduction of their number, presence of fluid and gas contents in the intestine, its peristaltic activity, jejunization of the ileum and enteroenteric intussusception. Furthermore, the size of the mesenteric lymph nodes and the width of the superior mesenteric artery were determined and the peritoneal cavity was evaluated in terms of the presence of free fluid. Statistically significant differences were obtained between the thickness of the small intestine in Crohn's disease or in ischemic conditions and the thickness in the remaining analyzed pathological entities. Small bowel obstruction was manifested by the presence of distended loops due to gas and fluid as well as by severe peristaltic contractions occurring periodically. In the course of ischemic disease, the intestinal walls were thickened without the signs of increased perfusion and in the majority of cases intestinal stenosis was observed. Fluid in the intestine was detected in all patients with coeliac disease, gas in 86.7% of patients, thickening of the folds in the jejunum in 86.7%, their reduction in 80%, increased (enhanced) peristalsis in 93.3% and jejunization in 40%. In 80% of coeliac disease cases, the intestine showed the features of hyperemia on color Doppler examination and in 53.3% of patients the dilated lumen of the superior mesenteric artery was detected. Enlarged mesenteric lymph nodes were visualized in 73.3% of the subjects, enteroenteric intussusception in 33.3% and free fluid in the peritoneal cavity in 60%. Small bowel obstruction is manifested by the presence of evidently dilated intestinal loops filled with gas and fluid and periodical severe deepened peristalsis.Ischemic changes and Crohn's disease are characterized by the presence of fragmentarily thickened intestinal walls and intestinal stenosis. Moreover, in Crohn's disease, increased wall perfusion and mesenteric adenomegaly is encountered.Coeliac disease is manifested by: increased amount of fluid mainly in the jejunum, thickened and hyperemic jejunal walls, increased peristalsis;hypertrophied mucosal folds - often their number is reduced, jejunization and transient enteroenteric intussusception;ultrasound changes that require the differentiation with small intestinal bacterial overgrowth syndrome and, to a lesser degree, with infectious diarrhea.


International Analysis of Electronic Health Records of Children and Youth Hospitalized With COVID-19 Infection in 6 Countries.
Additional sources of pediatric epidemiological and clinical data are needed to efficiently study COVID-19 in children and youth and inform infection prevention and clinical treatment of pediatric patients. To describe international hospitalization trends and key epidemiological and clinical features of children and youth with COVID-19. This retrospective cohort study included pediatric patients hospitalized between February 2 and October 10, 2020. Patient-level electronic health record (EHR) data were collected across 27 hospitals in France, Germany, Spain, Singapore, the UK, and the US. Patients younger than 21 years who tested positive for COVID-19 and were hospitalized at an institution participating in the Consortium for Clinical Characterization of COVID-19 by EHR were included in the study. Patient characteristics, clinical features, and medication use. There were 347 males (52%; 95% CI, 48.5-55.3) and 324 females (48%; 95% CI, 44.4-51.3) in this study's cohort. There was a bimodal age distribution, with the greatest proportion of patients in the 0- to 2-year (199 patients [30%]) and 12- to 17-year (170 patients [25%]) age range. Trends in hospitalizations for 671 children and youth found discrete surges with variable timing across 6 countries. Data from this cohort mirrored national-level pediatric hospitalization trends for most countries with available data, with peaks in hospitalizations during the initial spring surge occurring within 23 days in the national-level and 4CE data. A total of 27 364 laboratory values for 16 laboratory tests were analyzed, with mean values indicating elevations in markers of inflammation (C-reactive protein, 83 mg/L; 95% CI, 53-112 mg/L; ferritin, 417 ng/mL; 95% CI, 228-607 ng/mL; and procalcitonin, 1.45 ng/mL; 95% CI, 0.13-2.77 ng/mL). Abnormalities in coagulation were also evident (D-dimer, 0.78 ug/mL; 95% CI, 0.35-1.21 ug/mL; and fibrinogen, 477 mg/dL; 95% CI, 385-569 mg/dL). Cardiac troponin, when checked (n = 59), was elevated (0.032 ng/mL; 95% CI, 0.000-0.080 ng/mL). Common complications included cardiac arrhythmias (15.0%; 95% CI, 8.1%-21.7%), viral pneumonia (13.3%; 95% CI, 6.5%-20.1%), and respiratory failure (10.5%; 95% CI, 5.8%-15.3%). Few children were treated with COVID-19-directed medications. This study of EHRs of children and youth hospitalized for COVID-19 in 6 countries demonstrated variability in hospitalization trends across countries and identified common complications and laboratory abnormalities in children and youth with COVID-19 infection. Large-scale informatics-based approaches to integrate and analyze data across health care systems complement methods of disease surveillance and advance understanding of epidemiological and clinical features associated with COVID-19 in children and youth.


