Tissue Hypoxia and Alterations in Microvascular Architecture Predict Glioblastoma Recurrence in Humans.
Insufficient control of infiltrative glioblastoma (GBM) cells is a major cause of treatment failure and tumor recurrence. Hence, detailed insights into pathophysiologic changes that precede GBM recurrence are needed to develop more precise neuroimaging modalities for tailored diagnostic monitoring and therapeutic approaches. Overall, 168 physiologic MRI follow-up examinations of 56 patients with GBM who developed recurrence after standard therapy were retrospectively evaluated, that is, two post-standard-therapeutic follow-ups before and one at radiological recurrence. MRI biomarkers for microvascular architecture and perfusion, neovascularization activity, oxygen metabolism, and hypoxia were determined for brain areas that developed in the further course into recurrence and for the recurrent GBM itself. The temporal pattern of biomarker changes was fitted with locally estimated scatterplot smoothing functions and analyzed for pathophysiologic changes preceding radiological GBM recurrence. Our MRI approach demonstrated early pathophysiologic changes prior to radiological GBM recurrence in all patients. Analysis of the time courses revealed a model for the pathophysiology of GBM recurrence: 190 days prior to radiological recurrence, vascular cooption by GBM cells induced vessel regression, detected as decreasing vessel density/perfusion and increasing hypoxia. Seventy days later, neovascularization activity was upregulated, which reincreased vessel density and perfusion. Hypoxia, however, continued to intensify for 30 days and peaked 90 days before radiological recurrence. Hypoxia may represent an early sign for GBM recurrence. This might become useful in the development of new combined diagnostic-therapeutic approaches for tailored clinical management of recurrent GBM. Further preclinical and in-human studies are required for validation and evaluation.


Interpersonal emotion regulation.
Contemporary emotion regulation research emphasizes intrapersonal processes such as cognitive reappraisal and expressive suppression, but people experiencing affect commonly choose not to go it alone. Instead, individuals often turn to others for help in shaping their affective lives. How and under what circumstances does such interpersonal regulation modulate emotional experience? Although scientists have examined allied phenomena such as social sharing, empathy, social support, and prosocial behavior for decades, there have been surprisingly few attempts to integrate these data into a single conceptual framework of interpersonal regulation. Here we propose such a framework. We first map a "space" differentiating classes of interpersonal regulation according to whether an individual uses an interpersonal regulatory episode to alter their own or another person's emotion. We then identify 2 types of processes--response-dependent and response-independent--that could support interpersonal regulation. This framework classifies an array of processes through which interpersonal contact fulfills regulatory goals. More broadly, it organizes diffuse, heretofore independent data on "pieces" of interpersonal regulation, and identifies growth points for this young and exciting research domain.


Calcium and vitamin D supplementation: state of the art for daily practice.
Calcium and vitamin D play an essential role in bone metabolism but deficiency and/or inadequate intake are common. To describe a practical approach based on the literature regarding clinically important aspects of calcium and vitamin D supplementation. A systematic evaluation of relevant literature in Medline was conducted. We included physiological studies, publications on relevant guidelines, meta-analysis, randomized clinical trials, and cohort studies. An adequate calcium intake and vitamin D supplementation is recommended in most guidelines xon fracture prevention. Daily supplementation with 800 IU is advocated in most guidelines, appears to be safe, and with this approach it is generally not necessary to determine vitamin D levels. There are no data on additional effects of loading doses of vitamin D on fracture or fall prevention. Calcium supplementation should be tailored to the patient's need: usually 500 mg per day is required. The intestinal absorption of calcium citrate is approximately 24% better than that of calcium carbonate independent of intake with meals. Data on difference between calcium absorption with calcium carbonate compared to calcium citrate with simultaneous use of proton pump inhibitors are lacking. Concern has arisen about a possible link between calcium supplementation and an increased risk of myocardial infarction. Probably only well-designed prospective randomized controlled trials will be able to allow definite conclusions on this subject. Daily supplementation with 800 IU vitamin D is a practical and safe strategy without the need for prior determination of vitamin D levels. Calcium supplementation should be tailored to the patient's need based on total daily dietary calcium intake. In most patients 500 mg per day is required to achieve a total intake of 1,200 mg, or in some 1,000 mg per day. More calcium is absorbed from calcium citrate compared to calcium carbonate.


Allergen-specific immunotherapy in childhood asthma.
Immunotherapy has been shown to prevent rhinitis symptoms in seasonal allergic rhinitis, and to prevent anaphylaxis to hymenoptera and fire ant stings. The evidence supporting its effectiveness in the treatment of asthma is much more limited; it appears that clinical trials, until the past year, have only tested therapy for single allergens such as house dust mite, cats, pollen, and mold. In the past year, a double-blind placebo-controlled clinical trial was completed that tested immunotherapy with a mixture of multiple allergen extracts in 121 perennial asthmatic children. This was the first test of treatment with allergen mixtures. The trial showed that over 30% of children underwent a complete or partial remission during the 2.5 years of therapy, but the changes were almost identical in both treatment and placebo control groups. Other trials were reported that examined injection therapy using synthetic fragments of the major allergen responsible for allergic reactions to cats. In this trial, acute rhinitis and asthma during exposure to naturally occurring airborne particles of cat allergen were reduced significantly.


Differential diagnosis of congenital muscular dystrophies.
Congenital muscular dystrophies (CMDs) are defined by signs of muscle weakness in the first 6 months of life with myopathic changes in muscle biopsy. The progress in the last decade has helped to make molecular and genetic diagnoses in the majority of patients fulfilling these criteria. In a number of patients a definite diagnosis cannot be reached and these individuals are often grouped together as "merosin positive" congenital muscular dystrophy. In the last 5 years, 25 patients referred for assessment as possible congenital muscular dystrophy have been found to have alternative diagnoses. This paper aims to highlight these conditions as the common differentials or more difficult to diagnoses to consider in patients presenting as CMD.


A Case of Atypical Adult Presentation of Urea Cycle Disorder.
Urea cycle disorders are metabolic disorders of nitrogenous waste substances due to either complete or partial deficiency of enzymes. Hyperammonemia associated with urea cycle disorders should be addressed immediately in the acute setting, as it can cause irreversible neurological injury or death. We report the case of a 48-year-old woman who presented with lethargy, weakness, and altered mental status following prolonged nausea and vomiting despite an esophageal dilatation procedure 3 weeks prior. Further investigation with assistance from the genetics consult team revealed a partial enzyme deficiency associated with urea cycle disorder. Although many cases of urea cycle disorder present in neonates 24 to 48 hours following birth, a delayed presentation may be observed in female carriers with partial activity of any urea cycle enzyme leading to ammonia buildup. This is the result of stress-related events that form a catabolic state involving protein breakdown within the body that trigger increased ammonia levels. A diagnosis of urea cycle disorder should be suspected in patients who have had a recent stressor with progressive lethargy and confusion associated with hyperammonemia, so that treatment may begin with intravenous sodium benzoate and phenylacetate initially and hemodialysis at 8 hours if ammonia levels do not decrease to avoid permanent neurologic damage.


Calcaneo-stop procedure for paediatric flexible flatfoot.
Flexible flatfoot is a frequent deformity found in children. The aim of this study is to evaluate the pedographic outcome of the percutaneous arthroereisis with the use of a screw through the sinus tarsi into the talus. 43 calcaneo-stop procedures of 25 patients (18 bilateral, seven unilateral) were evaluated. Mean age at surgery was 10 years (7-14, SD 2.2) (SD: standard deviation), mean follow-up time was 9.7 months (3-19, SD 5.5). Patient satisfaction rate was recorded, the Meary's talus-first metatarsal angle was measured with lateral radiograms, and a dynamic pedographic assessment was also performed. Patient satisfaction rate was excellent for 33 feet of 19 children, good for eight feet of five children, and poor for either feet of one child. We did not observe any complications during or following the surgery.The mean rest heel valgus decreased from 13.4° (10°-17°, SD 1.5) to 2.8° (0°-6°, SD 1.7) post op. The Meary's angle improved from 160.2° (148°-177°, SD 6.8) to 175.9° (167°-179°, SD 3.5). By pedographic analysis, the area and the pressure-time integral (load amount, PTI) values increased on the lateral regions of the sole (except for the lesser toes) and decreased on the medial areas (except for the hallux). The relative contact time in the lateral midfoot increased from 63.8% (39.6-78.4%, SD 10.6) to 75.1% (50-86.1%, SD 9.4), and that in the lateral forefoot region from 81.2% (60.4-89.2%, SD 6.6) to 86.8% (78.1-97.1%, SD 4.8). The calcaneo-stop procedure is a simple and reliable method for the correction of severe flexible paediatric flatfoot. Our prospective, short-term results following the anterograde screw implantation into the talus correlate well with the results of similar or different arthroereisis methods. Further investigations are required to evaluate the long-term outcome of the screw calcaneo-stop method, including the conditions following implant removal.


PROP1 overexpression in corticotrophinomas: evidence for the role of PROP1 in the maintenance of cells committed to corticotrophic differentiation.
The expression of transcription factors involved in early pituitary development, such as PROP1 and POU1F1, has been detected in pituitary adenoma tissues. In this study, we sought to characterize the transcriptional profiles of PROP1, POU1F1, and TBX19 in functioning and nonfunctioning pituitary adenomas in an attempt to identify their roles in tumorigenesis and hormone hypersecretion. RT-qPCR analyses were performed to assess the transcriptional pattern of PROP1, POU1F1, TBX19, and hormone-producing genes in tissue samples of corticotrophinomas (n=10), somatotrophinomas (n=8), and nonfunctioning adenomas (n=6). Compared with normal pituitary tissue, POU1F1 was overexpressed in somatotrophinomas by 3-fold. PROP1 expression was 18-fold higher in corticotrophinomas, 10-fold higher in somatotrophinomas, and 3-fold higher in nonfunctioning adenomas. TBX19 expression was 27-fold higher in corticotrophinomas. Additionally, the level of TBX19 mRNA positively correlated with that of pro-opiomelanocortin (r=0.49, p=0.014). Our data demonstrate that PROP1 is overexpressed in pituitary adenomas, mainly in corticotrophinomas. Together with previously published data showing that patients who harbor PROP1 loss-of-function mutations present a progressive decline in corticotrope function, our results support a role for PROP1 in pituitary tumor development and in the maintenance of cell lineages committed to corticotrophic differentiation.


