Italian Expert Consensus on Clinical and Therapeutic Management of Multiple Chemical Sensitivity (MCS).
Multiple chemical sensitivity (MCS) is a multisystem, recurrent, environmental disorder that flares in response to different exposures (i.e., pesticides, solvents, toxic metals and molds) under the threshold limit value (TLV) calculated for age and gender in the general population. MCS is a syndrome characterized by cutaneous, allergic, gastrointestinal, rheumatological, endocrinological, cardiological and neurological signs and symptoms. We performed a systematic review of the literature to summarize the current clinical and therapeutic evidence and then oriented an eDelphi consensus. Four main research domains were identified (diagnosis, treatment, hospitalization and emergency) and discussed by 10 experts and an MCS patient. Thus, the first Italian MCS consensus had the double aim: (a) to improve MCS knowledge among healthcare workers and patients by standardizing the clinical and therapeutic management to MCS patients; and (b) to improve and shed light on MCS misconceptions not supported by evidence-based medicine (EBM).


Whole-genome sequencing.
The costs of whole-genome sequencing have rapidly decreased, and it is being increasingly deployed in large-scale clinical research projects and introduced into routine clinical care. This will lead to rapid diagnoses for patients with genetic disease but also introduces uncertainty because of the diversity of human genomes and the potential difficulties in annotating new genetic variants for individual patients and families. Here we outline the steps in organising whole-genome sequencing for patients in the neurology clinic and emphasise that close liaison between the clinician and the laboratory is essential.


Impact of long-term treatment with ivermectin on the prevalence and intensity of soil-transmitted helminth infections.
Control of soil-transmitted helminth (STH) infections relies on the periodic and long-term administration of anthelmintic drugs to high-risk groups, particularly school-age children living in endemic areas. There is limited data on the effectiveness of long-term periodic anthelmintic treatment on the prevalence of STHs, particularly from operational programmes. The current study investigated the impact of 15 to 17 years of treatment with the broad-spectrum anthelmintic ivermectin, used for the control of onchocerciasis, on STH prevalence and intensity in school-age and pre-school children. A cross-sectional study was conducted in communities that had received annual or twice-annual ivermectin treatments and geographically adjacent communities that had not received treatment in two districts of Esmeraldas Province in Ecuador. Stool samples were collected from school-age children and examined for STH infection using the Kato-Katz and formol-ether concentration methods. Samples were collected also from pre-school children and examined by the formol-ether concentration method. Data on risk factors for STH infection were collected by parental questionnaire. We sampled a total of 3,705 school-age children (6-16 years) from 31 treated and 27 non-treated communities, and 1,701 pre-school children aged 0-5 years from 18 treated and 18 non-treated communities. Among school-age children, ivermectin treatment had significant effects on the prevalence (adjusted OR = 0.06, 95% CI 0.03-0.14) and intensity of Trichuris trichiura infection (adjusted RR = 0.28, 95% CI 0.11-0.70), but appeared to have no impact on Ascaris lumbricoides or hookworm infection. Reduced prevalence and intensities of T. trichiura infection were observed among children not eligible to receive ivermectina, providing some evidence of reduced transmission of T. trichiura infection in communities receiving mass ivermectin treatments. Annual and twice-annual treatments with ivermectin over a period of up to 17 years may have had a significant impact on T. trichiura infection. The present data indicate that the long-term control of onchocerciasis with ivermectin may provide additional health benefits by reducing infections with trichuriasis. The addition of a second anthelmintic drug such as albendazole may be useful for a long-term effect on A. lumbricoides infection.


Female delinquent recidivism and the P greater than V sign on the WISC-R.
Examined the Performance-Verbal (P-V) discrepancy on the Wechsler Intelligence Scale for Children-Revised as a predictor for recidivism among 78 adjudicated white female delinquents. The P greater than V sign was displayed significantly more frequently among recidivists than among nonrecidivists. No significant relationship was found between amount of P-V difference and number of offenses for which an individual may be adjudicated. The findings support the view that cognitive differences differentiate recidivists from nonrecidivists.


Comparison of hybrid coronary revascularization versus coronary artery bypass grafting in patients≥65 years with multivessel coronary artery disease.
Hybrid coronary revascularization (HCR) combines minimally invasive left internal mammary artery-to-left anterior descending coronary artery grafting with percutaneous coronary intervention of non-left anterior descending coronary arteries. The safety and efficacy of HCR in patients≥65 years of age is unknown. In this study, patients aged≥65 years were included who underwent HCR at an academic center from October 2003 to September 2013. These patients were matched 1:4 to similar patients treated with coronary artery bypass grafting (CABG) using a propensity-score matching algorithm. Conditional logistic regression and Cox regression stratified on matched pairs were performed to evaluate the association between HCR and CABG, and 30-day major adverse cardiovascular and cerebrovascular events (a composite of mortality, myocardial infarction, and stroke), periprocedural complications, and 3-year all-cause mortality. Of 715 patients (143 of whom underwent HCR and 572 CABG) in the propensity score-matched cohort, rates of 30-day major adverse cardiovascular and cerebrovascular events were comparable after HCR and CABG (5.6% vs 3.8%, odds ratio 1.46, 95% confidence interval 0.65 to 3.27, p=0.36). Compared with CABG, HCR resulted in fewer procedural complications (9.1% vs 18.2%, p=0.018), fewer blood transfusions (28.0% vs 53.3%, p<0.0001), less chest tube drainage (838±484 vs 1,100±579 cm3, p<0.001), and shorter lengths of stay (<5 days: 45.5% vs 27.4%, p=0.001). Over a 3-year follow-up period, mortality rates were similar after HCR and CABG (13.2% vs 16.6%, hazard ratio 0.81, 95% confidence interval 0.46 to 1.43, p=0.47). Subgroup analyses in high-risk patients (Charlson index≥6, age≥75 years) rendered similar results. In conclusion, although the present data are limited, we found that in older patients, the use of HCR is safe, has fewer procedural complications, entails less blood product use, and results in faster recovery with similar longitudinal outcomes relative to conventional CABG.


Examining Device-Assessed Physical Activity During the Transition Into Emerging Adulthood: Results From the MovingU Study.
The purpose of the present study was to conduct the first longitudinal investigation using accelerometers to assess physical activity behavior change during individuals' acute transition out of high school. Participants in the current investigation were a part of a prospective cohort study called the MovingU Study. Participants were 163 adolescents (Mage = 16.9 ± .5; n = 88 females) recruited at the beginning of their final year at high school, with follow-up at 6 and 18 months. Participants wore the ActiGraph Link for 7 days at each assessment period. Results from the mixed-effects models found no significant differences in moderate-to-vigorous physical activity or total physical activity between baseline and follow-up at 6 months (Estimates = 1.91 and -2.26, p's > .05), respectively; however, significant differences in both moderate-to-vigorous physical activity and total physical activity between baseline and follow-up at 18 months after the transition out of highschool (Estimate = -123.62 and -15.38, p's < .01). Current findings provide additional compelling data to show precipitous declines in physical activity as adolescents transition out of high school and into emerging adulthood. Continued efforts to maintain or increase physical activity during adolescence and the prevention of physical activity declines as they enter emerging adulthood could have important public health benefits.


Characterization of postoperative "fibrin web" formation after canine cataract surgery.
To describe the occurrence and associated factors for "fibrin web" (FW) formation following phacoemulsification in dogs. A retrospective review of medical records of all dogs undergoing phacoemulsification (MU-Veterinary Health Center, 2014-2018) was conducted to associate FW formation with signalment, systemic co-morbidities, cataract stage, surgeon (resident vs faculty), phacoemulsification time, IOL, and intracameral injections including viscoelastic type. Both univariate and multivariate statistical analyses were performed to evaluate associations among variables with FW formation. Data from 398 eyes on 201 dogs were included; 4 left eyes (4 dogs) developed presumptive endophthalmitis and were excluded from further analysis. Forty-eight eyes did not have cataract surgery. Hence, 350 eyes on 201 dogs were included in the analyses. Among these, 84 eyes (59 dogs) developed a FW. Univariate analyses showed that the odds of FW increased with age and phacoemulsification time. Additionally, FW web was associated lens type, lens brand, and viscoelastic type. Multivariate analyses showed that when comparing lens types in combination with a particular viscoelastic, viscoelastic impacted the estimated prevalence of FW formation the most. In contrast, when the data were analyzed by lens brand, lens brand impacted prevalence more than viscoelastic type. Diabetes mellitus was not associated with FW formation. Based on the available data, intraocular lens implantation, viscoelastic type, dog age, and phacoemulsification time were associated with FW formation. Diabetes mellitus, gender, cataract stage, surgeon, intracameral injections other than viscoeleastic, and intra- and postoperative complications were not associated with FW formation.


A systematic review on the effectiveness and impact of clinical decision support systems for breathlessness.
Breathlessness is a common presenting symptom in practice. This systematic review aimed to evaluate the impact of CDSS on breathlessness and associated diseases in real-world clinical settings. Studies published between 1 January 2000 to 10 September 2021 were systematically obtained from 14 electronic research databases including CENTRAL, Embase, Pubmed, and clinical trial registries. Main outcomes of interest were patient health outcomes, provider use, diagnostic concordance, economic evaluation, and unintended consequences. The review protocol was prospectively registered in PROSPERO (CRD42020163141). A total of 4294 records were screened and 37 studies included of which 30 were RCTs. Twenty studies were in primary care, 13 in hospital outpatient/emergency department (ED), and the remainder mixed. Study duration ranged from 2 weeks to 5 years. Most were adults (58%). Five CDSS were focused on assessment, one on assessment and management, and the rest on disease-specific management. Most studies were disease-specific, predominantly focused on asthma (17 studies), COPD (2 studies), or asthma and COPD (3 studies). CDSS for COPD, heart failure, and asthma in adults reported clinical benefits such as reduced exacerbations, improved quality of life, improved patient-reported outcomes or reduced mortality. Studies identified low usage as the main barrier to effectiveness. Clinicians identified dissonance between CDSS recommendations and real-world practice as a major barrier. This review identified potential benefits of CDSS implementation in primary care and outpatient services for adults with heart failure, COPD, and asthma in improving diagnosis, compliance with guideline recommendations, promotion of non-pharmacological interventions, and improved clinical outcomes including mortality.


