Urinalysis in children and adolescents.
Urinalysis is the most commonly performed biochemical test in infancy and early childhood. The urine sample should be correctly obtained, age-specific aspects should be considered, and age-dependent reference values should be used. This review is based on a selective literature search in electronic databases, textbooks, and guidelines from Germany and abroad on the acquisition of urine samples and the performance of urinalysis in infancy and early childhood. The timing and mode of acquisition of the urine sample affect the assessment of hematuria, proteinuria, leukocyturia, nitrituria, and the uropathogenic bacterial colony count in the urine culture. Dipstick tests can be used for targeted screening for these features. The test results should be interpreted together with the findings of urine microscopy, the medical history, and the physical examination. Proteinuria should be quantified and differentiated; both of these things can be done either from collected urine or (especially in infants and young children) from a spontaneously voided urine sample, by determination of the protein/creatinine quotient. Orthostatic proteinuria in an adolescent requires no further evaluation or treatment. Hematuria should be characterized as either glomerular or non-glomerular erythrocyturia. Asymptomatic, isolated microhematuria in childhood is not uncommon and often transient; in the absence of a family history, it usually does not require an extensive work-up. Proteinuria combined with hematuria should arouse the suspicion of glomerulonephritis. Urinalysis in infancy and early childhood is a simple and informative diagnostic test as long as the urine sample has been obtained properly and the results are interpreted appropriately for this age group.


Prevalence and factors associated to gestational diabetes mellitus among pregnant women in Libreville: a cross-sectional study.
mainly occurring in low and middle income countries, gestational diabetes mellitus (GDM) represents 84% of hyperglycemia during pregnancy throughout the world. Moreover, being black is a risk factor to develop the disease. Our objective was to determine the prevalence and the associated factors of GDM in Libreville (Gabon). a cross-sectional study was carried out. Known diabetic women were excluded from the study and we had submitted asymptomatic pregnant women to a 2 steps 75g oral glucose tolerance test (T0-T2H), regardless of the stage of pregnancy at the moment of recruitment. The threshold for positivity was set at blood glucose level ≥ 8.5mmol/L World Health Organization (WHO 2013 threshold) and ≥ 7.8mmol/L (WHO 1999 threshold). Data were analyzed using Statview® for descriptive statistics, for both bivariate and multivariate analysis. among 245 participants, we have found a GDM prevalence of 10.2% according to WHO 1999 threshold and 4.5% according to WHO 2013 threshold. Applying the WHO 1999 threshold, the associated factors were high maternal weight (p= 0.0498), overweight at recruitment (p=0.0246), personal history of GDM (p< 0.0001), age becomes an associated factor only if it is combined with high parity (p=0.0061). ceaserian-section and macrosomia were the two outcomes of GDM. Libreville has a high prevalence of GDM when the WHO 1999 criteria is compared to the WHO 2013 criteria. Discordance is also found with the identified associated factors. Further studies are needed to better appreciate gestational diabetes in Gabon.


DNA methylase induced by bacteriophage phiX174.
A cytosine-specific DNA methylase activity, which is normally absent in the Escherichia coli B strain, was found to be induced in these cells by infection with bacteriophage varphiX174. In vivo experiments revealed a single 5-methylcytosine residue in the phage DNA molecule and 5-methylcytosine residues in the infected host DNA, in addition to the 6-methylaminopurine residues present in the uninfected cells. In vitro, a partially purified enzyme from infected cells methylated DNA from uninfected cells, but showed no activity with cellular DNA from infected cells. The partially purified methylase derived from uninfected cells lacks this activity.


Chemical genomic approaches to study model microbes.
Recent genome-scale analyses of genetic interactions in model microbes have revealed the inherent functional organization of the cell as a dense network of highly interconnected pathways. While classical one gene at a time paradigms offer limited insight into cellular systems, genome-scale approaches are making considerable headway. Indeed, where small organic compounds are ideal probes of biological complexity, systematic chemical genomic methods are emerging as requisite and powerful approaches to describing both the small molecule probe and network with which it interacts. Here, we highlight various chemical genomic approaches that are being pioneered in model microbes.


Microfinance loan officers before and during Covid-19: Evidence from India.
The Microfinance industry has been severely affected by Covid-19. We provide detailed insights into how loan officers, the key personnel linking the lender to its borrowers, are affected in their performance and adapt their work to the pandemic. We use administrative records of an Indian Microfinance Institution and detailed panel survey data on performance, performed tasks, and work organization to document how the work environment became more challenging during the pandemic. Loan officers operate in a setting where work from home is hard to implement due to the nature of the tasks and technological constraints. The usual performance indicators appear to be mainly driven by external factors such as the nation-wide debt moratorium. Loan officers worked similar hours, but engaged less in planning activities and completed fewer of the usual tasks. Work perceptions and mental health of loan officers reflect these changes, and perceived stress was particularly high during the period of the debt moratorium.