[State of GABA-benzodiazepine receptor complex in diabetic neuropathy: effect of nicotinamide and nicotinoyl-GABA].
An increase in GABA uptake by isolated rat brain synaptic endings as well as a decrease of pharmacologically active GABA analogue muscimol specific binding have indicated a physiologically drastic failure in realization of GABA-mediated inhibitory effects in CNS induced by diabetic encephalopathy. In spite of the impairment of inhibitory function of GABAergic transmission in diabetes a crucial activation of benzodiazepine receptors was determined, as it is tested by the increase in specific binding of flunitrazepam by synaptic membranes. This increase may play an important role in endogenous control of neural activity associated with the factors undefined so far. Using the approach that GABA, and several synthetic GABA agonists, appear to increase the affinity of the benzodiazepine recognition sites for such ligands, presumably by some allosteric mechanism, the findings concerning the in vitro binding assay technique confirm at least some of the functional characteristics observed between GABA and benzodiazepine receptors in vivo under pathological conditions. Indeed, the absence of activating effect on the affinity of flunitrazepam specific binding in the presence of micromolar concentrations of exogenous GABA implicate diabetes-induced alterations in coupling GABA- and benzodiazepine receptors that might be linked to changes in conformantial state of this membrane-bound complex and could partially explain diabetes-induced impairments of GABAergic transmission evaluated in the present study. Our study suggests that nicotinamide and especially GABA play an important role in improving the functioning of brain GABA-benzodiazepine complex impaired in diabetes through specific ligand-mediated mechanism and can be useful in the management of diabetes-associated brain failures.


Laser induced injury caused hyperglycemia-like effect in Drosophila larva: a possible insect model for posttraumatic diabetes.
Diabetic patients need particular care in case of infection, digestive disorder or external injury, because external stress often exasperates the glucose metabolism, which is known as "sick day management". In addition, severe trauma can be a cause of hyperglycemia with insulin resistance. In spite of critical component of the treatment, the precise mechanisms of how trauma develops posttraumatic diabetes remain unknown. Here, we ablated body wall muscles in Drosophila larvae by laser beam and found that the level of trehalose, the principal sugar circulating in the hemolymph or in the tissues of most insects, was increased. The model may provide a helpful tool to understand the relationship between trauma and sugar metabolism.


EVALUATION OF PREIMPLANTATION GENETIC ANEUPLOIDY SCREENING CASES AT A REFERENCE GENETICS CENTER: 10 YEARS' EXPERIENCE.
The aim of this study is to review and evaluate our preimplantation genetic screening (PGS) records in terms of their demographic data, indications, cytogenetic results, pregnancy outcomes and discuss these findings in different aspects. PGS was performed in a total of 84 couples (87 cycles) between the period 2005 to 2015. Biopsied blastomeres from embryos on day 3 were fixed and fluorescence in situ hybridization was carried out for chromosomes 13, 16, 18, 21, 22, X and Y depending on the indication. The diagnostic and clinical data were retrospectively evaluated. A total of 450 blastomeres were biopsied. Ninety-eight of them were found to be suitable for transfer. They were transferred to 72 patients in 75 cycles resulting in 23 pregnancies and 20 healthy births. The most common indication was unexplained infertility. The implantation rate was calculated as 23.4% whereas the take-home baby rate was 26.6% per transfer. The highest rate of healthy living births is achieved in patients having low grade maternal mosaic sex chromosomal aneuploidy. All living births achieved by PGS had normal chromosomal structure which we can propose it as an alternative test for couples at risk to select normal embryos to improve the outcomes of assisted reproductive procedures and to avoid the transfer of chromosomally unbalanced and multiple embryos.


Atopy patch test to Dermatophagoides mix in a self-selected population in Beijing.
Dermatophagoides is one of the most common inhalant allergens in the pathogenesis of atopic dermatitis (AD). The prevalence of atopic patch test (APT) to it in the general population, however, is largely unknown. The aim of this study was to detect the frequency of APT to Dermatophagoides in a self-selected population in Beijing. Healthy university student volunteers were recruited and patch tested with a commercial Dermatophagoides (pteronyssinus/pharinae) mix. Of 201 students studied, 25.9% exhibited positive results. The positivity rate was not correlated to gender but increased with age. In volunteers without eczema, allergic rhinitis, or asthma, the positivity rate of APT was as high as 13.6% but is much lower than that of volunteers who had allergic rhinitis or asthma (56.1%, P < 0.05, χ2 test). One volunteer had AD and was tested positive, but only 27.3% of those who had other types of eczema but without allergic rhinitis or asthma were tested positive. This study confirmed that APT to Dermatophagoides mix is highly related not only to AD but also to respiratory allergy. The high positivity rate of APT in volunteers without eczema or respiratory allergy implied that a large number of positive APTs in patients with AD may be not relevant.


Unlocking the Role of sMyBP-C: A Key Player in Skeletal Muscle Development and Growth.
Skeletal muscle is the largest organ in the body, responsible for gross movement and metabolic regulation. Recently, variants in the MYBPC1 gene have been implicated in a variety of developmental muscle diseases, such as distal arthrogryposis. How MYBPC1 variants cause disease is not well understood. Here, through a collection of novel gene-edited mouse models, we define a critical role for slow myosin binding protein-C (sMyBP-C), encoded by MYBPC1 , across muscle development, growth, and maintenance during prenatal, perinatal, postnatal and adult stages. Specifically, Mybpc1 knockout mice exhibited early postnatal lethality and impaired skeletal muscle formation and structure, skeletal deformity, and respiratory failure. Moreover, a conditional knockout of Mybpc1 in perinatal, postnatal and adult stages demonstrates impaired postnatal muscle growth and function secondary to disrupted actomyosin interaction and sarcomere structural integrity. These findings confirm the essential role of sMyBP-C in skeletal muscle and reveal specific functions in both prenatal embryonic musculoskeletal development and postnatal muscle growth and function.


Different co-culture systems have the same impact on bovine embryo transcriptome.
During the last few years, several co-culture systems using either BOEC or VERO feeder cells have been developed to improve bovine embryo development and these systems give better results at high oxygen concentration (20%). In parallel, the SOF medium, used at 5% O2, has been developed to mimic the oviduct fluid. Since 2010s, the SOF medium has become popular in improving bovine embryo development and authors have started to associate this medium to co-culture systems. Nevertheless, little is known about the putative benefit of this association on early development. To address this question, we have compared embryo transcriptomes in four different culture conditions: SOF with BOEC or VERO at 20% O2, and SOF without feeders at 5% or 20% O2 Embryos have been analyzed at 16-cell and blastocyst stages. Co-culture systems did not improve the developmental rate when compared to 5% O2 Direct comparison of the two co-culture systems failed to highlight major differences in embryo transcriptome at both developmental stages. Both feeder cell types appear to regulate the same cytokines and growth factors pathways, and thus to influence embryo physiology in the same way. In blastocysts, when compared to culture in SOF at 5% O2, BOEC or VERO seems to reduce cell survival and differentiation by, at least, negatively regulating STAT3 and STAT5 pathways. Collectively, in SOF medium both blastocysts rate and embryo transcriptome suggest no influence of feeder origin on bovine early development and no beneficial impact of co-culture systems when compared to 5% O2.


Population-level interventions to reduce alcohol-related harm: an overview of systematic reviews.
To analyse available review-level evidence on the effectiveness of population-level interventions in non-clinical settings to reduce alcohol consumption or related health or social harm. Health, social policy and specialist review databases between 2002 and 2012 were searched for systematic reviews of the effectiveness of population-level alcohol interventions on consumption or alcohol-related health or social outcomes. Data were extracted on review research aim, inclusion criteria, outcome indicators, results, conclusions and limitations. Reviews were quality-assessed using AMSTAR criteria. A narrative synthesis was conducted overall and by policy area. Fifty-two reviews were included from ten policy areas. There is good evidence for policies and interventions to limit alcohol sale availability, to reduce drink-driving, to increase alcohol price or taxation. There is mixed evidence for family- and community-level interventions, school-based interventions, and interventions in the alcohol server setting and the mass media. There is weak evidence for workplace interventions and for interventions targeting illicit alcohol sales. There is evidence of the ineffectiveness of interventions in higher education settings. There is a pattern of support from the evidence base for regulatory or statutory enforcement interventions over local non-regulatory approaches targeting specific population groups.


ESOP-1, a secreted protein expressed in the hematopoietic, nervous, and reproductive systems of embryonic and adult mice.
To isolate soluble factors expressed in early phases of hematopoietic differentiation, we applied the signal sequence trap method to the in vitro murine hematopoietic differentiation system, in which ES cells are cocultured with OP-9 stroma cells. This strategy allowed us to isolate cDNA for a secreted protein, ESOP-1, of 160 amino acids, the sequence of which shows 64% identity with human ESOP-1/MD-2. ESOP-1 mRNA was highly expressed in the mouse embryos at 7.5 days after coitus. Expression of the ESOP-1 mRNA and protein was shown in the embryonic and adult hematopoietic system. In addition, the ESOP-1 protein was found in the yolk sac-blood islands, the developing nervous system, and the adult reproductive system. These results suggest that ESOP-1 may play some roles in the development or maintenance of hematopoietic, nervous, and reproductive systems.


The effects of experimental hyperthyroidism on hemorheology and plasma fibrinogen concentration.
The present study in female rats determined the effects of experimental hyperthyroidsm on hemorheological parameters and fibrinogen concentration. To induce experimental hyperthyroidism L-thyroxine (0.4 mg/100 g fodder) was added to the fodder of the experimental group rats for 20 d. After experimental duration, T3, T4, and TSH levels, plasma and blood viscosity, hematocrit, erythrocyte rigidity index, and plasma fibrinogen concentration values of both the control and the experimental group animals were determined and evaluated. In the experimental group, T3 and T4 levels were higher and TSH levels lower than that of the control rats (respectively, p < 0.01, p < 0.001, p < 0.001). Plasma viscosity and fibrinogen concentration of hyperthyroid group were found significantly higher than controls (p < 0.01). However there was no significant difference found in blood viscosity, hematocrit, and erythrocyte rigidity index between control and experimental groups. Thus, hyperthyroidism induced increased fibrinogen concentration can alter the rheological structure of blood by inducing increase in plasma viscosity.