A Metabolomic Analysis of the Sex-Dependent Hispanic Paradox.
In Mexican Americans, metabolic conditions, such as obesity and type 2 diabetes (T2DM), are not necessarily associated with an increase in mortality; this is the so-called Hispanic paradox. In this cross-sectional analysis, we used a metabolomic analysis to look at the mechanisms behind the Hispanic paradox. To do this, we examined dietary intake and body mass index (BMI; kg/m2) in men and women and their effects on serum metabolomic fingerprints in 70 Mexican Americans (26 men, 44 women). Although having different BMI values, the participants had many similar anthropometric and biochemical parameters, such as systolic and diastolic blood pressure, total cholesterol, and LDL cholesterol, which supported the paradox in these subjects. Plasma metabolomic phenotypes were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS). A two-way ANOVA assessing sex, BMI, and the metabolome revealed 23 significant metabolites, such as 2-pyrrolidinone (p = 0.007), TMAO (p = 0.014), 2-aminoadipic acid (p = 0.019), and kynurenine (p = 0.032). Pathway and enrichment analyses discovered several significant metabolic pathways between men and women, including lysine degradation, tyrosine metabolism, and branch-chained amino acid (BCAA) degradation and biosynthesis. A log-transformed OPLS-DA model was employed and demonstrated a difference due to BMI in the metabolomes of both sexes. When stratified for caloric intake (<2200 kcal/d vs. >2200 kcal/d), a separate OPLS-DA model showed clear separation in men, while females remained relatively unchanged. After accounting for caloric intake and BMI status, the female metabolome showed substantial resistance to alteration. Therefore, we provide a better understanding of the Mexican-American metabolome, which may help demonstrate how this population-particularly women-possesses a longer life expectancy despite several comorbidities, and reveal the underlying mechanisms of the Hispanic paradox.


Hip fractures in the elderly-: A Clinical Anatomy Review.
As elderly populations rise worldwide, the amount of hip fractures have continued to increase and result in substantial medical burdens in many countries. This increase goes hand-in-hand with an increase in surgical procedures to correct hip fractures. The medical burden imparted by hip fractures and their corrective surgeries necessitate a clinically relevant understanding of the hip joint including the vascular, neural, and musculoskeletal structures directly associated with and neighboring the joint. It is critical to appreciate how the normal hip anatomy is disrupted by a fracture and how this disruption is heavily influenced by the fracture's location. The effects of advancing age on the integrity of the hip joint and the risk of hip fractures further complicate hip anatomy. Consequentially, normal hip anatomy, aging and the pathology introduced by fractures play major roles in how hip fractures are approached surgically. This article aims to review the clinically relevant anatomy of the healthy hip joint, age-related changes that influence the joint, hip fractures, and corrective surgeries for hip fractures. Clin. Anat. 30:89-97, 2017. © 2016 Wiley Periodicals, Inc.


Structural characterization and in vitro-in vivo evaluation of effect of a polysaccharide from Sanguisorba officinalis on acute kidney injury.
We report here an acidic polysaccharide, namely RSP-3, which ameliorates acute kidney injury and is obtained from Sanguisorba officinalis. We extracted and purified two polysaccharides from this herb based on the acidity and screened them for their effect in regulating the immunological activity of macrophages. Among them, RSP-3 exhibited significant anti-inflammatory activity against lipopolysaccharide (LPS)-stimulated macrophages by decreasing TNF-α and IL-6 levels. Subsequently, we found that RSP-3 suppressed ER stress, reduced ROS production and blocked NF-κBp65 translocation. After fully characterizing RSP-3 with a series of analytical technologies, we tested its anti-acute kidney injury (AKI) effect in vivo. In a murine AKI model induced by LPS, treatment with RSP-3 effectively ameliorated renal function. Besides, it decreased the levels of TNF-α and IL-6 in serum and reduced macrophage infiltration in injured kidney tissue. In sum, RSP-3, with a significant protective effect against AKI by showing anti-inflammatory activity, may become a meaningful drug candidate for treatment of AKI.


Improving the efficiency of feed utilization in poultry by selection. 2. Genetic parameters of excretion traits and correlations with anatomy of the gastro-intestinal tract and digestive efficiency.
Poultry production has been widely criticized for its negative environmental impact related to the quantity of manure produced and to its nitrogen and phosphorus content. In this study, we investigated which traits related to excretion could be used to select chickens for lower environmental pollution.The genetic parameters of several excretion traits were estimated on 630 chickens originating from 2 chicken lines divergently selected on apparent metabolisable energy corrected for zero nitrogen (AMEn) at constant body weight. The quantity of excreta relative to feed consumption (CDUDM), the nitrogen and phosphorus excreted, the nitrogen to phosphorus ratio and the water content of excreta were measured, and the consequences of such selection on performance and gastro-intestinal tract (GIT) characteristics estimated. The genetic correlations between excretion, GIT and performance traits were established. Heritability estimates were high for CDUDM and the nitrogen excretion rate (0.30 and 0.29, respectively). The other excretion measurements showed low to moderate heritability estimates, ranging from 0.10 for excreta water content to 0.22 for the phosphorus excretion rate. Except for the excreta water content, the CDUDM was highly correlated with the excretion traits, ranging from -0.64 to -1.00. The genetic correlations between AMEn or CDUDM and the GIT characteristics were very similar and showed that a decrease in chicken excretion involves an increase in weight of the upper part of the GIT, and a decrease in the weight of the small intestine. In order to limit the environmental impact of chicken production, AMEn and CDUDM seem to be more suitable criteria to include in selection schemes than feed efficiency traits.


Papnet-assisted cytological diagnosis intensifies the already marked variability among cytological laboratories.
The main objective was to assess the sensitivity, specificity and reliability of PAPNET-assisted diagnosis in comparison with conventional screening. Seven Italian and one English University or Research Institutes, and a random sample of an other 20 Italian Laboratories of the Italian National Health Service (INHS) provided the cervical smears. During the training phase every center examined in rotation four sets of slides for a total of 300 representative slides. Afterwards, 900 "positive" slides were added to the 3,100 slides which were collected consecutively without any selection or exclusion. The eight main centers were divided into four couples and each couple of centers examined 775 slides with the PAPNET system, "blindly" to the original diagnosis. An expert cytopathologist (M.A.) of the National Institute of Health (NIH) reassessed 40% of the slides with an original negative diagnosis to evaluate the false negative rate. Two expert NIH cytopathologists (M.A., G.M.) re-examined all slides where a disagreement had been observed between the original and one or both of the study diagnoses. The main analyses concerned the following three main categories: WNL and unsatisfactory for evaluation; ASCUS, AGUS and LSIL; HSIL and carcinoma. A special algorithm was devised to define the reference diagnosis for sensitivity and specificity assessment. Laboratories, even belonging to the same couple, classified as "no review" a very different proportion of slides ranging from 35% to 74%. The index of kappa agreement between the members of couples examining the same sets of slides was low or very low, ranging from 0.30 to 0.03. The sensitivity of the review classification was particularly low in some laboratories. Surprisingly, only a small correlation was observed between the sensitivity of the review classification and the proportion of slides classified as "review". The "tentative" diagnosis on PAPNET tiles of the "review" slides was almost as reliable as the microscopic diagnosis. In the overall performance, there were many significant differences among the eight laboratories. The best laboratory had a sensitivity of 95% and a specificity of 96%. At least three laboratories displayed unacceptably low sensitivity and one a very low specificity. Altogether these results seem to confirm that there are wide differences among cytological laboratories per se, and that these differences are intensified by the use of an instrument like PAPNET. The huge variation in performance may be explained by differences in basic skills and by different training, but it is difficult to understand exactly what could have been done to reduce it.


Mapping HSA10 homologous loci in cattle.
Loci homologous to those on human chromosome 10 (HSA10) map to five mouse chromosomes, MMU2, MMU7, MMU10, MMU14, and MMU19. In cattle, one unassigned syntenic group (U26) was previously defined by the HSA10/MMU19 isoenzyme marker glutamic-oxaloacetic transaminase 1 (GOT1). To evaluate the syntenic arrangement of other HSA10 loci in cattle, seven genes were physically mapped by segregation analysis in a bovine x hamster hybrid somatic cell panel. The genes mapped include: vimentin (VIM) on HSA10 and MMU2; interleukin 2 receptor (IL2R) on HSA10 and MMU?; ornithine aminotransferase (OAT) on HSA10 and MMU7; hexokinase 1 (HK1) on HSA10 and MMU10; retinol-binding protein 3 (RBP3) on HSA10 and MMU14; plasminogen activator, urokinase type (PLAU) on HSA10 and MMU14; and alpha-2-adrenergic receptor (ADRA2) on HSA10 and MMU19. VIM and IL2R mapped to U11; ADRA2 and OAT mapped to U26; and RBP3, PLAU, and HK1 mapped to U28.


The practicality of mesoporous silica nanoparticles as drug delivery devices and progress toward this goal.
Mesoporous silica nanoparticles (MSNs) have been proposed as drug delivery devices for approximately 15 years. The history of in vitro studies has been promising, demonstrating that MSNs have the capability for stimulus-responsive controlled release, good cellular uptake, cell specific targeting, and the ability to carry a variety of cargoes from hydrophobic drug molecules to imaging agents. However, the translation of the in vitro findings to in vivo conditions has been slow. Herein, we review the current state-of-the-art in the use of MSN for systemic drug delivery in vivo and provide critical insight into the future of MSNs as systemic drug delivery devices and directions that should be undertaken to improve their practicality.


Patient Phenotyping for Atopic Dermatitis with Transformers and Machine Learning.
Atopic dermatitis (AD) is a chronic skin condition that millions of people around the world live with each day. Performing research studies into identifying the causes and treatment for this disease has great potential to provide benefit for these individuals. However, AD clinical trial recruitment is a non-trivial task due to variance in diagnostic precision and phenotypic definitions leveraged by different clinicians as well as time spent finding, recruiting, and enrolling patients by clinicians to become study subjects. Thus, there is a need for automatic and effective patient phenotyping for cohort recruitment. Our study aims to present an approach for identifying patients whose electronic health records suggest that they may have AD. We created a vectorized representation of each patient and trained various supervised machine learning methods to classify when a patient has AD. Each patient is represented by a vector of either probabilities or binary values where each value indicates whether they meet a different criteria for AD diagnosis. Results: The most accurate AD classifier performed with a class-balanced accuracy of 0.8036, a precision of 0.8400, and a recall of 0.7500 when using XGBoost (Extreme Gradient Boosting). Creating an automated approach for identifying patient cohorts has the potential to accelerate, standardize, and automate the process of patient recruitment for AD studies; therefore, reducing clinician burden and informing knowledge discovery of better treatment options for AD.