Risk markers for suicidality in autistic adults.
Research has shown high rates of suicidality in autism spectrum conditions (ASC), but there is lack of research into why this is the case. Many common experiences of autistic adults, such as depression or unemployment, overlap with known risk markers for suicide in the general population. However, it is unknown whether there are risk markers unique to ASC that require new tailored suicide prevention strategies. Through consultation with a steering group of autistic adults, a survey was developed aiming to identify unique risk markers for suicidality in this group. The survey measured suicidality (SBQ-R), non-suicidal self-injury (NSSI-AT), mental health problems, unmet support needs, employment, satisfaction with living arrangements, self-reported autistic traits (AQ), delay in ASC diagnosis, and 'camouflaging' ASC. One hundred sixty-four autistic adults (65 male, 99 female) and 169 general population adults (54 males, 115 females) completed the survey online. A majority of autistic adults (72%) scored above the recommended psychiatric cut-off for suicide risk on the SBQ-R; significantly higher than general population (GP) adults (33%). After statistically controlling for a range of demographics and diagnoses, ASC diagnosis and self-reported autistic traits in the general population significantly predicted suicidality. In autistic adults, non-suicidal self-injury, camouflaging, and number of unmet support needs significantly predicted suicidality. Results confirm previously reported high rates of suicidality in ASC, and demonstrate that ASC diagnosis, and self-reported autistic traits in the general population are independent risk markers for suicidality. This suggests there are unique factors associated with autism and autistic traits that increase risk of suicidality. Camouflaging and unmet support needs appear to be risk markers for suicidality unique to ASC. Non-suicidal self-injury, employment, and mental health problems appear to be risk markers shared with the general population that are significantly more prevalent in the autistic community. Implications for understanding and prevention of suicide in ASC are discussed.


Identification of macrophages and smooth muscle cells in human atherosclerosis using monoclonal antibodies.
Sections of human atherosclerotic plaques were stained by the indirect immunoperoxidase technique using three rat anti-human monoclonal antibodies: YAML 501.4 (anti-'leukocyte-common' (T200) antigen; YTH 8.18 (antimacrophage cytoplasm); and YPC 1/3 . 12 (anti-smooth muscle cell). The cells of diffuse intimal thickening were almost all smooth muscle cells but there were rare subendothelial macrophages. Focal lesions, in contrast, contained numerous macrophages as well as smooth muscle cells. Macrophage 'foam cells' were particularly numerous in fatty streaks and in advanced fibro-fatty plaques, but were less conspicuous in focal fibro-elastic lesions. The results confirm that macrophages are an important component of atherosclerotic plaques and suggest that they may have a significant role in atherogenesis in man.


Timing of Immigration Effects Asset Change Among Hispanic Caregivers of Older Family Members.
Given the cultural value of family in Hispanic culture, older Hispanic immigrants are likely to have family caregivers. This study examined the economic implications of caring for older Hispanic adults regarding non-housing financial wealth over time. Using the 2008, 2010, and 2012 waves of the Health and Retirement Study (HRS) and RAND HRS data files, this study compares changes in the non-housing financial wealth between 2008 and 2012 by caregiving and immigration status among Hispanics. This study examined differences in assets between Hispanic caregivers and non-caregivers and more specifically examined the subpopulation of Hispanic caregivers who immigrated prior to and after 1968 as compared to U.S.-born caregivers to better understand the effect of the Immigration and Nationality Amendment Act of 1965 on asset change. Results indicate that caregiving itself did not have a statistically significant association with wealth, but the timing of immigration to the US had a statistically significant correlation (p < .05) with changes in the financial wealth. The findings of this study have implications for policy and program development targeting older adults and caregiving for this population.