An Exploratory Study of Pragmatic Language Use Across Contexts With the Pragmatic Rating Scale-School Age Among Autistic Boys and Boys With Fragile X Syndrome Plus Autism.
Autistic boys and boys with co-occurring fragile X syndrome and autism spectrum disorder (FXS + ASD) demonstrate similar pragmatic language difficulties. The Pragmatic Rating Scale-School Age (PRS-SA) captures ecologically valid metrics of pragmatic language impairments in these populations. It is traditionally scored based on the Autism Diagnostic Observation Schedule (ADOS), which may limit the use of the PRS-SA more broadly in research and clinical contexts. This study evaluated the feasibility of the PRS-SA based on a shorter, semistructured conversational context compared to the ADOS in school-age autistic boys (n = 16) and boys with FXS + ASD (n = 16), matched on ASD traits. Differences across ADOS and conversational contexts and associations with ASD-related social difficulties were evaluated. Findings revealed differences in PRS-SA scores between ADOS and conversational contexts, but only for the FXS + ASD group. Limited associations were observed between PRS-SA scores and ASD traits. Results from this study indicate the feasibility of using the PRS-SA in a shorter conversational context than the ADOS to assess pragmatic language among autistic boys. For boys with FXS + ASD, contextual differences warrant careful consideration in future work.


Aortic annulus displacement assessed by contrast left ventriculography during invasive coronary angiography as a predictor of adverse events.
We propose the use of aortic annulus displacement (AAD) detected on contrast left ventriculography (LVG) during invasive coronary angiography as a marker of left ventricular (LV) long-axis shortening. In the present study, we aimed to investigate whether AAD is associated with adverse events in patients who underwent coronary angiography because of suspected coronary artery disease. In this retrospective study, we evaluated the medical records of 998 consecutive patients who underwent invasive coronary angiography and LVG. LV lengths were measured from the apex to the aortic valve insertion by using LVG images. AAD (%) was calculated as [(LV end-diastolic length-LV end-systolic length)/LV end-diastolic length]×100. The participants' median age was 67 years. Ninety-six adverse events (composite events; all-cause death, 39; congestive heart failure, 21; late revascularization, 34; and myocardial infarction, 2) were observed during a median follow-up period of 3.1 years. In multivariate Cox regression analysis, adverse events were associated with lower AAD (hazard ratio, 0.703; p=0.002), after adjusting for traditional risk factors and coronary artery stenosis. The area under the curve of AAD for predicting adverse events was greater than that of LV ejection fraction (0.656 vs. 0.541, p<0.05). AAD was superior to LV ejection fraction as a predictor of adverse events in patients with and without coronary arterial stenosis. AAD may be the optimal method for assessing longitudinal LV systolic function in the catheter laboratory.


Zika Virus: Immune Evasion Mechanisms, Currently Available Therapeutic Regimens, and Vaccines.
The sudden emergence of infectious pathogens such as Zika virus (ZIKV) holds global health concerns. Recent dissemination of ZIKV from Pacific to Americas with an upsurge of congenital anomalies and Guillain Barre Syndrome (GBS) in adults has created an alarming situation. High-throughput studies are in progress to understand ZIKV's mode of pathogenesis and mechanism of immune escape, yet the pathogenesis remains obscure. Mainly ZIKV's envelope (E) protein and nonstructural proteins (mainly NS1 and NS5) manipulate host cell to support viral immune escape by modulation of the interferon pathway and complement antagonism. The development of direct therapeutics for ZIKV infection is required to overcome the rapidly evolving viral threat. Currently, the existing strategies for ZIKV treatment are only supportive. Although, there is no prophylactic or therapeutic vaccine presently available, however, recent efforts have brought up ZIKV vaccines into clinical trial phase 1. This review presents the highlights of recent advances in understanding immune evasion strategies adapted by ZIKV and existing therapies against the virus.


Predictive value of family history in detecting hypercholesterolemia in predominantly Hispanic adolescents.
Plasma levels of total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were obtained in 110 senior high school students who were predominantly Hispanic. Results were compared with family history of premature coronary heart disease or hypercholesterolemia. The level of high-density lipoprotein cholesterol was significantly lower in Hispanic adolescents than in non-Hispanics (P less than 0.05). A positive family history was found in 22% of the subjects. Only 25% of the students with high levels of total cholesterol had a positive family history. The positive predictive value of family history for a high level of total cholesterol was only 38%. These results suggest that adolescents should be screened for hypercholesterolemia regardless of a positive family history.


Individual plastic responses by males to rivals reveal mismatches between behaviour and fitness outcomes.
Plasticity in behaviour is of fundamental significance when environments are variable. Such plasticity is particularly important in the context of rapid changes in the socio-sexual environment. Males can exhibit adaptive plastic responses to variation in the overall level of reproductive competition. However, the extent of behavioural flexibility within individuals, and the degree to which rapidly changing plastic responses map onto fitness are unknown. We addressed this by determining the behaviour and fitness profiles of individual Drosophila melanogaster males subjected to up to three episodes of exposure to rivals or no rivals, in all combinations. Behaviour (mating duration) was remarkably sensitive to the level of competition and fully reversible, suggesting that substantial costs arise from the incorrect expression of even highly flexible behaviour. However, changes in mating duration matched fitness outcomes (offspring number) only in scenarios in which males experienced zero then high competition. Following the removal of competition, mating duration, but not offspring production, decreased to below control levels. This indicates that the benefit of increasing reproductive investment when encountering rivals may exceed that of decreasing investment when rivals disappear. Such asymmetric fitness benefits and mismatches with behavioural responses are expected to exert strong selection on the evolution of plasticity.


Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor-associated macrophages.
Antiangiogenic strategies can be effective for cancer therapy, but like all therapies resistance poses a major clinical challenge. Hypoxia and nutrient starvation select for aggressive qualities that may render tumors resistant to antiangiogenic attack. Here, we show that hypoxia and nutrient starvation cooperate to drive tumor aggressiveness through epigenetic regulation of the histone demethylase JMJD1A (JHDM2A; KDM3A). In cancer cells rendered resistant to long-term hypoxia and nutrient starvation, we documented a stimulation of AKT phosphorylation, cell morphologic changes, cell migration, invasion, and anchorage-independent growth in culture. These qualities associated in vivo with increased angiogenesis and infiltration of macrophages into tumor tissues. Through expression microarray analysis, we identified a cluster of functional drivers such as VEGFA, FGF18, and JMJD1A, the latter which was upregulated in vitro under conditions of hypoxia and nutrient starvation and in vivo before activation of the angiogenic switch or the prerefractory phase of antiangiogenic therapy. JMJD1A inhibition suppressed tumor growth by downregulating angiogenesis and macrophage infiltration, by suppressing expression of FGF2, HGF, and ANG2. Notably, JMJD1A inhibition enhanced the antitumor effects of the anti-VEGF compound bevacizumab and the VEGFR/KDR inhibitor sunitinib. Our results form the foundation of a strategy to attack hypoxia- and nutrient starvation-resistant cancer cells as an approach to leverage antiangiogenic treatments and limit resistance to them.


The relation of retail tobacco availability to initiation and continued smoking.
Used an ecological analysis employing multilevel random-effects regression analyses to model Level 1 (individual and social) and Level 2 (environmental) correlates of smoking initiation and continued smoking among 6th-, 7th-, and 8th-grade students. Data from 5,234 youth in 11 Midwestern communities were examined. Results indicate higher levels of retail tobacco availability (RTA) were associated with increased odds that a youth initiated smoking but not continued smoking. Among the Level 1 factors, youth who were older, male, had an adult tobacco user in the home, and had more peers who use tobacco had increased odds of initiating smoking. In contrast, only the presence of an adult tobacco user in the home and the number of peers who use tobacco were associated with increased odds that a youth continued smoking. Examining individual, social, and environmental factors simultaneously provides a clearer and more accurate model of these complex ecological influences.


Complement Targets Newborn Retinal Ganglion Cells for Phagocytic Elimination by Microglia.
Microglia play important roles in shaping the developing CNS, and at early stages they have been proposed to regulate progenitor proliferation, differentiation, and neuronal survival. However, these studies reveal contradictory outcomes, highlighting the complexity of these cell-cell interactions. Here, we investigate microglia function during embryonic mouse retina development, where only microglia, progenitors, and neurons are present. In both sexes, we determine that microglia primarily interact with retinal neurons and find that depletion of microglia via conditional KO of the Csf1 receptor results in increased density of retinal ganglion cells (RGCs). Pharmacological inhibition of microglia also results in an increase in RGCs, with no effect on retinal progenitor proliferation, RGC genesis, or apoptosis. We show that microglia in the embryonic retina are enriched for phagocytic markers and observe engulfment of nonapoptotic Brn3-labeled RGCs. We investigate the molecular pathways that can mediate cell engulfment by microglia and find selective downregulation of complement pathway components with microglia inhibition, and further show that C1q protein marks a subset of RGCs in the embryonic retina. KO of complement receptor 3 (CR3; Itgam), which is only expressed by microglia, results in increased RGC density, similar to what we observed after depletion or inhibition of microglia. Thus, our data suggest that microglia regulate neuron elimination in the embryonic mouse retina by complement-mediated phagocytosis of non-apoptotic newborn RGCs.SIGNIFICANCE STATEMENT Microglia are emerging as active and important participants in regulating neuron number in development, during adult neurogenesis, and following stem cell therapies. However, their role in these contexts and the mechanisms involved are not fully defined. Using a well-characterized in vivo system, we provide evidence that microglia regulate neuronal elimination by complement-mediated engulfment of nonapoptotic neurons. This work provides a significant advancement of the field by defining in vivo molecular mechanisms for microglia-mediated cell elimination. Our data add to a growing body of evidence that microglia are essential for proper nervous system development. In addition, we elucidate microglia function in the developing retina, which may shed light on microglia involvement in the context of retinal injury and disease.


The role of cell swelling and haemolysis in Sendai virus-induced cell fusion and in the diffusion of incorporated viral antigens.
The role of the haemolytic activity of Sendai virus in cell-cell fusion has been examined in monolayers of human erythrocytes and erythrocyte ghosts fused with either haemolytic or non-haemolytic virus. Morphological observations indicate that cell swelling and haemolysis is a distinct event in cell-cell fusion irrespective of whether it is virally induced or, in the case of non-haemolytic virus, experimentally induced. Osmotic swelling appears to be the driving force by which cells which have established sites of membrane fusion expand such sites to form poly-erythrocytes. Immunofluorescent labelling of viral antigens incorporated into the erythrocyte membrane as a result of viral envelope-cell fusion indicates that diffusion of antigens in the plane of the membrane is restricted in intact erythrocytes and resealed erythrocyte ghosts but not in haemolysed erythrocytes or unsealed ghosts. A perturbation of the erythrocyte membrane resulting from osmotic lysis appears to form a prerequisite for the lateral diffusion of viral elements.