Effects of intravenous antidepressant drugs on the excitability of human motor cortex: a study with paired magnetic stimulation on depressed patients.
The effect of various drugs was investigated by using transcranial magnetic stimulation (TMS) both in healthy subjects and patients, and the results indicated an influence of antidepressant drugs (ADs) on motor excitability. The aim of our study was to analyze the effects of two ADs, the tricyclic (TCA) clomipramine and the serotoninergic antidepressant (SSRI) citalopram on the motor cortex excitability in major depressed patients with TMS. Thirty affected subjects were placed into three groups: two received an intravenous dose of 25 mg clomipramine or 40 mg citalopram, and one received an injection of a placebo. Motor cortex excitability was studied by single and paired TMS before and after 3.5, 8, and 24 hours from administration of the drugs and placebo. Motor cortical excitability was measured using different TMS parameters: resting motor threshold (RMT), motor-evoked potential (MEP) amplitude, intracortical inhibition (ICI), and intracortical facilitation (ICF). The results indicated a temporary but significant increase of RMT and ICI and a decrease of ICF after the administration of both drugs, with a longer inhibition for the clomipramine rather than the citalopram. MEP amplitude was not significantly affected by the antidepressant injections. Our findings highlight that a single intravenous dose of clomipramine or citalopram exerts a significant but transitory suppression of motor cortex excitability in depressed patients. TMS represents a useful research tool in assessing the effects of motor cortical excitability of drugs used in the treatment of mental disorders.


An endemiological study of enteric virus infections: poliomyelitis, coxsackie, and orphan (ECHO) viruses isolated from normal children in two socioeconomic groups.
An endemiological study of enteric viruses was conducted among 136 normal children, living in households in two socio-economic groups, over a 29 month period in Charleston, West Virginia. A repeatable seasonal incidence of enteric virus excretion was noted with over 90 per cent of isolations occurring in the months of June to October. Of 592 stools examined in District I, a lower socio-economic group, 8.3 per cent yielded virus as compared to 3.1 per cent of 966 stools examined in District IV, an upper middle class district with good environmental sanitation. Among the 77 viruses isolated in tissue cultures of monkey kidneys, 44 per cent were ECHO or orphan viruses, 37 per cent Coxsackie viruses, and 19 per cent poliomyelitis viruses. Among poliovirus carriers, and 15 family contacts, 10 individuals had simultaneous heterotypic and type-specific antibody responses. The heterotypic ones were usually present at low levels and were transient in nature. Family infection with certain orphan viruses was also evident from antibody development which occurred following isolation of virus in the sentinel child.


Nineteen years' experience of out-of-hospital cardiac arrest in Gothenburg--reported in Utstein style.
To describe the outcome in the Utstein style for out of hospital cardiac arrest in Gothenburg, over a period of 19 years. All consecutive cases of cardiac arrest between 1980 and 1999 in which the emergency medical service (EMS) system responded and attempted resuscitation were reported and followed up for 1 year. In all, there were 5270 attempts. 3871 (73%) of which were regarded as being of a cardiac aetiology. In these cases, information on witnessed status was missing in 782 cases (20%). Of the remaining 3089 cases, 2066 (67%) were bystander witnessed, 791 (26%) were unwitnessed and 232 (8%) crew witnessed. The median interval between a call for the ambulance and the arrival of the first ambulance was 5 min. Thirteen percent of the bystander-witnessed cases were discharged from hospital. Of the unwitnessed cases, only 2% were discharged from hospital, whereas 22% of the crew-witnessed cases were discharged. Of the patients with a bystander-witnessed cardiac arrest of a cardiac aetiology found in ventricular fibrillation (VF), 20% were discharged from hospital. In this large Utstein style study of out of hospital cardiac arrest stretching over almost 19 years, we report high survival rates both for patients suffering a bystander-witnessed cardiac arrest, and for the subgroup suffering a bystander-witnessed cardiac arrest with VF as the first recorded rhythm. These high survival rates can in part be explained by the short time intervals from calls being received by the emergency dispatch centre (EDC) to the arrival of the emergency medical service at the scene.


Structural characterization of a peptoid with lysine-like side chains and biological activity using NMR and computational methods.
N-substituted glycine oligomers or peptoids with charged side chains are a novel class of cell penetrating peptide mimetics and have been shown to serve as drug delivery agents. Here, we investigated by NMR spectroscopy and quantum chemical calculations whether a Rhodamine B labelled peptoid [RhoB(Spiro)-Ahx]-[But](6A)NH(2) with lysine-like side chains adopts structural motifs similar to regular peptides. Due to a low chemical shift dispersion, high resolution structure determination with conventional NMR-derived distance restraints and J-couplings was not possible. Instead, a combined assignment and structure refinement strategy using the QM/MM force field COSMOS-NMR was developed to interpret the highly ambiguous chemical shift and distance constraints and obtain a medium resolution three-dimensional structural model. This allowed us to select for the all cis-amide conformation of the peptide with a pseudo-helical arrangement of extended side chains as a faithful representative structure of [RhoB(Spiro)-Ahx]-[But](6A)NH(2). We tested the biological activity of the peptoid by live-cell imaging, which showed that the cellular uptake of the peptoid was comparable to conventional cell-penetrating peptides.


Is the Tyme Wear Smart Shirt Reliable and Valid at Detecting Personalized Ventilatory Thresholds in Recreationally Active Individuals?
The aim of this study was to determine the extent to which the Tyme Wear smart shirt is as reliable and valid in detecting personalized ventilatory thresholds when compared to the Parvo Medics TrueOne 2400. In this validation study, 19 subjects were recruited to conduct two graded exercise test (GXT) trials. Each GXT trial was separated by 7 to 10 days of rest. During the GXT, gas exchange and heart rate data were collected by the TrueOne 2400 (TRUE) in addition to the ventilation data collected by the Tyme Wear smart shirt (S-PRED). Gas exchange data from TRUE were used to detect ventilatory threshold 1 (VT1) and ventilatory threshold 2 (VT2). TRUE and S-PRED VT1 and VT2 were compared to determine the reliability and validity of the smart shirt. Of the 19 subjects, data from 15 subjects were used during analysis. S-PRED exhibited excellent (intraclass correlation coefficient-CC > 0.90) reliability for detection of VT1 and VT2 utilizing time point and workload and moderate (0.90 > ICC > 0.75) reliability utilizing heart rate. TRUE exhibited excellent reliability for detection of VT1 and VT2 utilizing time point, workload, and heart rate. When compared to TRUE, S-PRED appears to underestimate the VT1 workload (p > 0.05) across both trials and heart rate (p < 0.05) for trial 1. However, S-PRED appears to underestimate VT2 workload (p < 0.05) and heart rate (p < 0.05) across both trials. The result from this study suggests that the Tyme Wear smart shirt is less valid but is comparable in reliability when compared to the gold standard. Moreover, despite the underestimation of S-PRED VT1 and VT2, the S-PRED-detected personalized ventilatory thresholds provide an adequate training workload for most individuals. In conclusion, the Tyme Wear smart shirt provides easily accessible testing to establish threshold-guided training zones but does not devalue the long-standing laboratory equivalent.


Radiogenomics predicting tumor responses to radiotherapy in lung cancer.
The recently developed ability to interrogate genome-wide data arrays has provided invaluable insights into the molecular pathogenesis of lung cancer. These data have also provided information for developing targeted therapy in lung cancer patients based on the identification of cancer-specific vulnerabilities and set the stage for molecular biomarkers that provide information on clinical outcome and response to treatment. In addition, there are now large panels of lung cancer cell lines, both non-small-cell lung cancer and small-cell lung cancer, that have distinct chemotherapy and radiation response phenotypes. We anticipate that the integration of molecular data with therapy response data will allow for the generation of biomarker signatures that predict response to therapy. These signatures will need to be validated in clinical studies, at first retrospective analyses and then prospective clinical trials, to show that the use of these biomarkers can aid in predicting patient outcomes (eg, in the case of radiation therapy for local control and survival). This review highlights recent advances in molecular profiling of tumor responses to radiotherapy and identifies challenges and opportunities in developing molecular biomarker signatures for predicting radiation response for individual patients with lung cancer.


Development, growth and maintenance of β-cell mass: models are also part of the story.
Pancreatic β-cells in the islets of Langerhans play a crucial role in regulating glucose homeostasis in the circulation. Loss of β-cell mass or function due to environmental, genetic and immunological factors leads to the manifestation of diabetes mellitus. The mechanisms regulating the dynamics of pancreatic β-cell mass during normal development and diabetes progression are complex. To fully unravel such complexity, experimental and clinical approaches need to be combined with mathematical and computational models. In the natural sciences, mathematical and computational models have aided the identification of key mechanisms underlying the behavior of systems comprising multiple interacting components. A number of mathematical and computational models have been proposed to explain the development, growth and death of pancreatic β-cells. In this review, we discuss some of these models and how their predictions provide novel insight into the mechanisms controlling β-cell mass during normal development and diabetes progression. Lastly, we discuss a handful of the major open questions in the field.


A new, female-specific irritability rating scale.
Irritability is a prominent symptom in the spectrum of female-specific mood disorders, and in some women, irritability is serious enough to disrupt their lives and warrant treatment. The objective of this research was to develop a new, female-specific state measure of irritability. We constructed self-rating and observer rating scales using items derived from spontaneous descriptions of irritability by women with mood disturbances related to the menstrual cycle, childbearing or menopause. Following a pretest, the scales were shortened to the core items of irritability (annoyance, anger, tension, hostility, sensitivity to noise and touch) and tested on a new cohort of patients. The 14-item Self-Rating Scale and the 5-item Observer Rating Scale showed evidence for internal consistency (Self-Rating: n = 36 patients, Cronbach's alpha = 0.9257, mean interitem correlation = 0.4690; Observer Rating: Cronbach's alpha = 0.7418, mean interitem correlation = 0.3616), Self-Rating test-retest reliability (n = 29 patients, r(s) = 0.704, p = 0.01) and interrater reliability (n = 20 patients; tau(b) = 1.000, p = 0.001). This new, female-specific scale for rating irritability has the potential to further the evaluation of this prominent symptom cluster and increase specificity in clinical assessments of emotional disturbances related to reproductive cyclicity in women.