Expression of mutant p53 in melanoma.
Mutant p53 has been noted in a variety of human malignancies including carcinomas of lung, breast, and colon, which have also been reported to have frequent karyotype anomalies involving the locus of the p53 gene (17p13). Whereas chromosomal abnormalities of chromosomes 1, 6, and 7 have been noted previously in melanoma, frequent aberrations in chromosome 17 have not been reported previously. Due to the common mutation of this locus in so many types of neoplasms, a range of melanomas from different stages of tumor progression were examined immunohistochemically for expression of mutant p53, in order to assess its prevalence and consider the role of this oncogene in the biological progression of melanoma. Forty-five of 53 (85%) specimens from a range of primary and metastatic melanomas were found to have detectable evidence of p53 gene mutation, by virtue of the immunohistochemical detection of mutant p53 protein. Significantly increased prevalence of mutant p53 was found in metastatic melanoma, compared with primary tumors (P less than 0.05). These findings represent one of the highest incidences of this oncogenic mutation yet recorded in a human malignancy and support the concept that p53 may have a functional role in development of the metastatic tumor phenotype.


Brow lift in facial rejuvenation: a systematic literature review of open versus endoscopic techniques.
Currently, there are many well-described surgical approaches to address brow aesthetics (i.e., open versus endoscopic versus combination techniques). Each technique has associated benefits and limitations. The authors' discussion in this article is intended to review current worldwide surgical approaches to brow aesthetics and to explore the following question: Are open brow lifts still pertinent in the modern era of cosmetic surgery? A systematic review of current available literature for the dates 1992 until the present was performed using the MEDLINE, PubMed, Cochrane Central Register of Controlled Trials, and CINAWL databases. Inclusion criteria required that individual studies contain original content; provide patient outcome data, including complications; and maintain a sufficient sample size of no fewer than 20 patients. One hundred eighty-nine articles were reviewed from the initial keyword searches of four major databases and plastic surgery journals. Fifteen articles were included in the analysis after careful review established that the necessary criteria were met. From direct analysis of these articles, no clear evidence exists to indicate that open methods of brow surgery are inferior to endoscopic approaches. Brow-lift surgery has clearly evolved since the inception of endoscopic techniques in the early 1990s. However, currently there are no prospective randomized trials in the literature that compare the surgical outcomes of differing approaches. This thorough review of current worldwide English-language literature highlights the relative paucity of good comparative studies and serves as a reminder that there is still an important role for the open approach to brow aesthetic dilemmas. Therapeutic, IV.


A colloidal heterostructured quantum dot sensitized carbon nanotube-TiO2 hybrid photoanode for high efficiency hydrogen generation.
Solar-driven photoelectrochemical (PEC) hydrogen (H2) generation is a promising approach to harvest solar energy for the production of a clean chemical fuel. However, the low photon-to-fuel conversion efficiency and long-term stability of PEC devices are major challenges to be addressed to enable large-scale commercialization. Here we report a simple, fast and cost-effective approach to fabricate high efficiency and stable PEC devices for H2 generation, by fabricating a hybrid photoanode obtained by incorporating small amounts of multiwall carbon nanotubes (MWCNTs) into a TiO2 mesoporous film and sensitizing with colloidal heterostructured CdSe/(CdSexS1-x)5/(CdS)2 quantum dots (QDs). The latter were specially designed to accelerate the exciton separation through a band engineering approach. The PEC devices based on the TiO2/QD-MWCNT (T/Q-M) hybrid photoanode with an optimized amount of MWCNTs (0.015 wt%) yield a saturated photocurrent density of 15.90 mA cm-2 (at 1.0 VRHE) under one sun illumination (AM 1.5G, 100 mW cm-2), which is 40% higher than that of the reference device based on TiO2/QD (T/Q) photoanodes. This is attributed to a synergistic effect of the promising optoelectronic properties of the colloidal heterostructured QDs and improved electron transport (reduced charge transfer resistance) within the TiO2-MWCNT hybrid anodes enabled by the directional path of MWCNTs for the photo-injected electrons towards FTO. Furthermore, the PEC device based on the T/Q-M hybrid photoanode is more stable (∼19% loss of its initial photocurrent density) when compared with the T/Q photoanode (∼35% loss) after two hours of continuous one sun illumination. Our results provide fundamental insights and a different approach to improve the efficiency and long-term stability of PEC devices and represent an essential step towards the commercialization of this emerging solar-to-fuel conversion technology.