Risks from GMOs due to horizontal gene transfer.
Horizontal gene transfer (HGT) is the stable transfer of genetic material from one organism to another without reproduction or human intervention. Transfer occurs by the passage of donor genetic material across cellular boundaries, followed by heritable incorporation to the genome of the recipient organism. In addition to conjugation, transformation and transduction, other diverse mechanisms of DNA and RNA uptake occur in nature. The genome of almost every organism reveals the footprint of many ancient HGT events. Most commonly, HGT involves the transmission of genes on viruses or mobile genetic elements. HGT first became an issue of public concern in the 1970s through the natural spread of antibiotic resistance genes amongst pathogenic bacteria, and more recently with commercial production of genetically modified (GM) crops. However, the frequency of HGT from plants to other eukaryotes or prokaryotes is extremely low. The frequency of HGT to viruses is potentially greater, but is restricted by stringent selection pressures. In most cases the occurrence of HGT from GM crops to other organisms is expected to be lower than background rates. Therefore, HGT from GM plants poses negligible risks to human health or the environment.


Neoadjuvant dual HER2-targeted therapy with lapatinib and trastuzumab improves pathologic complete response in patients with early stage HER2-positive breast cancer: a meta-analysis of randomized prospective clinical trials.
Randomized clinical trials (RCT) that evaluated the addition of lapatinib to trastuzumab plus neoadjuvant chemotherapy (NAC) in patients with HER2-positive, operable breast cancer revealed a questionable improvement in pathologic complete response (pCR) rate. We performed a meta-analysis of prospective RCTs that examined the effect of adding lapatinib to trastuzumab and NAC on pCR rate. PubMed databases and abstracts from the proceedings of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium were searched for RCTs that compared lapatinib plus trastuzumab and NAC with trastuzumab in combination with NAC and that included pCR as the primary outcome. Our main objective was to estimate the effect of adding lapatinib to trastuzumab plus NAC on pCR rate, defined as no residual invasive cancer in breast and axillary lymph nodes. In total, 1,017 patients with early stage breast cancer from 5 trials were included. Four trials examined the addition of lapatinib to trastuzumab plus NAC; this resulted in statistically significant improvement in pCR, defined as no residual carcinoma in breast and lymph nodes. The pCR rate was 55.76% and 38.36% in the lapatinib plus trastuzumab and the trastuzumab plus NAC arms, respectively (odds ratio [OR]: 1.94; 95% confidence interval [CI]: 1.44-2.60). In three trials, the rates of pCR, defined as no residual invasive carcinoma in breast only, for the lapatinib plus trastuzumab and trastuzumab-alone groups were 55.01% and 40.70%, respectively, also resulting in significant improvement (OR: 1.78; 95% CI: 1.27-2.50). The addition of lapatinib to trastuzumab in combination with neoadjuvant chemotherapy significantly improves pCR rates in patients with HER2-positive breast cancer.


Body-composition development during early childhood and energy expenditure in response to physical activity in 1.5-y-old children.
The prevalence of childhood overweight and obesity has increased recently, but the mechanisms involved are incompletely known. Previous research has shown a correlation between the percentage of total body fat (TBF) and physical activity level (PAL). However, the PAL values used may involve a risk of spurious correlations because they are often based on predicted rather than measured estimates of resting energy metabolism. We studied the development of body composition during early childhood and the relation between the percentage of TBF and PAL on the basis of the measured resting energy metabolism. Body composition was previously measured in 108 children when they were 1 and 12 wk old. When 44 of these children (21 girls and 23 boys) were 1.5 y old, their total energy expenditure and TBF were assessed by using the doubly labeled water method. Resting energy metabolism, which was assessed by using indirect calorimetry, was used to calculate PAL. Significant correlations were shown for TBF (r = 0.32, P = 0.035) and fat-free mass (r = 0.34, P = 0.025) between values (kg) assessed at 12 wk and 1.5 y of age. For TBF (kg) a significant interaction (P = 0.035) indicated a possible sex difference. PAL at 1.5 y was negatively correlated with the percentage of TBF (r = -0.40, P = 0.0076) and the increase in the percentage of TBF between 12 wk and 1.5 y (r = -0.38, P = 0.0105). The results indicate that body fatness and physical activity interact during early childhood and thereby influence obesity risk. Our results are based on a small sample, but nevertheless, they motivate additional studies in boys compared with girls regarding the development of body composition during early life.


Oligomeric amyloid-beta induces MAPK-mediated activation of brain cytosolic and calcium-independent phospholipase A2 in a spatial-specific manner.
Alzheimer's disease (AD) is histopathologically characterized by the build-up of fibrillar amyloid beta (Aβ) in the form of amyloid plaques and the development of intraneuronal neurofibrillary tangles consisting of aggregated hyperphosphorylated Tau. Although amyloid fibrils were originally considered responsible for AD pathogenesis, recent convincing evidence strongly implicates soluble oligomeric Aβ as the primary neurotoxic species driving disease progression. A third largely ignored pathological hallmark, originally described by Alois Alzheimer, is the presence of "adipose inclusions", suggestive of aberrant lipid metabolism. The molecular mechanisms underlying these "lipoid granules", as well as their potential link to soluble and/or fibrillar Aβ remain largely unknown. Seeking to better-understand these conundrums, we took advantage of the powerful technology of multidimensional mass spectrometry-based shotgun lipidomics and an AD transgenic mouse model overexpressing mutant amyloid precursor protein (APP E693Δ-Osaka-), where AD-like pathology and neurodegeneration occur as a consequence of oligomeric Aβ accumulation in the absence of amyloid plaques. Our results revealed for the first time that APP overexpression and oligomeric Aβ accumulation lead to an additive global accumulation of nonesterified polyunsaturated fatty acids (PUFAs) independently of amyloid plaques. Furthermore, we revealed that this accumulation is mediated by an increase in phospholipase A2 (PLA2) activity, evidenced by an accumulation of sn-1 lysophosphatidylcholine and by MAPK-mediated phosphorylation/activation of group IV Ca2+-dependent cytosolic (cPLA2) and the group VI Ca2+-independent PLA2 (iPLA2) independently of PKC. We further revealed that Aβ-induced oxidative stress also disrupts lipid metabolism via reactive oxygen species-mediated phospholipid cleavage leading to increased sn-2 lysophosphatidylcholine as well as lipid peroxidation and the subsequent accumulation of 4-hydroxynonenal. Brain histological studies implicated cPLA2 activity with arachidonic acid accumulation within myelin-rich regions, and iPLA2 activity with docosahexaenoic acid accumulation within pyramidal neuron-rich regions. Taken together, our results suggest that PLA2-mediated accumulation of free PUFAs drives AD-related disruption of brain lipid metabolism.


Fate of claudicants after femoropopliteal vein bypass: prospective, long-term follow-up of 100 patients.
Femoropopliteal bypass grafting for claudication is a controversial procedure. One hundred consecutive patients so treated were analysed for vein-graft patency, subsequent operation and survival. Initial success, treatment of incipient graft failure and attrition from death were the three critical factors influencing long-term benefit. Cumulative graft patency, after revision when necessary, was 89%, 86% and 78% at 2, 5 and 10 years respectively. In assessing the real benefit of surgery in this group, it is important to consider the effect of late deaths, as the life expectancy of these patients is so often shortened by related disease; the "cumulative palliation" (patient alive and graft patent) was 82%, 67% and 28% at the same time intervals. The concept of cumulative palliation sets a high standard in assessing results of vascular surgery, adding important information to the usual graft patency rates that ignore the effect of death. These results suggest a place for femoropopliteal vein bypass grafting in selected claudicants.


WIF1 prevents Wnt5A mediated LIMK/CFL phosphorylation and adherens junction disruption in human vascular endothelial cells.
Wnt5A is released by activated macrophages and elevated levels have been detected in sepsis patients with severe systemic inflammation. However, the signalling and functional effects of Wnt5A in the vascular endothelial cells (VEC) remained unclear. Recently, we showed that Wnt5A affects barrier function in human VEC through Ryk interaction. Wnt5A/Ryk signalling activates LIMK to inactivate the actin depolymerisation factor CFL by phosphorylation, promotes actin polymerisation and disrupts endothelial adherens junctions. Here, we investigate the antagonistic effect of the Ryk specific secreted Wnt antagonist Wnt inhibitory factor (WIF)-1 on Wnt5A-mediated activation/inactivation of LIMK/CFL, and adherens junction disruption in human VEC. In human coronary artery endothelial cells (HCAEC), treatment with Wnt5A enhanced the phosphorylation of LIMK and CFL that was significantly prevented by WIF1. The presence of WIF1 suppressed Wnt5A-mediated disruption of β-catenin and VE-cadherin adherens junctions in HCAEC, thereby preventing barrier dysfunction caused by Wnt5A. We conclude that WIF1 or molecules with similar properties could be potent tools for the prevention of vascular leakage due to Wnt5A-mediated actin cytoskeleton remodeling in diseases associated with systemic inflammation.


Determining the factors affecting chemotherapy-induced nausea and vomiting in children with cancer.
We evaluated the factors affecting chemotherapy-induced nausea and vomiting (CINV) in children with cancer. This cross-sectional study was conducted with 62 children aged 9 to 18 years old with a solid tumor who received chemotherapy for the first time, and their parents. Data were collected using a data collection form, the State-Trait Anxiety Inventory for Children, the Beck Anxiety Inventory, the Spielberger State-Trait Anxiety Inventory, and the Baxter Retching Faces Scale. Data were analyzed using Spearman's correlation and logistic regression analyses. Risk factors related to the child, treatment, and parent were examined. Child-related factors were determined as diagnosis (odds ratio [OR] = 5.5), time since diagnosis (OR = 1.9, OR = 4.7), pretreatment anxiety of the child (r = 0.439, r = 0.422), and past experience of nausea and vomiting before treatment (OR = 1.2). Treatment-related factors involved anti-emetic prophylaxis (OR = 4.9, OR = 9.2). Parent-related factors included pretreatment anxiety of the parent (r = 0.271, r = 0.287), accommodation (OR = 5.5), not eating (OR = 1.2, OR = 1.3), and bad smell (OR = 1.2), which were described amongst parents' as factors that trigger CINV. The occurrence of CINV is significantly affected by child-, treatment-, and parent-related risk factors. Pediatric nurses should create an environment for children and their parents to reduce their anxiety and provide basic knowledge and skills about the management of CINV.