Conservative management of abdominal injuries: audit of criteria for discharge.
This prospective study was conducted to audit the discharge criteria of patients admitted for the conservative management of abdominal trauma. A total of 184 patients who were admitted to Groote Schuur Hospital (GSH) with penetrating or blunt abdominal injuries and who were conservatively managed according to the GSH protocol were assessed. The study concluded that patients with abdominal trauma who do not require emergency laparotomy can be safely discharged after a period of conservative management provided they are pain-free, hungry and passing flatus.


Net financial benefits of averting HIV infections among people who inject drugs in Urumqi, Xinjiang, Peoples Republic of China (2005-2010).
To quantify the contribution of locally implemented prevention programmes in contributing to reductions in treatment and care costs by averting HIV infections among those who inject drugs this study calculates net financial benefit of providing harm reduction programmes using information from services being implemented in Urumqi, Xinjiang Uighur Autonomous Region of China ( between 2005 and 2010). Information was collected to assess cost of providing methadone treatment (MMT) and needle and syringe programmes (NSP). HIV incidence was estimated among people who inject drugs (PWID). HIV infections averted were calculated. Net benefit was assessed by estimating costs of providing prevention programmes and comparing these to the costs of providing care. An estimated 5678 (range 3982-7599) HIV infections were averted between 2005 and 2010 and the net financial benefit of providing harm reduction programmes compared to treatment and care costs for HIV infections averted was USD 4.383 million during the same time period. These results demonstrate the net and accumulating benefit of investing in harm reduction programmes for PWID in Urumqi. The return on investment progressively increased during the time period studied and it is clear that these cost savings will continue to accrue with the continued implementation of HIV prevention interventions in the community that include harm reduction programmes targeted at PWID.


Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine.
In a previous study, we found that human neural stem cells (HNSCs) exposed to high concentrations of secreted amyloid-precursor protein (sAPP) in vitro differentiated into mainly astrocytes, suggesting that pathological alterations in APP processing during neurodegenerative conditions such as Alzheimer's disease (AD) may prevent neuronal differentiation of HNSCs. Thus, successful neuroplacement therapy for AD may require regulating APP expression to favorable levels to enhance neuronal differentiation of HNSCs. Phenserine, a recently developed cholinesterase inhibitor (ChEI), has been reported to reduce APP levels in vitro and in vivo. In this study, we found reductions of APP and glial fibrillary acidic protein (GFAP) levels in the hippocampus of APP23 mice after 14 days treatment with (+)-phenserine (25 mg/kg) lacking ChEI activity. No significant change in APP gene expression was detected, suggesting that (+)-phenserine decreases APP levels and reactive astrocytes by posttranscription regulation. HNSCs transplanted into (+)-phenserine-treated APP23 mice followed by an additional 7 days of treatment with (+)-phenserine migrated and differentiated into neurons in the hippocampus and cortex after 6 weeks. Moreover, (+)-phenserine significantly increased neuronal differentiation of implanted HNSCs in hippocampal and cortical regions of APP23 mice and in the CA1 region of control mice. These results indicate that (+)-phenserine reduces APP protein in vivo and increases neuronal differentiation of HNSCs. Combination use of HNSC transplantation and treatment with drugs such as (+)-phenserine that modulate APP levels in the brain may be a useful tool for understanding mechanisms regulating stem cell migration and differentiation during neurodegenerative conditions in AD.


The haplotype-resolved T2T reference genome highlights structural variation underlying agronomic traits of melon.
Melon (Cucumis melo L.) is an important vegetable crop that has an extensive history of cultivation. However, the genome of wild and semi-wild melon types that can be used for the analysis of agronomic traits is not yet available. Here we report a chromosome-level T2T genome assembly for 821 (C. melo ssp. agrestis var. acidulus), a semi-wild melon with two haplotypes of ~373 Mb and ~364 Mb, respectively. Comparative genome analysis discovered a significant number of structural variants (SVs) between melo (C. melo ssp. melo) and agrestis (C. melo ssp. agrestis) genomes, including a copy number variation located in the ToLCNDV resistance locus on chromosome 11. Genome-wide association studies detected a significant signal associated with climacteric ripening and identified one candidate gene CM_ac12g14720.1 (CmABA2), encoding a cytoplasmic short chain dehydrogenase/reductase, which controls the biosynthesis of abscisic acid. This study provides valuable genetic resources for future research on melon breeding.


Highly Stable trans-Cyclooctene Amino Acids for Live-Cell Labeling.
trans-Cyclooctene groups incorporated into proteins via non-canonical amino acids (ncAAs) are emerging as specific handles for bioorthogonal chemistry. Here, we present a highly improved synthetic access to the axially and the equatorially linked trans-cyclooct-2-ene isomers (1 a,b). We further show that the axially connected isomer has a half-life about 10 times higher than the equatorial isomer and reacts with tetrazines much faster, as determined by stopped-flow experiments. The improved properties resulted in different labeling performance of the insulin receptor on the surface of intact cells.


An anti-peptide antibody targeted to a specific region of rat cytochrome P-450IA2 inhibits enzyme activity.
An anti-peptide antibody has been produced which binds to and specifically inhibits the activity of cytochrome P-450IA2 in rat hepatic microsomes. This was achieved by raising an antibody against a synthetic peptide (Ser-Glu-Asn-Tyr-Lys-Asp-Asn), the sequence of which occurs in cytochrome P-450IA2 at positions 290-296. The selection of this region of cytochrome P-450IA2 was based on several criteria, including prediction of surface and loop areas, identification of variable regions between cytochromes P-450IA2 and P-450IA1, and consideration of a site on cytochrome P-450IA1 where chemical modification has been shown to cause substantial enzyme inactivation. The specificity of antibody binding was determined by enzyme-linked immunosorbent assay and by immunoblotting using hepatic microsomal preparations and purified cytochrome P-450 isoenzymes. This showed that the antibody binds specifically to rat and mouse cytochrome P-450IA2 and to no other cytochrome P-450, as was predicted from the amino acid sequences of the peptide and the cytochromes P-450. The effect of the antibody upon enzyme activity was studied in hepatic microsomes from rats treated with 3-methylcholanthrene. The antibody was shown to inhibit specifically the activity of reactions catalysed by cytochrome P-450IA2 (phenacetin O-de-ethylase and 2-acetylaminofluorene activation), but had no effect on aryl hydrocarbon hydroxylase activity, which is catalysed by cytochrome P-450IA1, or on aflatoxin B1 activation.


Chloroplast import characteristics of chimeric proteins.
We have examined the import of a series of chimeric precursor proteins into chloroplasts. These fusion proteins contained the transit peptide, and various amounts of the amino-terminal region of the mature peptide, from the small subunit of ribulose 1,5-bisphosphate carboxylase, linked to the coat protein of brome mosaic virus. Chimeric genes were cloned into SP6 plasmids and in vitro transcription/translation was used to produce fusion proteins, which were examined in a quantitative in vitro import assay. A chimeric protein which contained only the transit peptide fused to the coat protein was imported into chloroplasts. A second chimeric precursor, which also contained a small portion of the mature peptide, was imported at nearly the same rate. A chimeric protein which contained the transit peptide and most of the mature peptide fused to the coat protein was not imported. These results suggest that secondary or tertiary structural features of precursor proteins are important for protein import, and that the presence of a transit peptide in a protein does not necessarily ensure import of that protein into chloroplasts.


An insight into genetic landscape of inflammatory bowel disease.
Inflammatory bowel disease has been regarded to be chronic intestinal inflammation characterised by a dsyregulatory immune response. The disease pathophysiology is known to be complex. Growing pieces of evidences underpin the involvement of various environmental and genetic determinants in the disease onset. The current narrative review was planned to manifest the contribution of genetic drivers for disease onset and to target signalling pathways that might present a therapeutic potential for further research. The factors of the disease that provide the genetic nature and understanding of the pathways involved have been researched in recent times. Also, numerous diseasedeveloping factors have been studied and assessed. Among them genetic determinants of disease onset have further improved the understanding of disease development. Genetic contributors to the onset of disease as well as important therapeutic targets need to be understood as predictive genetic risk factors have a potential implication for personalised treatment.