The differences in brain stem transcriptional profiling in hypertensive ISIAH and normotensive WAG rats.
The development of essential hypertension is associated with a wide range of mechanisms. The brain stem neurons are essential for the homeostatic regulation of arterial pressure as they control baroreflex and sympathetic nerve activity. The ISIAH (Inherited Stress Induced Arterial Hypertension) rats reproduce the human stress-sensitive hypertensive disease with predominant activation of the neuroendocrine hypothalamic-pituitary-adrenal and sympathetic adrenal axes. RNA-Seq analysis of the brain stems from the hypertensive ISIAH and normotensive control WAG (Wistar Albino Glaxo) rats was performed to identify the differentially expressed genes (DEGs) and the main central mechanisms (biological processes and metabolic pathways) contributing to the hypertensive state in the ISIAH rats. The study revealed 224 DEGs. Their annotation in databases showed that 22 of them were associated with hypertension and blood pressure (BP) regulation, and 61 DEGs were associated with central nervous system diseases. In accordance with the functional annotation of DEGs, the key role of hormonal metabolic processes and, in particular, the enhanced biosynthesis of aldosterone in the brain stem of ISIAH rats was proposed. Multiple DEGs associated with several Gene Ontology (GO) terms essentially related to modulation of BP were identified. Abundant groups of DEGs were related to GO terms associated with responses to different stimuli including response to organic (hormonal) substance, to external stimulus, and to stress. Several DEGs making the most contribution to the inter-strain differences were detected including the Ephx2, which was earlier defined as a major candidate gene in the studies of transcriptional profiles in different tissues/organs (hypothalamus, adrenal gland and kidney) of ISIAH rats. The results of the study showed that inter-strain differences in ISIAH and WAG brain stem functioning might be a result of the imbalance in processes leading to the pathology development and those, exerting the compensatory effects. The data obtained in this study are useful for a better understanding of the genetic mechanisms underlying the complexity of the brain stem processes in ISIAH rats, which are a model of stress-sensitive form of hypertension.


Sexual Reproductive Biology of a Colonial Rotifer Sinantherina socialis (Rotifera: Monogononta): Do mating strategies vary between colonial and solitary rotifer species?
In many aquatic invertebrates including monogonont rotifers, sex provides genetic variation and dormant stages that allows dispersal in time and space. While the reproductive biology of some solitary monogonont rotifer species is known, little is known concerning mating behaviors in colonial rotifers. Coloniality poses unique challenges to the typical mating behavior of solitary rotifers. For instance, most species engage in circling behavior, where the male swims in close proximity to the female. In colonial forms, access to a particular female may be hindered by nearby colony mates. Here we provide descriptions of (1) male morphology, (2) mating behavior, and (3) types of eggs of the widespread colonial rotifer Sinantherina socialis, and discuss modifications in mating strategies as a consequence of coloniality. Two important differences from mating patterns documented in solitary rotifers were found in S. socialis. First, duration of circling phase of mating is protracted for males encountering small colonies of females as compared to solitary females. Males encountering single females removed from their colonies behave similarly to those of solitary species. Second, duration of copulation in S. socialis is the shortest reported for any rotifer species. Endogamy might occur in this species as sons copulate with their sisters and mothers, at least under laboratory conditions. Examples of behaviour in linked video clips.


Psychosis risk individuals show poor fitness and discrepancies with objective and subjective measures.
Exercise is a promising intervention for individuals at clinical high-risk for psychosis (CHR). However, these youth may not be reliable reporters on fitness. There have been no investigations that utilized objective fitness assessment in this population. The present study objectively characterizes the level of fitness in CHR youth, compares the accuracy of self-report measures to objective fitness indices, and explores clinical factors that may influence the accuracy of self-reported measures of fitness. Forty CHR individuals completed an exercise survey and objective indices of fitness (i.e., VO2max and BMI). Forty healthy volunteers completed objective indices of fitness and a structured clinical interview ruling out the presence of psychiatric illness. CHR youth showed greater BMI and lowered VO2max compared to healthy volunteers. In the CHR group, self-report items (perceived fitness) did not reflect objective indices of fitness, whereas specific exercise behaviors (intensity of exercise) showed stronger correlations with objective fitness measurements. Exploratory analyses suggested that symptoms (grandiosity and avolition) related to errors in self-perception. Results indicate that CHR individuals are less fit than controls as indexed by objective measures of fitness and that it is important to consider unique population clinical characteristics when employing self-report data.