A computer generated index for the assessment of coronary angiography.
Mortality in patients with coronary artery disease is related to its severity. The commonly used classification of 1, 2 or 3 vessel disease is relatively insensitive. We have designed a new classification which takes into account site, severity and effect of multiple lesions in the coronary circulation. Data is recorded on Mark Sense computer cards and a coronary index (CI) obtained. We have collected data from 1100 patients and shown correlations of the index with clinical variables, ventricular function and in particular, mortality.


Energy Dependent Stereodynamics of the Ne(^{3}P_{2})+Ar Reaction.
The stereodynamics of the Ne(^{3}P_{2})+Ar Penning and associative ionization reactions have been studied using a crossed molecular beam apparatus. The experiment uses a curved magnetic hexapole to polarize the Ne(^{3}P_{2}), which is then oriented with a shaped magnetic field in the region where it intersects with a beam of Ar(^{1}S). The ratios of Penning to associative ionization were recorded over a range of collision energies from 320 to 500 cm^{-1} and the data were used to obtain Ω state dependent reactivities for the two reaction channels. These reactivities were found to compare favorably to those predicted in the theoretical work of Brumer et al.


Tibial Tuberosity-Trochlear Groove Distance Shows no Change in Patients with or Without Knee Osteoarthritis.
The primary aim of this study is to compare tibial tuberosity-trochlear groove (TTTG) distance in patients with or without knee osteoarthritis. Additionally, the variability of tibial tubercle according to trochlear groove was evaluated. In this retrospective cohort study, TTTG distance was measured with two different methods on magnetic resonance (MR) images. TTTG distance was measured by the familiar method on 173 MR images, and by the novel method on 157 MR images of 175 patients totally. The patients were divided into two groups as group 1 (Kellgren Lawrence osteoarthritis grade <2) and group 2 (Kellgren Lawrence osteoarthritis grade ≥2). TTTG values measured by both methods were compared between groups. The coefficient of variation for all patients in TTTG values were calculated. A p-value <0.05 was considered as significant. The mean age, sex distributions, and side ratios were different between groups. There was no statistical difference in TTTG values between group 1 and 2. There was no statistically significant difference between the two measurement methods. The coefficient of variation for all patients in TTTG values were high (43.95% for familiar method and 44.64% for novel method). There was excellent interrater reliability for two measurement methods in both groups. The TTTG distance is similar in patients with/without knee osteoarthritis. The position of the tibial tubercle according to the trochlear groove is variable, so the tibial tubercle may not be a good reference point for rotational position of the tibial component in total knee arthroplasty.


Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia: A Randomized Clinical Trial.
Agitation is a prevalent, distressing, and burdensome manifestation of Alzheimer dementia in need of an efficacious, safe, and well-tolerated treatment. To confirm the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer dementia. This randomized clinical trial was a 12-week, double-blind, placebo-controlled, fixed-dose, parallel-arm trial that ran from May 2018 to June 2022 at 123 clinical trial sites in Europe and the United States. Participants included patients with agitation in Alzheimer dementia in a care facility or community-based setting. Stable Alzheimer disease medications were permitted. In this 2-arm trial, patients were randomized to receive oral brexpiprazole or placebo (2:1 ratio) for 12 weeks. Within the brexpiprazole arm, patients were further randomized to receive fixed doses of 2 mg/d or 3 mg/d in a 1:2 ratio. The primary end point was change in Cohen-Mansfield Agitation Inventory total score (which measures the frequency of 29 agitated behaviors) from baseline to week 12 for brexpiprazole, 2 or 3 mg, vs placebo. Safety was assessed by standard measures, including treatment-emergent adverse events. A total of 345 patients were randomized to receive brexpiprazole (n = 228) or placebo (n = 117); completion rates were 198 (86.8%) for brexpiprazole and 104 (88.9%) for placebo. Mean (SD) age was 74.0 (7.5) years, and 195 of 345 patients were female (56.5%). Patients receiving brexpiprazole, 2 or 3 mg (n = 225), demonstrated statistically significantly greater improvement than those taking placebo (n = 116) in Cohen-Mansfield Agitation Inventory total score from baseline to week 12 (brexpiprazole baseline, 80.6, mean change, -22.6; placebo baseline, 79.2, mean change, -17.3; least-squares mean difference, -5.32; 95% CI, -8.77 to -1.87; P = .003; Cohen d effect size, 0.35). No treatment-emergent adverse events had an incidence of 5% or more with brexpiprazole and greater incidence than placebo. The proportion of patients who discontinued because of adverse events was 12 of 226 (5.3%) for brexpiprazole and 5 of 116 (4.3%) for placebo. In this study, patients with Alzheimer dementia who took brexpiprazole, 2 or 3 mg, showed a statistically significant improvement vs placebo in agitation over 12 weeks. Brexpiprazole was generally well tolerated over 12 weeks in this vulnerable patient population. ClinicalTrials.gov Identifier: NCT03548584.


The FRED for Cerebral Aneurysms of the Posterior Circulation: A Subgroup Analysis of the EuFRED Registry.
Flow diversion for the posterior circulation remains a promising treatment option for selected posterior circulation aneurysms. The Flow-Redirection Intraluminal Device (FRED) system has not been previously assessed in a large cohort of patients with posterior circulation aneurysms. The purpose of the present study was to assess safety and efficacy of FRED in this location. Consecutive patients with posterior circulation aneurysms treated at 8 centers participating in the European FRED study (EuFRED) between April 2012 and January 2019 were retrospectively reviewed. Complication and radiographic and functional outcomes were evaluated. Eighty-four patients (median age, 54 years) with 84 posterior circulation aneurysms were treated with the FRED. A total of 25 aneurysms (29.8%) had previously ruptured, even though most aneurysms were diagnosed incidentally (45.2%). The intradural vertebral artery was the most common location (50%), and saccular, the most common morphology (40.5%). The median size was 7 mm. There were 8 (9.5%) symptomatic thromboembolic and no hemorrhagic complications. Thromboembolic complications occurred mostly (90.9%) in nonsaccular aneurysms. On last follow-up at a median of 24 months, 78.2% of aneurysms were completely occluded. Functional outcome at a median of 27 months was favorable in 94% of patients. All mortalities occurred in patients with acute subarachnoid hemorrhage and its sequelae. The largest cohort of posterior circulation aneurysms treated with the FRED to date demonstrated favorable safety and efficacy profiles of the device for this indication. Treatment in the setting of acute subarachnoid hemorrhage was strongly related to mortality, regardless of whether procedural complications occurred.


Intraspecific variation in soy across the leaf economics spectrum.
Intraspecific trait variation (ITV) is an important dimension of plant ecological diversity, particularly in agroecosystems, where phenotypic ITV (within crop genotypes) is an important correlate of key agroecosystem processes including yield. There are few studies that have evaluated whether plants of the same genotype vary along well-defined axes of biological variation, such as the leaf economics spectrum (LES). There is even less information disentangling environmental and ontogenetic determinants of crop ITV along an intraspecific LES, and whether or not a plant's position along an intraspecific LES is correlated with reproductive output. We sought to capture the extent of phenotypic ITV within a single cultivar of soy (Glycine max) - the world's most commonly cultivated legume - using a data set of nine leaf traits measured on 402 leaves, sampled from 134 plants in both agroforestry and monoculture management systems, across three distinct whole-plant ontogenetic stages (while holding leaf age and canopy position stable). Leaf traits covaried strongly along an intraspecific LES, in patterns that were largely statistically indistinguishable from the 'universal LES' observed across non-domesticated plants. Whole-plant ontogenetic stage explained the highest proportion of phenotypic ITV in LES traits, with plants progressively expressing more 'resource-conservative' LES syndromes throughout development. Within ontogenetic stages, leaf traits differed systematically across management systems, with plants growing in monoculture expressing more 'resource-conservative' trait syndromes: trends largely owing to an approximately ≥50% increases in leaf mass per area (LMA) in high-light monoculture vs. shaded agroforestry systems. Certain traits, particularly LMA, leaf area and maximum photosynthetic rates, correlated closely with plant-level reproductive output. Phenotypic ITV in soy is governed by constraints in trait trade-offs along an intraspecific LES, which in turn (1) underpins plant responses to managed environmental gradients, and (2) reflects shifts in plant functional biology and resource allocation that occur throughout whole-plant ontogeny.


Toll-Like Receptors -2, -3, -4 and -7 Expression Patterns in the Liver of a CLP-Induced Sepsis Mouse Model.
Objective: To investigate the expression of toll-like receptors (TLRs) in the liver of septic mouse model. Materials and methods: For this study seventy-two C57BL/6J mice were utilized. Sepsis was induced by cecal ligation and puncture (CLP) in the mice of the three septic (S) groups (euthanized at 24 hours, 48 hours and 72 hours). Sham (laparotomy)- operated mice constituted the control (C) groups (euthanized at 24, 48 and 72 hours). Blood samples were drawn and liver tissues were extracted and examined histologically. The expression of TLRs 2, 3, 4 and 7 was assessed via immunohistochemistry (IHC) and qrt-PCR (quantitative- Polymerase Chain Reaction). Results: Liver function tests were elevated in all S-groups in contrast to their time-equivalent control groups (S24 versus C24, S48 versus C48 and S72 versus C72) (p < 0.05). Liver histology displayed progressive deterioration in the septic groups. IHC and qrt-PCR both showed an increased expression of all TLRs in the septic mice in comparison to their analogous control ones (p < 0.05). Analysis of livers and intestines of the septic animals proved that all TLRs were significantly expressed in higher levels in the intestinal tissues at 24h and 48h (p < 0.05) except for TLR 3 in S48 (p > 0.05); whereas at 72 hours only TLR 4 levels were significantly elevated in the intestine (p < 0.05). Conclusion: TLRs seem to be expressed in significant levels in the livers of septic rodents, indicating that they have a possible role in the pathophysiology of liver damage in septic conditions.