Lipid emulsions for parenterally fed term and late preterm infants.
Lipid emulsions (LE) form a vital component of infant nutrition for critically ill, late preterm or term infants, particularly for those with gastrointestinal failure. Conventionally used soybean oil-based LE (S-LE) have high polyunsaturated fatty acid (PUFA) content and phytosterols, which may contribute to adverse effects including parenteral nutrition-associated liver disease (PNALD). To compare the safety and efficacy of all LE for parenteral nutrition (PN) in term and late preterm infants (between 34 weeks' gestation and 36 weeks' and six days' gestation) with or without surgical conditions or PNALD within first six months of life, using all possible direct comparisons. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE (1946 to 18 June 2018), Embase (1974 to 18 June 2018), CINAHL (1982 to 18 June 2018), MIDRIS (1971 to 31 May 2018), conference proceedings, trial registries (ClinicalTrials.gov and the WHO's Trials Registry), and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Randomised or quasi-randomised controlled studies in term and late preterm infants, with or without surgical conditions or PNALD. Data collection and analysis conformed to the methods of Cochrane Neonatal. We used the GRADE approach to assess the quality of evidence for important outcomes in addition to reporting the conventional statistical significance of results. The review included nine randomised studies (n = 273). LE were classified in three broad groups: 1. all fish oil-containing LE including pure fish oil (F-LE) and multisource LE (e.g. medium-chain triglycerides (MCT)-olive-fish-soybean oil-LE (MOFS-LE), MCT-fish-soy oil-LE (MFS-LE) and olive-fish-soy-LE (OFS-LE)); 2. conventional pure S-LE; 3. alternative-LE (e.g. MCT-soy-LE (MS-LE), olive-soy-LE (OS-LE) and borage oil-based LE).We considered four broad comparisons: 1. all fish oil LE versus non-fish oil LE (6 studies; n = 182); 2. fish oil LE versus another fish oil LE (0 studies); 3. alternative-LE versus S-LE (3 studies; n = 91); 4. alternative-LE versus another alternative-LE (0 studies) in term and late preterm infants (0 studies), term and late preterm infants with surgical conditions (7 studies; n = 233) and term and late preterm infants with PNALD/cholestasis (2 studies; n = 40).PNALD/cholestasis was defined as conjugated bilirubin (Cbil) 2 mg/dL or greater and resolution of PNALD/cholestasis as Cbil less than 2 mg/dL. We put no restriction on timing of PNALD detection. There was heterogeneity in definitions and time points for detecting PNALD in the included studies.We found one study each in surgical infants and in infants with cholestasis, showing no evidence of difference in incidence or resolution of PNALD/cholestasis (Cbil cut-off: 2 mg/dL) with use of fish oil-containing LE compared to S-LE.We considered an outcome allowing for any definition of PNALD (different Cbil cut-off levels). In infants with surgical conditions and no pre-existing PNALD, meta-analysis showed no difference in the incidence of PNALD/cholestasis (any definition) with use of fish oil-containing LE compared to S-LE (typical risk ratio (RR) 1.20, 95% confidence interval (CI) 0.38 to 3.76; typical risk difference (RD) 0.03, 95% CI -0.14 to 0.20; 2 studies; n = 68; low-quality evidence). In infants with PNALD/cholestasis (any definition), use of fish oil-LEs was associated with significantly less cholestasis compared to the S-LE group (typical risk ratio (RR) 0.54, 95% confidence interval (CI) 0.32 to 0.91; typical risk difference (RD) -0.39, 95% CI -0.65 to -0.12; number needed to treat for additional beneficial outcome (NNTB) 3, 95% CI 2 to 9; 2 studies; n = 40; very low-quality evidence). This outcome had very low number of participants from two small studies with differences in study methodology and early termination in one study, which increased uncertainty about the effect estimates.One study in infants with cholestasis reported significantly better weight gain with a pure fish oil LE compared to a 10% S-LE (45 g/week, 95% CI 15.0 to 75.0; n = 16; very low-quality evidence). There were no significant differences in growth parameters in studies with surgical populations.For the secondary outcomes, in infants with cholestasis, one study (n = 24) reported significantly lower conjugated bilirubin levels but higher gamma glutamyl transferase levels with MOFS-LE (SMOFlipid) versus S-LE (Intralipid) and another study (n = 16), which was terminated early, reported significantly higher rates of rise in alanine aminotransferase (ALT) and conjugated bilirubin levels in the S-LE group compared to pure F-LE (Omegaven).In surgical infants, two studies each reported on hypertriglyceridaemia and Cbil levels with one study in each outcome showing significant benefit with use of a F-LE and the other study showing no difference between the groups. Meta-analysis was not performed for either of these outcomes as there were only two studies showing conflicting results with high heterogeneity between the studies.There was no evidence of differences in death, sepsis, alkaline phosphatase and ALT levels in infants with surgical conditions or cholestasis (very low-quality evidence).One study reported neurodevelopmental outcomes at six and 24 months in infants with surgical conditions (n = 11) with no evidence of difference with use of pure F-LE versus S-LE. Another study in infants with cholestasis (n = 16) reported no difference in head growth velocity between pure F-LE versus S-LE.GRADE quality of evidence ranged from low to very low as the included studies were small single-centre studies. Three of the six studies that contributed data to the review were terminated early for various reasons. Based on the current review, there is insufficient data from randomised studies to determine with any certainty, the potential benefit of any LE including fish oil-containing LEs over another LE, for prevention or resolution of PNALD/cholestasis or any other outcomes in term and late preterm infants with underlying surgical conditions or cholestasis. There were no studies in infants without surgical conditions or cholestasis.Further research is required to establish role of fish oil or lipids from other sources in LEs to improve PNALD/cholestasis, and other clinical outcomes in parenterally fed term and late preterm infants.


Assessing the use of co-design to produce bespoke assistive technology solutions within a current healthcare service: a service evaluation.
Co-design involves engaging with the end-user in the design process and may help reduce the barriers to assistive technology use. Previous research has used co-design in the provision of assistive technology, but no research has looked at applying it within a healthcare setting. This service evaluation examines the use of co-design in providing customized assistive devices within a current UK healthcare based Rehabilitation Engineering department. This evaluation reports on three case studies. Individuals identified a range of challenges in daily living. The participants worked with the clinician in trialling prototypes and providing feedback to develop custom devices. A mixed-method approach of questionnaires and semi-structured interviews were used to evaluate the devices provided and the co-design approach. The resources required to provide the device were also calculated. Five different devices were developed, which were able to overcome the challenges identified. Results indicated participants were satisfied with both the devices and service provided. Participants expressed other benefits including increased independence, increased positive emotions and reduced mental load. Participants indicated they liked being involved in the design process and their feedback helped ensure the devices were customized to their needs. The use of co-design was able to produce customized assistive device that met the needs of the individuals within a current healthcare service. Further work is required to assess the feasibility of utilising a co-design approach for the provision of other custom assistive technology in the future and explore if this can overcome the barriers to assistive technology use.Implications for rehabilitationEnd-user involvement, the design process can help enable customized assistive devices to be provided that better meet the user's needs.The custom assistive devices provided not only helped the individuals overcome the challenges identified but had wider reaching benefits for the individuals physical and mental health and wellbeing.End-users valued being able to input into the co-design process and working closely with the clinician in developing the device.


Site- and Structure-Specific Glycosylation Signatures of Bovine, Caprine, Porcine, and Human Milk-Derived Extracellular Vesicles.
Extracellular vesicles (EVs) are membrane-bound vesicles released by living cells. As vesicles for macromolecule transmission and intercellular communication, EVs are broadly applied in clinical diagnosis and biomimetic drug delivery. Milk-derived EVs (MEVs) are an ideal choice for scale-up applications because they exhibit biocompatibility and are easily obtained. Herein, intact glycopeptides in MEVs from bovines, caprines, porcines, and humans were comprehensively analyzed by high-resolution mass spectrometry using the sceHCD, followed by the EThcD fragment method, revealing that protein glycosylation is abundant and heterogeneous in MEVs. The dominant glycans in all MEVs were sialic acid-modified N-linked glycans (over 50%). A couple of species-specific glycans were also characterized, which are potentially markers of different original EVs. Interestingly, the Neu5Gc-modified glycans were enriched in caprine milk-derived EVs (58 ± 2%). Heterogeneity of MEV protein glycosylation was observed for glycosites and glycan compositions, and the structural heterogeneity of protein glycosylation was also identified and validated. The glycosignatures of EV biogenesis- and endocytosis-related proteins (CD63 and MFGE8) were significantly different in these four species. Overall, we comprehensively characterized the glycosylation signature of MEVs from four different species and provided insight into protein glycosylation related to drug target delivery.


The -403 G-->A promoter polymorphism in the RANTES gene is associated with atopy and asthma.
Asthma is a complex inflammatory condition often associated with bronchial hyperreactivity and atopy. Genetic and environmental factors are implicated and several candidate genes have been implicated. Of these, the chemokine RANTES is responsible for the recruitment of inflammatory cells such as eosinophils and T-lymphocytes. We have recently identified a polymorphism within the RANTES promoter (-403 G-->A) and have examined its role, using a PCR-RFLP assay, in the development of atopy and asthma in 201 Caucasian subjects. Atopic status was determined using skin prick testing and serum IgE levels. Severity of airway dysfunction was assessed using spirometric measurement (FEV1) and methacholine challenge (PC20). The -403 A allele was associated with an increased susceptibility to both atopy and asthma. Thus, the proportion of subjects carrying this allele was higher in each of atopic non-asthmatics, non-atopic asthmatics and atopic asthmatics compared with non-atopic, non-asthmatic controls. In particular, this allele was associated with skin test positivity but not IgE level. Homozygosity for the -403 A allele conferred a 6.5-fold increased risk of moderate/severe airway obstruction (FEV1 < or = 80% predicted), a marker for established asthma. Our data, whilst preliminary, indicate that the association of RANTES genotype with both atopy and asthma reflect independent effects, suggesting different mechanisms for the role of this chemokine in atopy and development of airway obstruction.


Viruses as vesicular carriers of the viral genome: a functional module perspective.
Enveloped viruses and cellular transport vesicles share obvious morphological and functional properties. Both are composed of a closed membrane, which is lined with coat proteins and encases cargo. Transmembrane proteins inserted into the membrane define the target membrane area with which the vesicle or virus is destined to fuse. Here we discuss recent insight into the functioning of enveloped viruses in the framework of the "functional module" concept. Vesicular transport is an exemplary case of a functional module, as defined as a part of the proteome that assembles to perform a specific autonomous function in a living cell. Cellular vesicles serve to transport cargo between membranous organelles inside the cell, while enveloped viruses can be seen as carriers of the viral genome delivering their cargo from an infected to an uninfected cell. The turnover of both vesicles and viruses involves an analogous series of submodular events. This comprises assembly of elements, budding from the donor compartment, uncoating and/or maturation, docking to and finally fusion with the target membrane to release the cargo. This modular perception enables us to define submodular building blocks so that mechanisms and elements can be directly compared. It will be analyzed where viruses have developed their own specific strategy, where they share functional schemes with vesicles, and also where they even have "hijacked" complete submodular schemes from the cell. Such a perspective may also include new and more specific approaches to pharmacological interference with virus function, which could avoid some of the most severe side effects.


High-flow nasal cannula and bilevel positive airway pressure for pediatric status asthmaticus: a single center, retrospective descriptive and comparative cohort study.
We aimed to describe patient characteristics and clinical outcomes for children hospitalized for status asthmaticus (SA) receiving high-flow nasal cannula (HFNC) or bilevel positive airway pressure (BiPAP). We performed a single center, retrospective cohort study among 39 children admitted for SA aged 5-17 years from January 2016 to May 2019 to a quaternary pediatric intensive care unit (PICU). Cohorts were defined by BiPAP versus HFNC exposure and assessed to determine if differences existed in demographics, anthropometrics, comorbidities, asthma severity indices, historical factors, duration of noninvasive ventilation, and asthma-related clinical outcomes (i.e. length of stay, mechanical ventilation rates, exposure to concurrent sedatives/anxiolysis, and rate of adjunctive therapy exposure). Thirty-three percent (n = 13) received HFNC (33%) and 67% (n = 26) BiPAP. Children receiving BiPAP had greater age (10.9 ± 3.7 vs. 6.8 ± 2.2 years, P < 0.01), asthma severity (proportion with severe NHLBI classification: 38% vs. 0%, P < 0.01; median pediatric asthma severity score: 13[12,14] vs. 10[9,12], P < 0.01), previous PICU admissions (62% vs. 15%, P = 0.01), frequency of prescribed anxiolysis/sedation (42% vs. 8%, P = 0.02), and median duration of continuous albuterol (1.7[1,3.1] vs. 0.9[0.7,1.6] days, P = 0.03) compared to those on HFNC. Those on HFNC more commonly were treated comorbid bacterial pneumonia (69% vs. 19%, P < 0.01). No differences in NIV duration, mortality, mechanical ventilation rates, or LOS were observed. Our data suggest a trial of BiPAP or HFNC appears well tolerated in children with SA. Prospective trials are needed to establish modality superiority and identify patient or clinical characteristics that prompt use of HFNC over BiPAP.