Glypican 3 overexpression in primary and metastatic Wilms tumors.
Glypican 3 (GPC3), a heparan sulfate proteoglycan, plays a role in cell growth and differentiation. Mutations of the GPC3 gene are responsible for Simpson-Golabi-Behmel syndrome, which is characterized by anomalies of postnatal overgrowth and an increased risk of developing pediatric malignancies, mostly Wilms tumor and liver cancer. In order to understand the possible role of GPC3 in renal development and Wilms tumor formation, we analyzed messenger RNA (mRNA) and protein levels of GPC3 in sporadic Wilms tumors and compared it to normal kidneys and other common renal epithelial tumors. By using Affymetrix HGU133 oligonucleotide gene expression microarray data from 191 renal tumors and 12 normal kidneys, we found significant overexpression of GPC3 in Wilms tumors (p < 0.01), with 3.5-fold higher expression in comparison to normal kidneys and 6.5-fold higher than any type of renal tumors. The GPC3 gene product in Wilms tumor was further evaluated by immunohistochemistry and quantified by an automated image analysis. Cytoplasmic and membranous GPC3 immunoreactivity was present in 77 % of primary Wilms tumors (23/30), 93 % of metastatic Wilms tumors (13/14), 50 % of metanephric adenomas (4/8), 33 % of congenital mesoblastic nephromas (2/6), 100 % of nephrogenic rests (11/11), and 100 % of fetal kidneys (5/5). GPC3 staining was predominantly identified in blastemal and epithelial components of Wilms tumors, similar to that of fetal non-neoplastic kidney. All adult renal tumors (n = 60) and normal kidneys (n = 15) were GPC3 negative. These findings suggest the utility of GPC3 in differential diagnosis and follow-up of Wilms tumors. Our data also indicate that GPC3 is an oncofetal protein with a potential therapeutic value.


Establishing in vitro-in vivo correlations for Aspergillus fumigatus: the challenge of azoles versus echinocandins.
Two clinical isolates of Aspergillus fumigatus, designated AT and DK, were recently obtained from patients failing caspofungin and itraconazole therapy, respectively. The isolates were tested by microdilution for susceptibility to itraconazole, voriconazole, posaconazole, ravuconazole, and caspofungin and by Etest for susceptibility to amphotericin B and caspofungin. Susceptibility testing documented that the DK isolate was azole resistant (itraconazole and posaconazole MICs, >4 microg/ml; voriconazole MIC, 2 microg/ml; ravuconazole MIC, 4 microg/ml), and the resistance was confirmed in a hematogenous mouse model, with mortality and the galactomannan index as the primary and secondary end points. Sequencing of the cyp51A gene revealed the M220K mutation, conferring multiazole resistance. The Etest, but not microdilution, suggested that the AT isolate was resistant to caspofungin (MIC, >32 microg/ml). In the animal model, this isolate showed reduced susceptibility to caspofungin. Sequencing of the FKS1 gene revealed no mutations; the enzyme retained full sensitivity in vitro; and investigation of the polysaccharide composition showed that the beta-(1,3)-glucan proportion was unchanged. However, gene expression profiling by Northern blotting and real-time PCR demonstrated that the FKS gene was expressed at a higher level in the AT isolate than in the susceptible control isolate. To our knowledge, this is the first report to document the presence of multiazole-resistant clinical isolates in Denmark and to demonstrate reduced susceptibility to caspofungin in a clinical A. fumigatus isolate with increased expression of the FKS gene. Further research to determine the prevalence of resistance in A. fumigatus worldwide, and to develop easier and reliable tools for the identification of such isolates in routine laboratories, is warranted.