Inhibition of alpha-synuclein seeded fibril formation and toxicity by herbal medicinal extracts.
Recent studies indicated that seeded fibril formation and toxicity of α-synuclein (α-syn) play a main role in the pathogenesis of certain diseases including Parkinson's disease (PD), multiple system atrophy, and dementia with Lewy bodies. Therefore, examination of compounds that abolish the process of seeding is considered a key step towards therapy of several synucleinopathies. Using biophysical, biochemical and cell-culture-based assays, assessment of eleven compounds, extracted from Chinese medicinal herbs, was performed in this study for their effect on α-syn fibril formation and toxicity caused by the seeding process. Salvianolic acid B and dihydromyricetin were the two compounds that strongly inhibited the fibril growth and neurotoxicity of α-syn. In an in-vitro cell model, these compounds decreased the insoluble phosphorylated α-syn and aggregation. Also, in primary neuronal cells, these compounds showed a reduction in α-syn aggregates. Both compounds inhibited the seeded fibril growth with dihydromyricetin having the ability to disaggregate preformed α-syn fibrils. In order to investigate the inhibitory mechanisms of these two compounds towards fibril formation, we demonstrated that salvianolic acid B binds predominantly to monomers, while dihydromyricetin binds to oligomeric species and to a lower extent to monomers. Remarkably, these two compounds stabilized the soluble non-toxic oligomers lacking β-sheet content after subjecting them to proteinase K digestion. Eleven compounds were tested but only two showed inhibition of α-syn aggregation, seeded fibril formation and toxicity in vitro. These findings highlight an essential beginning for development of new molecules in the field of synucleinopathies treatment.


A subset of pancreatic adenocarcinomas demonstrates coamplification of topoisomerase IIalpha and HER2/neu: use of immunolabeling and multicolor FISH for potential patient screening andtreatment.
We sought to identify the frequency of amplification of the topoisomerase IIalpha gene (TOP2A) in pancreatic cancer and determine the usefulness of TOP2A immunolabeling in screening for TOP2A and human epidermal growth factor receptor (HER)2/neu amplification. We examined 55 pancreatic adenocarcinoma specimens for TOP2A immunolabeling and identified TOP2A protein expression in all specimens with a nuclear labeling index (NLI; positive nuclei/total nuclei x 100) of 5% to 80%. Normal pancreatic ductal epithelium, proposed to give rise to pancreatic adenocarcinoma, did not demonstrate detectable TOP2A expression. In a subset of specimens selected for fluorescence in situ hybridization analysis of TOP2A and HER2/neu amplification using a recently developed multicolor probe, 7 of 8 lesions with an NLI of 25% or more demonstrated TOP2A amplification, in contrast with 2 of 14 lesions with a TOP2A NLI of less than 25%. In 8 of 9 TOP2A-amplified cases, coamplification of HER2/neu was present, suggesting a potential relationship between TOP2A and HER2/neu in pancreatic adenocarcinoma. We propose that TOP2A immunolabeling be used in conjunction with a newly developed multicolor probe to screen patients with pancreatic adenocarcinoma to determine the best potential therapeutic modalities, such as TOP2A inhibitors, trastuzumab, or both.


Antitussive effect of nociceptin/orphanin FQ in experimental cough models.
Cough is an important defensive pulmonary reflex that removes irritants, fluids or foreign materials from the airways. However, often cough is non-productive and requires suppression. Opioid mu receptor agonists, such as codeine are commonly used as antitussive agents and are among the most widely administered drugs in the world. Codeine suppresses the responsiveness of one or more components of the central reflex pathway for cough and is an efficacious antitussive drug for cough due to diverse aetiologies. However, opioids produce side effects that include sedation, addiction potential and constipation. Therefore, novel cough suppressant therapies should maintain or improve upon the antitussive efficacy profile of opioids. Moreover, these novel therapies should have a safety profile significantly better than current antitussive therapies. Presently, we discuss preclinical findings showing that activation of the 'opioid-like' receptor (NOP(1)) inhibits cough in the guinea pig and cat.


Artificial Solid Electrolyte Interphase-Protected LixSi Nanoparticles: An Efficient and Stable Prelithiation Reagent for Lithium-Ion Batteries.
Prelithiation is an important strategy to compensate for lithium loss in lithium-ion batteries, particularly during the formation of the solid electrolyte interphase (SEI) from reduced electrolytes in the first charging cycle. We recently demonstrated that LixSi nanoparticles (NPs) synthesized by thermal alloying can serve as a high-capacity prelithiation reagent, although their chemical stability in the battery processing environment remained to be improved. Here we successfully developed a surface modification method to enhance the stability of LixSi NPs by exploiting the reduction of 1-fluorodecane on the LixSi surface to form a continuous and dense coating through a reaction process similar to SEI formation. The coating, consisting of LiF and lithium alkyl carbonate with long hydrophobic carbon chains, serves as an effective passivation layer in the ambient environment. Remarkably, artificial-SEI-protected LixSi NPs show a high prelithiation capacity of 2100 mA h g(-1) with negligible capacity decay in dry air after 5 days and maintain a high capacity of 1600 mA h g(-1) in humid air (∼10% relative humidity). Silicon, tin, and graphite were successfully prelithiated with these NPs to eliminate the irreversible first-cycle capacity loss. The use of prelithiation reagents offers a new approach to realize next-generation high-energy-density lithium-ion batteries.


An Inversion Recovery NMR Kinetics Experiment.
A convenient laboratory experiment is described in which NMR magnetization transfer by inversion recovery is used to measure the kinetics and thermochemistry of amide bond rotation. The experiment utilizes Varian spectrometers with the VNMRJ 2.3 software, but can be easily adapted to any NMR platform. The procedures and sample data sets in this article will enable instructors to use inversion recovery as a laboratory activity in applied NMR classes and provide research students with a convenient template with which to acquire inversion recovery data on research samples.


Delivery and funding are provincial matters in Canada.
The following article is one of a series that deal with the provision of health care services around the world. Other countries in the series include Germany, Italy, Japan, Mexico, the Netherlands, and the United States. Countries scheduled for coverage in the series include Austria, France, Singapore, Spain, and the United Kingdom. The countries are described using a grid of characteristics so that comparisons may be made more easily. All of the analyses, along with further comparative data, will be gathered into a freestanding book to be published later in the year. Dr. Mendoza serves as editor for the project.


Atypical genotoxicity of carcinogenic nickel(II): Linkage to dNTP biosynthesis, DNA-incorporated rNMPs, and impaired repair of TOP1-DNA crosslinks.
Cancer is a genetic disease requiring multiple mutations for its development. However, many carcinogens are DNA-unreactive and nonmutagenic and consequently described as nongenotoxic. One of such carcinogens is nickel, a global environmental pollutant abundantly emitted by burning of coal. We investigated activation of DNA damage responses by Ni and identified this metal as a replication stressor. Genotoxic stress markers indicated the accumulation of ssDNA and stalled replication forks, and Ni-treated cells were dependent on ATR for suppression of DNA damage and long-term survival. Replication stress by Ni resulted from destabilization of RRM1 and RRM2 subunits of ribonucleotide reductase and the resulting deficiency in dNTPs. Ni also increased DNA incorporation of rNMPs (detected by a specific fluorescent assay) and strongly enhanced their genotoxicity as a result of repressed repair of TOP1-DNA protein crosslinks (TOP1-DPC). The DPC-trap assay found severely impaired SUMOylation and K48-polyubiquitination of DNA-crosslinked TOP1 due to downregulation of specific enzymes. Our findings identified Ni as the human carcinogen inducing genome instability via DNA-embedded ribonucleotides and accumulation of TOP1-DPC which are carcinogenic abnormalities with poor detectability by the standard mutagenicity tests. The discovered mechanisms for Ni could also play a role in genotoxicity of other protein-reactive carcinogens.


Implantation of human colorectal carcinoma cells in the liver studied by in vivo fluorescence videomicroscopy.
In vivo fluorescence videomicroscopy (IVFM) was used to analyse the behavior of weakly and highly metastatic human colorectal carcinoma (CRC) cells during implantation in the liver. A highly metastatic human CRC cell line, CX-1, and a weakly metastatic line, Clone A, were double-labeled with rhodamine B isothiocyanate-dextran (Rd-Dx) to locate cells and with calcein AM to assess cell metabolic activity in an experimental metastasis model. Double-labeled CRC cells (2.0 x 10(6)) were injected into the spleens of groups of nude mice and the livers observed by IVFM over the next 72 h. CRC cells were implanted within 30 s after injection into either portal venules or the proximal third of hepatic sinusoids. Approximately 0.5% of CRC cells traversed the liver through portal-central venous shunts and implanted in the lung. The number of CX-1 cells in the liver was similar to that of Clone A cells during the first 12 h. However, more CX-1 cells than Clone A cells remained in the liver at 4 h and were in groups of 8-12 cells whereas only a few, single Clone A cells were detected in the liver at 72 h. Not all Clone A cells are committed to die within 4 h of implantation because cells harvested 4 h after hepatic implantation proliferated normally in vitro when removed from the hepatic microenvironment. Since the stress of mechanical deformation during implantation may cause differences in cell survival, CX-1 and Clone A cells were passed through filters with 8 microM pores in vitro at 10-15 cm of water pressure to recreate the trauma of hepatic implantation. Approximately 50% of both CX-1 and Clone A cells were lysed. Furthermore, both CRC lines remained metabolically active when co-cultivated with liver cells for at least 24 h in vitro. Thus, the difference in metastatic potential between the two CRC lines may reside in their response to the combination of mechanical implantation and subsequent growth in the liver parenchyma.


Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse Model.
Asthma and allergies are complex, chronic inflammatory diseases in which genetic and environmental factors are crucial. Protection against asthma and allergy development in the context of farming environment is established by early animal contact, unpasteurized milk consumption and gut microbiota maturation. The human β-defensin 2 (hBD-2) is a host defense peptide present almost exclusively in epithelial tissues, with pronounced immunomodulatory properties, which has recently been shown to ameliorate asthma and IBD in animal models. We hypothesized that adequate hBD-2 secretion plays a role in the protection against asthma and allergy development and that genetic variations in the complex gene locus coding for hBD-2 may be a risk factor for developing these diseases, if as a consequence, hBD-2 is insufficiently produced. We used MALDI-TOF MS genotyping, sequencing and a RFLP assay to study the genetic variation including mutations, polymorphisms and copy number variations in the locus harboring both genes coding for hBD-2 (DEFB4A and DEFB4B). We administered hBD-2 orally in a mouse model of house dust mite (HDM)-asthma before allergy challenge to explore its prophylactic potential, thereby mimicking a protective farm effect. Despite the high complexity of the region harboring DEFB4A and DEFB4B we identified numerous genetic variants to be associated with asthma and allergy in the GABRIELA Ulm population of 1,238 children living in rural areas, including rare mutations, polymorphisms and a lack of the DEFB4A. Furthermore, we found that prophylactic oral administration of hBD-2 significantly curbed lung resistance and pulmonary inflammation in our HDM mouse model. These data indicate that inadequate genetic capacity for hBD-2 is associated with increased asthma and allergy risk while adequate and early hBD-2 administration (in a mouse model) prevents atopic asthma. This suggests that hBD-2 could be involved in the protective farm effect and may be an excellent candidate to confer protection against asthma development.


The role of the fat mass and obesity associated gene (FTO) in breast cancer risk.
Obesity has been shown to increase breast cancer risk. FTO is a novel gene which has been identified through genome wide association studies (GWAS) to be related to obesity. Our objective was to evaluate tissue expression of FTO in breast and the role of FTO SNPs in predicting breast cancer risk. We performed a case-control study of 354 breast cancer cases and 364 controls. This study was conducted at Northwestern University. We examined the role of single nucleotide polymorphisms (SNPs) of intron 1 of FTO in breast cancer risk. We genotyped cases and controls for four SNPs: rs7206790, rs8047395, rs9939609 and rs1477196. We also evaluated tissue expression of FTO in normal and malignant breast tissue. We found that all SNPs were significantly associated with breast cancer risk with rs1477196 showing the strongest association. We showed that FTO is expressed both in normal and malignant breast tissue. We found that FTO genotypes provided powerful classifiers to predict breast cancer risk and a model with epistatic interactions further improved the prediction accuracy with a receiver operating characteristic (ROC) curves of 0.68. In conclusion we have shown a significant expression of FTO in malignant and normal breast tissue and that FTO SNPs in intron 1 are significantly associated with breast cancer risk. Furthermore, these FTO SNPs are powerful classifiers in predicting breast cancer risk.


Cyanobacterial toxins: a qualitative meta-analysis of concentrations, dosage and effects in freshwater, estuarine and marine biota.
This paper reviews the rapidly expanding literature on the ecological effects of cyanobacterial toxins. The study employs a qualitative meta-analysis from the literature examining results from a large number of independent studies and extracts general patterns from the literature or signals contradictions. The meta-analysis is set up by putting together two large tables--embodying a large and representative part of the literature (see Appendix A). The first table (Table A.1) reviews the presence (concentrations) of different cyanobacterial toxins in the tissues of various groups of aquatic biota after exposure via different routes, experimentally in the lab or via natural routes in the environment. The second table (Table A.2) reviews the dose dependent effect of toxins on biota. The great majority of studies deal with the presence and effects of microcystin, especially of the MC-LR congener. Although this may partly be justified--MC-LR is an abundant and highly toxic protein--our review also emphasizes what is known about (i) other MC congeners (a number of studies showed a preferred accumulation of the less toxic variant MC-RR in animal tissues), (ii) nodularin (data on a range of biota from studies on the Baltic Sea), (iii) neurotoxins like anatoxin-a(s), which are conspicuously often present at times when mass mortalities of birds occur, (iv) a few studies on the presence and effects of cylindrospermposin, as well as (v) the first examples of ecological effects of newly identified bioactive compounds, like microviridin-J. Data were reorganized to assess to what extent bioconcentration (uptake and concentration of toxins from the water) or biomagnification (uptake and concentration via the food) of cyanobacterial toxins occurs in ecosystems. There is little support for the occurrence of biomagnification, and this reduces the risk for biota at higher trophic levels. Rather than biomagnification biodilution seems to occur in the foodweb with toxins being subject to degradation and excretion at every level. Nevertheless toxins were present at all tropic levels, indicating that some vectorial transport must take place, and in sufficient quantities for effects to possibly occur. Feeding seemed to be the most important route for exposure of aquatic biota to cyanobacterial toxins. A fair number of studies focus on dissolved toxins, but in those studies purified toxin typically is used, and biota do not appear very sensitive to this form of exposure. More effects are found when crude cyanobacterial cell lysates are used, indicating that there may be synergistic effects between different bioactive compounds. Aquatic biota are by no means defenseless against toxic cyanobacteria. Several studies indicate that those species that are most frequently exposed to toxins in their natural environment are also the most tolerant. Protection includes behavioral mechanisms, detoxication of MC and NODLN by conjugation with glutathione, and fairly rapid depuration and excretion. A common theme in much of the ecological studies is that of modulating factors. Effects are seldom straightforward, but are dependent on factors like the (feeding) condition of the animals, environmental conditions and the history of exposure (acclimation and adaptation to toxic cyanobacteria). This makes it harder to generalize on what is known about ecological effects of cyanobacterial toxins. The paper concludes by summarizing the risks for birds, fish, macroinvertebrates and zooplankton. Although acute (lethal) effects are mentioned in the literature, mass mortalities of--especially--fish are more likely to be the result of multiple stress factors that co-occur during cyanobacterial blooms. Bivalves appear remarkably resistant, whilst the harmful effects of cyanobacteria on zooplankton vary widely and the specific contribution of toxins is hard to evaluate.


Prostate cancer and black men.
Prostate cancer is a significant cause of death among men of all races in the United States, and it does disproportionately affect Black men. This disease poses a number of questions that desperately need answers. These questions involve not just the cause and prevention of the prostate cancer, but a very real and valid question is "does screening for and aggressive treatment of prostate cancer save lives." Almost all questions in prostate cancer are not questions unique to blacks or whites, or any specific population. These questions can only be answered through well-designed basic and clinical research studies. This research must be supported by both physician and patient participation. Conveying truthful, accurate information in this disease in which so much is unanswered is imperative. In American medical history, black men have often been misled or misinformed oftentimes by well-meaning paternalistic individuals. Physicians and laymen teaching about this disease must themselves realize and then truthfully convey "what is known, what is not known, and what is believed." This will allow the layman to make educated decisions regarding screening, treatment, and participation in clinical studies.


Monitoring the initiation and kinetics of human dendritic cell-induced polarization of autologous naive CD4+ T cells.
A crucial step in generating de novo immune responses is the polarization of naive cognate CD4+ T cells by pathogen-triggered dendritic cells (DC). In the human setting, standardized DC-dependent systems are lacking to study molecular events during the initiation of a naive CD4+ T cell response. We developed a TCR-restricted assay to compare different pathogen-triggered human DC for their capacities to instruct functional differentiation of autologous, naive CD4+ T cells. We demonstrated that this methodology can be applied to compare differently matured DC in terms of kinetics, direction, and magnitude of the naive CD4+ T cell response. Furthermore, we showed the applicability of this assay to study the T cell polarizing capacity of low-frequency blood-derived DC populations directly isolated ex vivo. This methodology for addressing APC-dependent instruction of naive CD4+ T cells in a human autologous setting will provide researchers with a valuable tool to gain more insight into molecular mechanisms occurring in the early phase of T cell polarization. In addition, it may also allow the study of pharmacological agents on DC-dependent T cell polarization in the human system.


Functional and Clinicopathologic Outcomes Using a Modified Vescica Ileale Padovana Technique.
To evaluate the clinicopathologic and functional outcomes of a modified Vescica ileale Padovana (VIP) neobladder technique. Data for 160 patients at a single institution who underwent radical cystectomy and orthotopic VIP neobladder creation between 1998 and 2013 were analyzed. Modified VIP technique involved longitudinal opening of the small bowel close to the anterior mesenteric border instead of along the true anti-mesentery. This allowed for creation of a dependent neourethral funnel and a large serosal surface for ureteral anastomosis, distant from any suture lines. Mean age for the entire cohort was 59.5, with 9% female and 64% with muscle invasive disease prior to cystectomy. Within 30 days of surgery, 16 patients (10%) developed a Clavien grade 3-4 complication and there were no deaths. Ninety-six percent reported minor or no daytime urinary leakage at 12 months, and 70% reported minor or no nighttime urinary leakage. Two- and five-year overall survival rates were 84.2% and 72.6% , respectively. Seven patients developed a ureteral stricture (4%), three (2%) had bladder neck contractures, two (1%) experienced urethral recurrence, and there were no vesicovaginal fistulas. This modified VIP neobladder technique achieves favorable functional, survival, and recurrence outcomes similar to other published orthotopic continent diversions. Its near spheroidal shape lowers internal pressure, allowing for improved continence at physiologic filling capacity, and its offset bowel opening helps prevent unnecessary stretch to the native urethra, even in large individuals. The widened uretero-enteric anastomosis site distant from bowel suture lines contributes to decreased stricture rates and its placement on the dome of the neobladder facilitates endoscopic access should strictures occur. Finally, lack of posterior overlapping suture lines also mitigates the risk of fistulae formation in females should anterior vaginal wall excision or entry be unavoidable.


[MicroRNA and cancer].
Review is devoted to analysis of the role of microRNA in progression of human tumors. The following aspects of this problem are discussed: general characteristics of microRNA, expression pattern of these RNAs in human tumors and specificity of this expression, putative role of microRNAs as oncogenes and tumor suppressors for tumor growth, participation of microRNAs in induction of transformed phenotypes of tumor cells, possible role of microRNAs for early diagnosis of the disease and prognosis.