[Dexmedetomidine: new opportunities in anesthesiology].
Dexmedetomidine is a novel a,-agonist with unique characteristics. The review contains description of main pharmacological and physiological features of this drug. The experience of off-label using of dexmedetomidine in anesthesia is discussed in details. Authors consider that dexmedetomidine can improve anesthesia management in various clinical situations due to specific sedation profile similar to natural human sleep pattern. It can be helpful in neurosurgery in overweight patients or in patients with high cardiac risk as well as in pediatric practice.


Topical chemotherapy of intradermal Walker 256 carcinosarcoma with diaziquone and doxorubicin in the rat.
A model for metastatic skin cancer using intradermal injection of Walker 256 carcinosarcoma has been developed in the rat. Using this model, antitumor activity of topically applied doxorubicin and diaziquone in Vanicream, Plastibase, and dimethyl sulfoxide (DMSO) as vehicles was compared with intraperitoneal injection of the drugs at the same doses beginning 4 days after injection of tumor cells. Doxorubicin applied topically at 0.5 mg/day for 4 days in Vanicream or Plastibase exhibited no antitumor activity, while i.p. administered doxorubicin at 0.5 mg/day for 4 days inhibited tumor growth at day 20 by 66%. Diaziquone applied topically at 0.1 mg/day for 4 days in Vanicream, Plastibase, or DMSO inhibited tumor growth at day 20 by 66, 86, and 43%, respectively, and cured animals of the skin tumor at a dose of 0.5 mg/day. Diaziquone administered i.p. at 0.5 mg/day for 4 days was lethal to rats, and at 0.1 mg/day it produced 93% inhibition of tumor growth at day 20. Diaziquone applied topically at 0.1 mg/day for 4 days in Plastibase cured rats of advanced tumor when treatment was begun 12 days after injection of tumor cells. The area under the plasma radioactivity time curve over 5 h for a single 0.64-mg dose of topically applied [ring-14C]diaziquone in DMSO was 0.01% that of the same dose of [ring-14C]diaziquone administered i.p. in non-tumored rats. The decrease in WBC count following topical application of diaziquone at a dose of 0.1 mg/day for 4 days, compared to the same dose of diaziquone administered i.p., was 62% in Vanicream, 81% in Plastibase and 33% in DMSO. Topical diaziquone was non-toxic to normal skin in the rat and in the domestic pig. It is concluded that topical application of diaziquone offers a therapeutic advantage over systemic treatment for metastatic cancer of the skin.


Testosterone/androstenedione ratio in the evaluation of women with ovarian androgen excess.
A plasma testosterone/androstenedione (T/A) ratio was calculated in 15 women with possible ovarian neoplasms and androgen excess and whose mean plasma concentration of testosterone approached or was greater than a twofold elevation. The T/A ratio approached unity in eight of nine patients with polycystic ovarian disease, whereas all patients with hyperthecosis and two of three patients with androgen-secreting tumors had a testosterone/androstenedione ratio above 1.5. In 13 of 16 patients with androgen-secreting tumors of the ovary reported in the literature, the testosterone/androstenedione ratio was above 1.5. An elevated testosterone/androstenedione ratio should raise the suspicion of either an ovarian androgen-secreting tumor or hyperthecosis.


Role of hemibonding in the structure and ultraviolet spectroscopy of the aqueous hydroxyl radical.
The presence of a hemibond in the local solvation structure of the aqueous hydroxyl radical has long been debated, as its appearance in ab initio simulations based on density functional theory is sensitive to self-interaction error (favoring a two-center, three-electron hemibond) but also to finite-size effects. Simulations reported here use a mixed quantum mechanics/molecular mechanics (QM/MM) framework in a very large periodic simulation cell, in order to avoid finite-size artifacts and to facilitate testing of various density functionals, in order to probe the effects of delocalization error. The preponderance of hemibonded structures predicted by generalized gradient approximations persists in simulations using the hybrid functionals B3LYP and PBE0, but is reduced to a minor population if the fraction of exact exchange is increased to 50%. The hemibonded population is also small in simulations employing the long-range corrected functional LRC-ωPBE. Electronic spectra are computed using time-dependent density functional theory, and from these calculations emerges a consensus picture in which hemibonded configurations play an outsized role in the absorption spectrum, even when present as a minority species. An intense 1b2(H2O) → 2pπ(˙OH) charge-transfer transition in hemibonded configurations of the radical proves to be responsible for an absorption feature at 230 nm that is strongly shifted with respect to the gas-phase absorption at 307 nm, but this intense feature is substantially diminished in aqueous geometries where the hemibond is absent. Although not yet sufficient to quantitatively establish the population of hemibonded ˙OH(aq), these simulations do suggest that its presence is revealed by the strongly shifted ultraviolet absorption spectrum of the aqueous radical.


Curcumin in epilepsy disorders.
Curcumin, a principal curcuminoid present in turmeric, has an antioxidant, anti-inflammatory and neuroprotective properties. Preclinical studies have indicated its beneficial effect for the treatment of epilepsy disorders. The molecule has an anti-seizure potential in preclinical studies, including chemical and electrical models of acute and chronic epilepsy. Curcumin also possesses an anti-epileptogenic activity as it reduces spontaneous recurrent seizures severity in a kainate model of temporal lobe epilepsy. The antioxidant and anti-inflammatory nature of curcumin might be responsible for its observed anti-seizure effects; nevertheless, the exact mechanism is not yet clear. The poor availability of curcumin to the brain limits its use in clinics. The application of nanoliposome and liposome technologies has been tested to enhance its brain availability and penetrability. Unfortunately, there are no randomized, double-blinded controlled clinical trials validating the use of curcumin in epilepsy. The present article analyzes different preclinical evidence illustrating the effect of curcumin in seizure models. The review encourages carrying out clinical trials in this important area of research. In conclusion, curcumin might be beneficial in patients with epilepsy disorders, if its bioavailability issues are resolved.


Following mechanical activation of salbutamol sulphate during ball-milling with isothermal calorimetry.
Formulation of actives for pulmonary delivery with dry powder inhaler devices frequently requires a particle size reduction step. The high-energy forces imparted to a material during milling, as well as reducing particle size, can cause a significant change in physicochemical properties, in particular mechanical activation of the surface (manifested as generation of amorphous regions) which can affect formulated product performance. It is not clear whether particle size reduction occurs prior to, or concomitantly with, generation of amorphous content. In this study the formation of amorphous content with time in crystalline salbutamol sulphate was quantified with isothermal gas perfusion calorimetry as the sample was ball-milled. The data showed that the most particle size reduction occurred initially (d(0.5) dropping from 12.83+/-0.4 to 4.2+/-0.4 within 5 min). During this time period, no detectable amorphous content was observed. Between 5 and 15 min milling time the particle size distribution remained relatively constant but the amorphous content increased non-linearly with time. After 20 min milling time the particle size increased slightly. The data suggest that particle size reduction occurs initially upon application of a force to the crystal. Once maximum particle size reduction has occurred the crystal absorbs the force being applied and the crystal lattice becomes disordered. After extended milling the conditions in the ball mill (heat and/or humidity) may cause crystallisation of some of the amorphous material resulting in particle-particle fusion. It would appear that the ball-milling process could be optimised to achieve the desired particle size distribution but without any loss of crystalline structure.


Rationale and design of a randomized placebo-controlled trial assessing the effects of etiologic treatment in Chagas' cardiomyopathy: the BENznidazole Evaluation For Interrupting Trypanosomiasis (BENEFIT).
Benznidazole is effective for treating acute and chronic (recently acquired) Trypanosoma cruzi infection (Chagas' disease). Recent data indicate that parasite persistence plays a pivotal role in the pathogenesis of chronic Chagas' cardiomyopathy. However, the efficacy of trypanocidal therapy in preventing clinical complications in patients with preexisting cardiac disease is unknown. BENEFIT is a multicenter, randomized, double-blind, placebo-controlled clinical trial of 3,000 patients with Chagas' cardiomyopathy in Latin America. Patients are randomized to receive benznidazole (5 mg/kg per day) or matched placebo, for 60 days. The primary outcome is the composite of death; resuscitated cardiac arrest; sustained ventricular tachycardia; insertion of pacemaker or cardiac defibrillator; cardiac transplantation; and development of new heart failure, stroke, or systemic or pulmonary thromboembolic events. The average follow-up time will be 5 years, and the trial has a 90% power to detect a 25% relative risk reduction. The BENEFIT program also comprises a substudy evaluating the effects of benznidazole on parasite clearance and an echo substudy exploring the impact of etiologic treatment on left ventricular function. Recruitment started in November 2004, and >1,000 patients have been enrolled in 35 centers from Argentina, Brazil, and Colombia to date. This is the largest trial yet conducted in Chagas' disease. BENEFIT will clarify the role of trypanocidal therapy in preventing cardiac disease progression and death.