Effects of different vegetable oils on rumen fermentation and conjugated linoleic acid concentration in vitro.
The objective of this study was to investigate the effect of different vegetable oils on rumen fermentation and concentrations of beneficial cis-9 trans-11 C18:2 conjugated linoleic acid (CLA) and trans-11 C18:1 fatty acid (FA) in the rumen fluid in an in vitro condition. Six vegetable oils including sunflower, soybean, sesame, rice bran, groundnut, and mustard oils were used at three dose levels (0%, 3% and 4% of substrate dry matter [DM] basis) in three replicates for each treatment in a completely randomized design using 6 × 3 factorial arrangement. Rumen fluid for microbial culture was collected from four goats fed on a diet of concentrate mixture and berseem hay at a ratio of 60:40 on DM basis. The in vitro fermentation was performed in 100 ml conical flakes containing 50 ml of culture media and 0.5 g of substrates containing 0%, 3% and 4% vegetable oils. Oils supplementation did not affect (p>0.05) in vitro DM digestibility, and concentrations of total volatile FAs and ammonia-N. Sunflower oil and soybean oil decreased (p<0.05) protozoal numbers with increasing levels of oils. Other oils had less pronounced effect (p>0.05) on protozoal numbers. Both trans-11 C18:1 FA and cis-9, trans-11 CLA concentrations were increased (p<0.05) by sunflower and soybean oil supplementation at 4% level with the highest concentration observed for sunflower oil. The addition of other oils did not significantly (p>0.05) increase the trans-11 C18:1 FA and cis-9, trans-11 CLA concentrations as compared to the control. The concentrations of stearic, oleic, linoleic, and linolenic acids were not altered (p>0.05) due to the addition of any vegetable oils. Supplementation of sunflower and soybean oils enhanced beneficial trans-11 C18:1 FA and cis-9, trans-11 CLA concentrations in rumen fluid, while sesame, rice bran, groundnut, and mustard oils were ineffective in this study.


Interaction of critical periods in the visual cortex of kittens.
The critical period for modifying the preferred direction in cat cortical units occurs earlier than that for monocular deprivation. The independence of the effects of these two types of deprivation from each other was tested by rearing six kittens with both reverse suture and reversed directional deprivation. The kittens were placed in a drum rotating in one direction with one eye open at ages 2 1/2 to 5 weeks; the drum rotation was reversed and the other eye opened when they were 5 to 12 weeks old. Recordings were then made in the visual cortex. The results were the sum of the effects of reverse suture and reversal of directional deprivation: most cells were driven by the eye that was open second, and most unidirectional cells preferred the direction to which the animals were exposed first. Consequently, many unidirectional cells preferred the first direction but were driven by the eye open second--a combination that the animal never saw during rearing. There was also an effect of ocular deprivation on directional properties and vice versa: reverse suture reduced the overall percentage of unidirectional cells, just as directional deprivation has been shown to affect the ocular dominance histogram. This result suggests that the same cells may be affected by both forms of deprivation.


A comparison of populations vaccinated in a public service and in a private hospital setting in the same area.
Improving immunisation rates in risk groups is one of the main objectives in vaccination strategies. However, achieving high vaccination rates in children with chronic conditions is difficult. Different types of vaccine providers may differently attract high risk children. To describe the characteristics of two populations of children who attended a private and a public immunisation provider in the same area. Secondarily, to determine if prevalence of patients with underlying diseases by type of provider differs and to study if the choice of different providers influences timeliness in immunisation. We performed a cross-sectional study on parents of children 2-36 months of age who attended a private hospital immunisation service or a public immunisation office serving the same metropolitan area of Rome, Italy. Data on personal characteristics and immunisation history were collected through a face to face interview with parents of vaccinees, and compared by type of provider. Prevalence of underlying conditions was compared in the two populations. Timeliness in immunisation and its determinants were analysed through a logistic regression model. A total of 202 parents of children 2-36 months of age were interviewed; 104 were in the public office, and 98 in the hospital practice. Children immunised in the hospital were more frequently firstborn female children, breast fed for a longer period, with a lower birthweight, and more frequently with a previous hospitalisation. The prevalence of high risk children immunised in the hospital was 9.2 vs 0% in the public service (P = 0.001). Immunisation delay for due vaccines was higher in the hospital practice than in the public service (DTP, polio, HBV, and Hib: 39.8% vs 22.1%; P = 0.005). Anyway multivariate analyses did not reveal differences in timeliness between the public and private hospital settings. Children with underlying diseases or a low birthweight were more frequently immunised in the hospital. This finding suggests that offering immunisations in a hospital setting may facilitate vaccination uptake in high risk groups. An integration between public and hospital practices and an effort to improve communication on vaccines to parents, may significantly increase immunisation rates in high risk groups and in the general population, and prevent immunisation delays.