Who are the superheroes? A cross-sectional study on the determinants of good health among Italian older adults.
People who reach old age enjoying good physical and mental health can be defined as (health) "superheroes", given their relatively low impact on healthcare expenditure and the desirable model they represent. To evaluate prevalence and possible determinants of being "physical superheroes" (i.e., free from the ten major chronic conditions, plus obesity), "mental superheroes" (i.e., free from major mental symptoms), and "superheroes" (i.e., both mental and physical superheroes). A telephone-based cross-sectional study (LOST in Lombardia) was conducted in November 2020 (i.e., during the COVID-19 pandemic) on a representative sample of 4,400 adults aged ≥ 65 years from Lombardy region, northern Italy. All participants provided both current data and data referring to one year before. Mental and physical superheroes were 59.0% and 17.6%, respectively. Superheroes were 12.8% overall, 15.1% among men, and 11.1% among women; 20.2% among individuals aged 65-69 years, 11.3% among 70-74, 10.0% among 75-79, and 8.3% among ≥ 80 years. Multivariable analysis showed that female sex, higher age, disadvantaged socio-economic status, and physical inactivity (p for trend < 0.001) were inversely related to being superheroes. People not smoking (adjusted odds ratio, aOR = 1.40), alcohol abstainers (aOR = 1.30), and those free from feelings of hopelessness (aOR = 5.92) more frequently met the definition of superheroes. During COVID-19 pandemic, the proportion of superheroes decreased by 16.3%. Differences in the older adults' health status are largely attributable to their lifestyles but are also likely due to gender, educational, and socio-economic disparities, which should be properly addressed by public health policies.


Patient-Centered Care Transition for Patients Admitted through the ED: Improving Patient and Employee Experience.
With increasing wait times in emergency departments (ED) across America, there is a need to streamline the inpatient admission process in order to decrease wait times and more important, to increase patient and employee satisfaction. One inpatient unit at New York-Presbyterian Weill Cornell Medical Center initiated a program to help expedite the inpatient admission process from the ED. The goal of the ED Bridge program is to ease the patient's transition from the ED to an inpatient unit by visiting the patient in the ED and introducing and setting expectations for the inpatient environment (i.e. telemetry alarms, roommates, hourly comfort rounds). Along with improving the patient experience, this program intends to improve the collaboration between ED nurses and inpatient nurses. With the continued support of our nurse management, hospital administrators and most important, our staff, this concept is aimed to increase patient satisfaction scores and subsequently employee satisfaction.


Options for reforming agricultural subsidies from health, climate, and economic perspectives.
Agricultural subsidies are an important factor for influencing food production and therefore part of a food system that is seen as neither healthy nor sustainable. Here we analyse options for reforming agricultural subsidies in line with health and climate-change objectives on one side, and economic objectives on the other. Using an integrated modelling framework including economic, environmental, and health assessments, we find that on a global scale several reform options could lead to reductions in greenhouse gas emissions and improvements in population health without reductions in economic welfare. Those include a repurposing of up to half of agricultural subsidies to support the production of foods with beneficial health and environmental characteristics, including fruits, vegetables, and other horticultural products, and combining such repurposing with a more equal distribution of subsidy payments globally. The findings suggest that reforming agricultural subsidy schemes based on health and climate-change objectives can be economically feasible and contribute to transitions towards healthy and sustainable food systems.


Gonadotropin-releasing hormone analog therapy failed to improve predicted final height in two children with central precocious puberty and microcephalus.
Long-acting gonadotropin-releasing hormone (GnRH) analog treatment for central precocious puberty (CPP) suppresses excessive bone maturation by inhibiting the pituitary-gonadal axis, and usually assures favorable results for growth potential. Recently, we encountered two children with CPP and microcephalus in whom GnRH analog therapy arrested pubertal development, but could not suppress bone age maturation effectively. Eventually, their final height deteriorated rather than improved. The reason why these two cases did not respond to GnRH analog therapy remains unknown. However, microcephalus and minor cerebral anomalies may have some links to deterioration of final height. Our cases suggest that careful evaluation will be required especially for CPP with microcephalus throughout treatment with GnRH analog.


[The characteristics of the electrical reactions of the sensorimotor cortex to real and mental movement in left-handed and ambidextrous subjects with speech disorders at age 6-7].
Responses of alpha-, theta- and beta-I rhythms of the sensorimotor cortex to sound, movement and its mental reproduction for the right and left hand are described in 8 normal and 11 children aged 6 to 7 years with general speech disorders (GSD). Differences in the responses of left-handers and ambidextrous children were recorded. They lie in the degree of the involvement of the hemispheres, in the character of asymmetry and rhythmical composition of the response. Ambidextrous children in health and with GSD were characterized by noticeable responsiveness of the theta rhythm. In left-handers with GSD, the responses towards movement did not differ from normal, with asymmetry of the response to sound being less. As compared to normal children, ambidextrous ones with GSD showed mirror reactions. It is assumed that in children with GSD ambidexterity may be of pathological nature.


Nanobodies: A Game-Changer in Cell-Mediated Immunotherapy for Cancer.
Nanobodies are small, single-domain antibodies that have emerged as a promising tool in cancer immunotherapy. These molecules can target specific antigens on cancer cells and trigger an immune response against them. In this mini-review article, we highlight the potential of nanobodies in cell-mediated immunotherapy for cancer treatment. We discuss the advantages of nanobodies over conventional antibodies, their ability to penetrate solid tumors, and their potential to enhance the efficacy of other immunotherapeutic agents. We also provide an overview of recent preclinical and clinical studies that have demonstrated the effectiveness of nanobody-based immunotherapy in various types of cancer.


[Iatrogenic colitis following immunotherapy : monocentric retrospective study at the University Hospital of Liège].
Checkpoint inhibitor colitis is a complication that is often underestimated when it is slow-grade, and results in relatively few hospital admissions compared to its frequency of occurrence. A strict history-taking approach, combined with an endoscopic work-up in cases of severity, is recommended. The use of the fecal calprotectin may also be useful. When used appropriately, the various lines of treatment are generally effective, and second-line therapies (biotherapies) are rarely used. However, recent evidence suggests that patients with severe symptoms should be treated more rapidly with biological therapies, especially if severity is endoscopically confirmed, as corticosteroids carry a greater risk of infection. The objective of this study is to demonstrate the efficacy of non-symptomatic, first and second line therapies for immunotherapy-related colitis in a population of patients at the CHU of Liège.


Role of cyclins in controlling progression of mammalian spermatogenesis.
Cyclins are key regulators of the mammalian cell cycle, functioning primarily in concert with their catalytic partners, the cyclin-dependent kinases (Cdks). While their function during mitosis in somatic cells has been extensively documented, their function during both mitosis and meiosis in the germ line is poorly understood. From the perspective of cell cycle regulation there are several aspects of mammalian spermatogenesis that suggest unique modes of regulation and hence, possible unique functions for the cyclins. This review will summarize our current understanding of cyclin expression and function in the male germ line, with particular focus on the A and E type cyclins in the mouse model. While the focus is on mammalian spermatogenesis, we note contrasts with similar functions in the female germ line when relevant and also draw upon observations in other model systems to provide further insight.


Chemogenomics approaches for receptor deorphanization and extensions of the chemogenomics concept to phenotypic space.
Chemogenomic approaches, which link ligand chemistry to bioactivity against targets (and, by extension, to phenotypes) are becoming more and more important due to the increasing number of bioactivity data available both in proprietary databases as well as in the public domain. In this article we review chemogenomics approaches applied in four different domains: Firstly, due to the relationship between protein targets from which an approximate relation between their respective bioactive ligands can be inferred, we investigate the extent to which chemogenomics approaches can be applied to receptor deorphanization. In this case it was found that by using knowledge about active compounds of related proteins, in 93% of all cases enrichment better than random could be obtained. Secondly, we analyze different cheminformatics analysis methods with respect to their behavior in chemogenomics studies, such as subgraph mining and Bayesian models. Thirdly, we illustrate how chemogenomics, in its particular flavor of 'proteochemometrics', can be applied to extrapolate bioactivity predictions from given data points to related targets. Finally, we extend the concept of 'chemogenomics' approaches, relating ligand chemistry to bioactivity against related targets, into phenotypic space which then falls into the area of 'chemical genomics' and 'chemical genetics'; given that this is very often the desired endpoint of approaches in not only the pharmaceutical industry, but also in academic probe discovery, this is often the endpoint the experimental scientist is most interested in.


[Optimization of the chest computed tomography scan by varying the position of the arms].
Computed tomography automatic exposure control (CT-AEC) technique is calculated from a localizer radiograph. When we perform neck and chest CT examination, at first, we acquire localizer radiograph and neck images by placing the arm in a lowered position. Next, the arm is raised for the chest scan. Therefore, the localizer radiograph and subject information are different in the chest scan. In this situation, the chest scan with the use of the CT-AEC causes radiation over-dose. The purpose of this study is to optimize the CT-AEC by controlling noise index (NI), and make a chest CT scan condition considering the position of the arms. We measured the image noise (SD) in the phantom by using CT-AEC. In addition, dose length product (DLP) was recorded. Moreover, we examined the correlation with the clinical images. The results of our experiments show that radiation dose can be reduced with the image quality kept by controlling NI.


Magnetic resonance spectroscopy detection of high lipid levels in intraaxial tumors without central necrosis: a characteristic of malignant lymphoma.
The differentiation of malignant lymphomas from gliomas or malignant gliomas by conventional MRI can be difficult. The authors studied Gd-enhanced MR images to obtain a differential diagnosis between malignant lymphomas and gliomas without central necrosis or cystic changes and investigated the diagnostic value of single-voxel proton MR spectroscopy ((1)H-MRS) using different parameters, including lipid levels. This was a retrospective study of patients with primary malignant CNS lymphoma (n = 17) and glioma (n = 122 [Grades I, II, III, and IV in 10, 30, 33, and 49 patients, respectively]) who were treated between 2007 and 2013. The authors focused on 15 patients with homogeneously enhanced primary malignant CNS lymphomas and 7 homogeneously enhanced gliomas. Images of all the included tumors were acquired with (1)H-MRS at 3 T, and the diagnoses were histologically confirmed. Using a short echo time (1)H-MRS, large lipid peaks were observed in all 17 patients with a malignant lymphoma, in 39 patients (79.6%) with a Grade IV glioma, and in 10 patients (30.3%) with a Grade III glioma. A focus on homogeneously enhanced tumors revealed large lipid peaks in 15 malignant lymphomas that were free of central necrosis on Gd-enhanced T1-weighted images. Conversely, in the 7 homogeneously enhanced gliomas (glioblastoma and anaplastic astrocytoma, n = 2 each; anaplastic oligodendroglioma, diffuse astrocytoma, and pilomyxoid astrocytoma, n = 1 each), lipid peaks were small or absent. Large lipid peaks on (1)H-MRS images of tumors without central necrosis were characteristic of malignant lymphomas. Conversely, small or absent lipid peaks in intraaxial tumors without central necrosis were strongly suggestive of glioma.