Combined effects of a parasite, QPX, and the harmful-alga, Prorocentrum minimum on northern quahogs, Mercenaria mercenaria.
Northern quahogs, Mercenaria mercenaria (L.), frequently are infected with the parasite Quahog Parasite Unknown (QPX, Labyrintohomorpha, Thraustochytriales), which can cause morbidity and mortality of the quahogs. Possible interactions between this parasitic disease and exposure to the harmful dinoflagellate Prorocentrum minimum in M. mercenaria were studied experimentally. Quahogs from Massachusetts with variable intensity of QPX infection were exposed, under controlled laboratory conditions, to cultured P. minimum added to the natural plankton at a cell density equivalent to a natural bloom. After 5 days of exposure, individual clams were diagnosed histologically to assess prevalence and intensity of parasitic infection, as well as other pathological conditions. Further, cellular defense status of clams was evaluated by analyzing hemocyte parameters (morphological and functional) using flow-cytometry. Exposure of quahogs to P. minimum resulted in: a lower percentage of phagocytic hemocytes, higher production of reactive oxygen species (ROS), larger hemocyte size, more-numerous hemocytic aggregates, and increased numbers of hemocytes in gills accompanied by vacuolation and hyperplasia of the water-tubular epithelial cells of the gills. Quahogs had a low prevalence of QPX; by chance, the parasite was present only in quahogs exposed to P. minimum. Thus, the effect of QPX alone on the hemocyte parameters of quahogs could not be assessed in this experiment, but it was possible to assess different responses of infected versus non-infected quahogs to P. minimum. QPX-infected quahogs exposed to P. minimum had repressed percentage of phagocytic hemocytes, consistent with immuno-modulating effect of P. minimum upon several molluscan species, as well as smaller hemocytes and increased hemocyte infiltration throughout the soft tissues. This experiment demonstrates the importance of considering interactive effects of different factors on the immunology and histopathology of bivalve shellfish, and highlights the importance of considering the presence of parasites when bivalves are subjected to harmful-algal blooms.


Culture expansion induces non-tumorigenic aneuploidy in adipose tissue-derived mesenchymal stromal cells.
Adipose tissue-derived mesenchymal stromal cells (ASCs) are of interest as a cell therapeutic agent for immunologic and degenerative diseases. During in vitro expansion, ASCs may be at risk for genetic alterations, and genetic screening is a prerequisite. We examined the presence of aneuploidy in ASCs and its origin and development during culture and evaluated the implications of aneuploidy for therapeutic use of ASCs. Adipose tissue of healthy individuals was used for isolation and expansion of ASCs. Chromosome copy numbers were studied using fluorescence in situ hybridization analysis. Aneuploidy was studied in freshly isolated ASCs, in ASCs cultured for 0-16 passages and in senescent cultures. To evaluate the plasticity of ploidy, ASCs were cloned, and the variation of ploidy in the clones was examined. Tumorigenicity was studied by subcutaneous injection of aneuploid ASCs in immunodeficient NOD/SCID mice. No aneuploidy was detected in freshly isolated ASCs. In low passages (passages 0-4), aneuploidy was detected in 3.4% of ASCs. Prolonged culture expansion of ASCs (passages 5-16) resulted in a significant increase of aneuploidy to 7.1%. With senescence, aneuploidy increased further to 19.8%. Aneuploidy was observed in clones of diploid ASCs, demonstrating the de novo development of aneuploidy. No transformation of ASCs was observed, and in contrast to cancer cell lines, aneuploid ASCs were incapable of tumor formation in immunodeficient mice. ASC cultures contain a stable percentage of aneuploid cells. Aneuploidy was not a predecessor of transformation or tumor formation. This finding indicates that aneuploidy is culture-induced but unlikely to compromise clinical application of ASCs.


Effect of Ca2(+)-channel agonists and antagonists on skeletal muscle sugar transport.
The purpose of this study was to determine whether changes in cellular Ca2+ caused by Ca2(+)-channel modifiers affect skeletal muscle sugar transport. Rat soleus muscles were isolated, and sugar transport was measured monitoring efflux of 3-O-methylglucose (3-MG). Muscles were "loaded" with 3-O-[methyl-14C]methyl-D-glucose in Krebs-Ringer-bicarbonate (KRB) media and then sequentially washed in radioisotope-free KRB. Cellular Ca2+ was modified by adding a Ca2+ agonist (BAY K 8644) and/or Ca2+ antagonists (nifedipine, nitrendipine, diltiazem) to the "load" and "wash" media. Alterations in cellular Ca2+ were determined from soleus muscle 45Ca2+ uptake measurements. Addition of 0.25 microM BAY K 8644 enhanced insulin-mediated 3-MG transport and 1 microM nifedipine prevented the agonist effect. A high concentration of BAY K 8644 (6 microM) led to increased basal but attenuated insulin-mediated 3-MG transport. Nifedipine (4 microM) and diltiazem (20 microM) blocked the BAY K 8644-induced changes in basal and insulin-mediated 3-MG transport. Nifedipine (4 microM) also attenuated the stimulation of cellular Ca2+ uptake by 6 microM BAY K 8644. Nitrendipine was unable to reverse the changes in basal or insulin-mediated 3-MG transport caused by BAY K 8644. These results indicate that a low concentration of BAY K 8644 enhanced insulin-stimulated skeletal muscle sugar transport, whereas a high concentration of the agonist led to a diminished ability of insulin to stimulate sugar transport. The effects of the Ca2+ agonist were presumably mediated through modulation of cellular Ca2+ as these effects were blunted by the Ca2+ antagonists.


Hepatitis B Virus Modulated Transcriptional Regulatory Map of Hepatic Cellular MicroRNAs.
Hepatitis B virus (HBV) is an enveloped, hepatotropic, noncytopathic virus with a partially double-stranded DNA genome. It infects hepatocytes and is associated with progression to liver fibrosis and cirrhosis, culminating in hepatocellular carcinoma (HCC), accounting for 55% of total HCC cases. MicroRNAs (miRNAs) regulated by HBV play an important role in these pathologies. Mapping the miRNAs responsive to HBV and HBV-specific proteins, including HBV X protein (HBx) that harbor the majority of HBV-human protein interactions, could aid accelerate the diagnostics and therapeutics innovation against the infection and associated diseases. With this in mind, we used a unique annotation strategy whereby we first amassed 362 mature HBV responsive-human Differentially Expressed miRNAs (HBV-hDEmiRs). The core experimentally-validated messenger RNA targets of the HBV-hDEmiRs were mostly associated with viral infections and hepatic inflammation processes. Moreover, our annotation strategy enabled the characterization of HBx-dependent/independent HBV-hDEmiRs as a tool for evaluation of the impact of HBx as a therapeutic target. Bioinformatics analysis of the HBV-human protein-protein interactome revealed new insights into the transcriptional regulatory network of the HBV-hDEmiRs. We performed a comparative analysis of data on miRNAs gathered from HBV infected cell line studies and from tissue studies of fibrosis, cirrhosis, and HCC. Accordingly, we propose hsa-miR-15a-5p that is downregulated by multiple HBV proteins, including HBx, as a potential biomarker of HBV infection, and its progression to HCC. In all, this study underscores (1) the complexity of miRNA regulation in response to HBV infection and its progression into other liver pathologies and (2) provides a regulatory map of HBV-hDEmiRs and the underlying mechanisms modulating their expression through a cross talk between HBV viral proteins and human transcription factors.


[Anatomically adapted endoprosthesis of the proximal end of the femur].
The marrow-cavities of several human femora were cleaned and filled with plastics; the femoral component design was developed based on these moulds. Different sizes of the stem were obtained by scaling down the biggest mould in steps of 10%. The stem has an oval cross-section and is twisted similar to the form of the marrow-cavity; therefore different designs for the left and right femur are necessary. As the marrow-cavity of the femur tapers down to the middle of the shaft the length of the prosthetic stem cannot be selected arbitrarily. The stem must end above the narrowest site of the cavity. Data are presented. To avoid disadvantageous frictional stresses between the collar of the prosthesis and the plane of resection of the femoral neck both must be aligned perpendicular to the most common direction of the load of the hip joint. Therefore a step-like osteotomy of the femoral neck becomes necessary without disturbing the calcar femorale instead of an inclined osteotomy. A firm contact between the femoral wall and the collar, which forms an angle of 64 degrees with the axis of the femoral shaft, guarantees that only small frictional stresses occur between collar and femoral cortex if the load of the hip joint varies within the physiological range. A set of ceramic femoral heads with three different conical borings yield different lengths of the neck of the prosthesis. Independent of which femoral head and which size of prosthesis are chosen the direction of the maximum hip load in any case thrusts the contact area between collar and femoral wall. Thus dangerous tilting moments round the medial calcar femorale do not occur, the incidence of a fracture of the prosthesis shaft is therefore reduced. After implantation of the anatomically designed femoral component both remodeling and resorption of the calcar femorale are observed. This reaction is independent of the kind of fixation, i.e. if a smooth stem was fixed with cement or a stem with a porous, cancellous bone-like metallic surface was implanted without cement fixation.(ABSTRACT TRUNCATED AT 250 WORDS)


A systematic review on self-management education campaigns for back pain.
Evidence-based clinical practice guidelines on back pain recommend early management and use of approaches that emphasise self-management, psychological and physical therapies. Lately, mass media campaigns, addressing misconceptions about back pain, have been conducted in developed countries. This study retrieved and synthesised the contents of back pain messages and described the outcomes and effectiveness of the media campaigns. Seventeen key words and 10 electronic databases were used to conduct a search between February and July 2018. Authors screened titles, abstracts and full-text articles independently to identify eligible studies. Data were reported using narratives because of heterogeneity in the outcomes. Appraisal of articles was done using the Physiotherapy Evidence Database scale for randomised controlled trials (RCT) (one) or the Joanna Briggs Institute checklist for non-RCT (four). The campaigns were conducted in the general population in Australia, Canada, Norway, the Netherlands and Scotland. The message 'stay as active as possible' increased participants' awareness and influenced their health beliefs and healthcare utilisation behaviours resulting in reductions in sick leave days, work disability, healthcare utilisation and claims. The back pain campaign message 'stay as active as possible' increased participants' awareness and influenced their health beliefs and healthcare utilisation behaviours. Even though the campaigns were done in high-income countries, their contents and methods are transferable to developing countries. However, their implementation must be tailored and efficient and cost-effective methods need to be explored. Providing information on back pain can contribute to significant changes in sickness behaviours and beliefs.


A Quality Improvement (QI) initiative in diagnostic stewardship of urine culture in an era of Laboratory Information Systems (LIS).
Standard urine culture is the gold standard for diagnosing urinary tract infections (UTIs) but fails to differentiate true UTI from asymptomatic bacteriuria, which is important to prevent the overuse of antibiotics. Correlation with the presence or absence of pyuria can be helpful in giving a hint of the true situation. With the help of Laboratory Information System (LIS), patients' urinalysis reports can be conveniently accessed and compared simultaneously with appropriate reports. In our study, a quality improvement initiative was planned for appropriate reporting of urine culture and antimicrobial susceptibility testing using information obtained through LIS.