Changes in field dose-response curves for demethylation inhibitor (DMI) and quinone outside inhibitor (QoI) fungicides against Zymoseptoria tritici, related to laboratory sensitivity phenotyping and genotyping assays.
Insensitivity of Zymoseptoria tritici to demethylation inhibitor (DMI) and quinone outside inhibitor (QoI) fungicides has been widely reported from laboratory studies, but the relationships between laboratory sensitivity phenotype or target site genotype and field efficacy remain uncertain. This article reports field experiments quantifying dose-response curves, and investigates the relationships between field performance and in vitro half maximal effective concentration (EC50 ) values for DMIs, and the frequency of the G143A substitution conferring QoI resistance. Data were analysed from 83 field experiments over 21 years. Response curves were fitted, expressed as percentage control, rising towards an asymptote with increasing dose. Decline in DMI efficacy over years was associated with a decrease in the asymptote, and reduced curvature. Field ED50 values were positively related to in vitro EC50 values for isolates of Z. tritici collected over a 14-year period. Loss of QoI efficacy was expressed through a change in asymptote. Increasing frequency of G143A was associated with changes in field dose-response asymptotes. New resistant strains are often detected by resistance monitoring and laboratory phenotyped/genotyped before changes in field performance are detected. The relationships demonstrated here between laboratory tests and field performance could aid translation between laboratory and field for other fungicide groups. © 2017 Society of Chemical Industry.


SUGAR-INSENSITIVE3, a RING E3 ligase, is a new player in plant sugar response.
Sugars, such as sucrose and glucose, have been implicated in the regulation of diverse developmental events in plants and other organisms. We isolated an Arabidopsis (Arabidopsis thaliana) mutant, sugar-insensitive3 (sis3), that is resistant to the inhibitory effects of high concentrations of exogenous glucose and sucrose on early seedling development. In contrast to wild-type plants, sis3 mutants develop green, expanded cotyledons and true leaves when sown on medium containing high concentrations (e.g. 270 mm) of sucrose. Unlike some other sugar response mutants, sis3 exhibits wild-type responses to the inhibitory effects of abscisic acid and paclobutrazol, a gibberellic acid biosynthesis inhibitor, on seed germination. Map-based cloning revealed that SIS3 encodes a RING finger protein. Complementation of the sis3-2 mutant with a genomic SIS3 clone restored sugar sensitivity of sis3-2, confirming the identity of the SIS3 gene. Biochemical analyses demonstrated that SIS3 is functional in an in vitro ubiquitination assay and that the RING motif is sufficient for its activity. Our results indicate that SIS3 encodes a ubiquitin E3 ligase that is a positive regulator of sugar signaling during early seedling development.


Prevalence of intestinal parasites among expatriated workers in Al-Ain, United Arab Emirates.
A retrospective study was conducted among expatriate workers in Al-Ain City, United Arab Emirates (UAE), to determine the prevalence of pathogenic parasitic infestation. The study was based largely on expatriates arriving from India, Pakistan, Bangladesh, Iran, Philippines, Sri Lanka, and other Arab countries and mainly employed as food handlers, housemaids, baby sitters, and private drivers. This group represents 45.7% of the total number of new arrivals of expatriates during the period between 1 January 1985-31 December 1988. Stool specimens were examined in 60,268 screened individuals, of which 14,010 were found to be positive with pathogenic intestinal parasitic disease. Overall parasitic prevalence was 23.1%. The most common parasites found included: Ancylostoma (2.4%), Ascaris lumbricoides (6.6%), Trichuris trichiura (6.2%), and Giardia lamblia (2.4%). The distribution of intestinal parasites among expatriates was different for all nationalities. The results showed that Giardia lamblia was more prevalent among Iranians (54.7%) and Pakistanis (42.2%). Ancylostome species was found to be more prevalent among Sri Lankans (33.3%) and Indians (39.6%). Ascaris lumbricoides was more prevalent among Bangladeshis (33.1%), and Trichuris trichiura was more prevalent among Filipinos (40.2%).


Immune surveillance of tumors.
The ability of the immune system to identify and destroy nascent tumors, and to thereby function as a primary defense against cancer, has been debated for many decades. Recent findings by a number of investigators in both mouse models of cancer and humans with cancer now offer compelling evidence that particular immune cell types, effector molecules, and pathways can sometimes collectively function as extrinsic tumor suppressor mechanisms. This work provides the basis for further study of natural immunity to cancer and for rational use of this information in the design of immunotherapies in combination with other conventional cancer treatments.