Inter-professional education and primary care: EFPC position paper.
Inter-professional education (IPE) can support professionals in developing their ability to work collaboratively. This position paper from the European Forum for Primary Care considers the design and implementation of IPE within primary care. This paper is based on workshops and is an evidence review of good practice. Enablers of IPE programmes are involving patients in the design and delivery, providing a holistic focus, focussing on practical actions, deploying multi-modal learning formats and activities, including more than two professions, evaluating formative and summative aspects, and encouraging team-based working. Guidance for the successful implementation of IPE is set out with examples from qualifying and continuing professional development programmes.


First-principles prediction of infrared phonon and dielectric function in biaxial hyperbolic van der Waals crystal α-MoO3.
Layered biaxial hyperbolic molybdenum trioxide (α-MoO3) with weak van der Waals (vdW) interlayer bonding recently received extensive attention due to its anisotropic dielectric response to infrared (IR) radiation, which couples to the lattice vibrations and allows for manipulating the radiative energy transport. However, the understanding of IR-active phonon modes and dielectric function of it has not yet been fully achieved. Here, by utilizing mode-level first-principles analysis based on density functional theory (DFT), the phonon modes contributing to the IR dielectric response of α-MoO3 are fully determined. The anisotropic IR-active modes are identified from lattice vibration analysis, allowing for a clear evaluation of the IR absorption contribution from the weak or strong IR phonon modes. By further employing anharmonic-lattice dynamics calculations, the damping of the corresponding IR modes is directly obtained. This approach enables predictions of IR optical properties without any fitting or assumed parameters. Our predictions bridge the scientific gap of comprehensively understanding the unreported IR-active phonon modes of α-MoO3 and overall agree well with available experimental data, placing our DFT-based method at a privileged stage for accurately predicting the IR optical properties of α-MoO3. These comprehensive understandings of the IR phonons and dielectric properties of α-MoO3 pave the way for nanophotonic devices with tunable functionalities and enable design of α-MoO3 for advanced optical devices.


Radiologic classification of posterior dislocations of the hip: refinements and pitfalls.
Seventeen traumatic hip dislocations seen during a 15-month period were evaluated. In 10 of the 14 cases of posterior hip dislocation, the final Thompson-Epstein classification differed from the initial radiographic classification. Dislocations of the hip often result in radiographically obscure femoral head and acetabular damage. High quality radiographs with oblique and coned-down views are of substantial aid in evaluating the dislocated hip. After closed reduction of a dislocated hip, further views and tomography are helpful but diagnostic pitfalls exist. A persistently widened hip joint, even with negative plain films and tomography, indicates possible intra-osteochondral debris or incompletely reduced femoral head fragments.


Arthroscopically-assisted semitendinosus and gracilis tendon graft for anterior and posterior cruciate ligament deficiency.
A simple, reliable, arthroscopically-assisted procedure is presented in which a doubled and suture woven semitendinosus and gracilis free tendon graft is used in the anterior or posterior cruciate ligament deficient knee. A ligament guide system is used for isocentric placement of tibial and femoral drill holes. The procedure is performed using a button and staple technique that allows accurate placement of the ligament substitution and facilitates early ambulation. At an average follow-up of 2.5 years, good and excellent results have been demonstrated in 97% of 74 knees in which this technique was used, with only a 3% risk of graft failure.


The perspectives and the challenges of Paediatric Radiology: An interview with Dr Georgia Papaioannou, Head of the Paediatric Radiology Department at the 'Mitera' Children's Hospital in Athens, Greece.
Dr Georgia Papaioannou, MD, PhD, Head of the Paediatric Radiology Department at 'Mitera' Children's Hospital in Athens (Greece), is one of the most talented Paediatric Radiologists in Greece. She graduated from the Medical School of Athens of the National and Kapodistrian University of Athens in 1996 and she was trained in Radiology at the 2nd Department of Radiology of the Medical School of Athens and in Paediatric Radiology in Great Ormond Street Hospital for Children (GOSH) in London (UK). Her special interests focus on foetal magnetic resonance imaging (MRI) and special applications of paediatric MRI, such as MR enterography and MR urography. According to Dr Papaioannou, medical education in Paediatric Radiology has to be of excellent quality, raising professional career and academic opportunities. Paediatric Radiology focuses on the diagnostic imaging of foetuses, neonates, infants, children and adolescents and represents the oldest subspecialty of Radiology. The advent in technology and computer science, which is strongly associated with Radiology, has launched a new era for Paediatric Radiology training and practice. Digital imaging and archiving, telemedicine, fused imaging, evolution of sonographic equipment, computed tomography (CT) and MRI scanners have opened new horizons to the understating of paediatric physiology and pathophysiology and have contributed significantly in precision Medicine and the implication of targeted therapies into clinical practice. Modern paediatric imaging focuses on radiation protection issues and launches faster sequences in all modalities, in order to reduce the number and duration of sedation. The diagnosis of neonatal and paediatric viral infections is routinely clinical and laboratory; however, Paediatric Radiology assists the diagnostic approach by excluding other entities, if that is required, i.e., in complex cases or hospitalized children, and mainly by revealing associated complications.


Prostate Cancer Radiation Therapy: What Do Clinicians Have to Know?
Radiotherapy (RT) for prostate cancer (PC) has steadily evolved over the last decades, with improving biochemical disease-free survival. Recently population based research also revealed an association between overall survival and doses ≥ 75.6 Gray (Gy) in men with intermediate- and high-risk PC. Examples of improved RT techniques are image-guided RT, intensity-modulated RT, volumetric modulated arc therapy, and stereotactic ablative body RT, which could facilitate further dose escalation. Brachytherapy is an internal form of RT that also developed substantially. New devices such as rectum spacers and balloons have been developed to spare rectal structures. Newer techniques like protons and carbon ions have the intrinsic characteristics maximising the dose on the tumour while minimising the effect on the surrounding healthy tissue, but clinical data are needed for confirmation in randomised phase III trials. Furthermore, it provides an overview of an important discussion issue in PC treatment between urologists and radiation oncologists: the comparison between radical prostatectomy and RT. Current literature reveals that all possible treatment modalities have the same cure rate, but a different toxicity pattern. We recommend proposing the possible different treatment modalities with their own advantages and side-effects to the individual patient. Clinicians and patients should make treatment decisions together (shared decision-making) while using patient decision aids.


Leaf traits and decomposition in tropical rainforests: revisiting some commonly held views and towards a new hypothesis.
Proper estimates of decomposition are essential for tropical forests, given their key role in the global carbon (C) cycle. However, the current paradigm for litter decomposition is insufficient to account for recent observations and may limit model predictions for highly diverse tropical ecosystems. In light of recent findings from a nutrient-poor Amazonian rainforest, we revisit the commonly held views that: litter traits are a mere legacy of live leaf traits; nitrogen (N) and lignin are the key litter traits controlling decomposition; and favourable climatic conditions result in rapid decomposition in tropical forests. Substantial interspecific variation in litter phosphorus (P) was found to be unrelated to variation in green leaves. Litter nutrients explained no variation in decomposition, which instead was controlled primarily by non-lignin litter C compounds at low concentrations with important soil fauna effects. Despite near-optimal climatic conditions, tropical litter decomposition proceeded more slowly than in a climatically less favourable temperate forest. We suggest that slow decomposition in the studied rainforest results from a syndrome of poor litter C quality beyond a simple lignin control, enforcing energy starvation of decomposers.We hypothesize that the litter trait syndrome in nutrient-poor tropical rainforests may have evolved to increase plant access to limiting nutrients via mycorrhizal associations.


pfmdr2 confers heavy metal resistance to Plasmodium falciparum.
Heavy metals are required by all organisms for normal function, but high levels of heavy metals are toxic. Therefore, homeostasis of these metals is crucial. In the human malaria-causing agent Plasmodium falciparum, the mechanisms of heavy metal transport have yet to be characterized. We have developed a P. falciparum line resistant to heavy metals from a wild-type line sensitive to heavy metals. A molecular and biochemical analysis of the involvement of the P. falciparum multidrug resistance 2 (pfmdr2) gene, an ABC-type transporter, in heavy metal homeostasis was studied. Using a novel uptake assay applied on these two strains, it was demonstrated that, when exposed to heavy metals, the sensitive line accumulates metal, whereas no accumulation was observed in the resistant line. The accumulation occurs within the parasite itself and not in the cytoplasm of the red blood cell. This difference in the accumulation pattern is not a result of amplification of the pfmdr2 gene or of a change in the expression pattern of the gene in the two lines. Sequencing of the gene from both lines revealed a major difference; a stop codon is found in the sensitive line upstream of the normal termination, resulting in a truncated protein that lacks 188 amino acids that contain a portion of the essential cytoplasmatic transporter domain, thereby rendering it inactive. In contrast, the resistant line harbors a full-length, active protein. These findings strongly suggest that the PFMDR2 protein acts as an efflux pump of heavy metals.


Percutaneous endovascular treatment of peripheral aneurysms.
To evaluate the feasibility and efficacy of percutaneous endovascular treatment of peripheral aneurysms. Forty-eight patients, M: 41, F: 7, mean age: 65.7 +/- 10.1 years (47-85 years), with 50 aneurysms were treated: 45 with covered stents (Cragg/Passager 22, Corvita 21, Wallgraft 1, Endotex 1) 4 with non-covered stents and 1 with stent graft. Twenty-six aneurysms located at the iliac artery, 12 at the femoral and 12 at the popliteal artery. Mean lesion length: 61.1 +/- 21.3 mm. Percutaneous approach used in all cases, femoral antegrade (n=24), retrograde (n=23), contralateral (n=2), popliteal (n=1). Stents used were 6-12 mm in diameter and 30-120 mm in length. Multiple stents used to cover all lesions in 20 cases. Immediate technical success was 96% (48/50). In 1 case of long, tortuous femoropopliteal aneurysm, it was impossible to cover the low part, due to rigidity of the device used, in 1 case of large iliac aneurysm there was incomplete immediate exclusion. No complication during the procedure. Four patients developed non-infectious fever/local pain. Eight thromboses occurred: 2 at iliac, 1 at femoral and 5 at the popliteal level. All other stents remained patent, the aneurysms completely excluded over a mean follow-up of 20.6 +/- 13.2 m, maximum 61 m. Primary patency: all lesions 82%, iliac 92%, femoropopliteal 78%. Secondary patency: all lesions 88%, iliac 96%, femoropopliteal 86%. Percutaneous endoluminal treatment of peripheral aneurysms seems safe and effective with high technical success and good long-term results, except for popliteal localization. It could be an alternative to surgery.