Fluorescence and Multiphoton Imaging for Tissue Characterization of a Model of Postmenopausal Ovarian Cancer.
To determine the efficacy of targeted fluorescent biomarkers and multiphoton imaging to characterize early changes in ovarian tissue with the onset of cancer. A transgenic TgMISIIR-TAg mouse was used as an animal model for ovarian cancer. Mice were injected with fluorescent dyes to bind to the folate receptor α, matrix metalloproteinases, and integrins. Half of the mice were treated with 4-vinylcyclohexene diepoxide (VCD) to simulate menopause. Widefield fluorescence imaging (WFI) and multiphoton imaging of the ovaries and oviducts were conducted at 4 and 8 weeks of age. The fluorescence signal magnitude was quantified, and texture features were derived from multiphoton imaging. Linear discriminant analysis was then used to classify mouse groups. Imaging features from both fluorescence imaging and multiphoton imaging show significant changes (P < 0.01) with age, VCD treatment, and genotype. The classification model is able to classify different groups to accuracies of 75.53%, 69.53%, and 86.76%, for age, VCD treatment, and genotype, respectively. Building a classification model using features from multiple modalities shows marked improvement over individual modalities. This study demonstrates that using WFI with targeted biomarkers, and multiphoton imaging with endogenous contrast shows promise for detecting early changes in ovarian tissue with the onset of cancer. The results indicate that multimodal imaging can provide higher sensitivity for classifying tissue types than using single modalities alone. Lasers Surg. Med. © 2020 Wiley Periodicals, Inc.


In-vitro activity of dicationic aromatic compounds and fluconazole against Cryptococcus neoformans and Candida spp.
We investigated the in-vitro activity of three selected dicationic aromatic compounds for nine clinical isolates of Cryptococcus neoformans and 93 clinical isolates of Candida spp., representing 12 different species, using a broth macrodilution method following NCCLS recommendations. All the clinical isolates were also tested for fluconazole susceptibility. The in-vitro data demonstrate that compounds 39 and 57 have excellent in-vitro activity for all tested strains (MIC 0.19-1.56 mg/L) except Candida pelliculosa. Moreover, compound 39 showed excellent in-vitro fungicidal activity against Candida krusei, Candida glabrata, Candida lusitaniae and Cryptococcus neoformans with MFCs in the range 0.39-6.25 mg/L. Both compounds 39 and 57 showed excellent in-vitro activity against fluconazole-resistant Candida albicans isolates, including a C. albicans strain that contains all known fluconazole-resistant mechanisms. Comparing MIC data from compounds 21, 39 and 57 with fluconazole, we found a statistically significant difference only with compound 39 (P = 0.043). However, comparing MFC data from compounds 21, 39 and 57 with fluconazole, we found statistically significant differences with all three compounds (P < 0.00001). These data indicate the potential antifungal breadth of two bis-benzimidazoles (compounds 39 and 57) as antifungal agents against yeasts. If it can be determined that compounds 39 and 57 are effective and non-toxic in vivo, the prospect of these compounds as clinically useful antifungal agents will be enhanced.


Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis.
Rheumatoid arthritis is a severe inflammatory polyarthritis that requires long-term treatment with disease-modifying antirheumatic drugs. There is increasing concern about the influence of rheumatoid arthritis therapy on the risk for hematologic malignant neoplasms. We used a case-control design nested in a cohort of 23,810 patients with rheumatoid arthritis assembled from administrative databases covering the population of Quebec, Canada. The study was carried out from January 1, 1980, through December 31, 2003. Case patients having hematologic malignant neoplasms were ascertained from physician billing and hospitalization records; each case patient was matched for age and sex with 10 control subjects. Adjusting for clinical variables and concomitant medications, we used conditional logistic regression to analyze potential associations between disease-modifying antirheumatic drug exposures and risk for hematologic malignant neoplasms. We estimated rate ratios attributable to each disease-modifying antirheumatic drug exposure. During the study, hematologic malignant neoplasms developed in 619 patients, including lymphomas in 346 patients, leukemia in 178 patients, and multiple myelomas in 95 patients. The unadjusted rate ratios for hematologic malignant neoplasms after drug exposures were as follows: methotrexate, 1.18 (95% confidence interval [CI], 0.99-1.40); azathioprine, 1.44 (95% CI, 1.01-2.03); and cyclophosphamide, 2.21 (95% CI, 1.52-3.20). Because biologic agents first appeared in the Régie d'Assurance Maladie du Quebec formulary in 2002, there were few exposures to these drugs. Adjusted estimates suggested that hematologic cancer risk was most elevated after exposure to cyclophosphamide (rate ratio, 1.84; 95% CI, 1.24-2.73). For lymphomas only, the adjusted rate ratio after cyclophosphamide exposure was 2.12 (95% CI, 1.33-3.54). In this large cohort of patients with rheumatoid arthritis, the greatest relative risk for hematologic malignant neoplasms was noted after use of cyclophosphamide. Assessments of risk related to newer and emerging therapies should carefully consider previous and concomitant medication exposures.


Reduced sleep in Drosophila Shaker mutants.
Most of us sleep 7-8 h per night, and if we are deprived of sleep our performance suffers greatly; however, a few do well with just 3-4 h of sleep-a trait that seems to run in families. Determining which genes underlie this phenotype could shed light on the mechanisms and functions of sleep. To do so, we performed mutagenesis in Drosophila melanogaster, because flies also sleep for many hours and, when sleep deprived, show sleep rebound and performance impairments. By screening 9,000 mutant lines, we found minisleep (mns), a line that sleeps for one-third of the wild-type amount. We show that mns flies perform normally in a number of tasks, have preserved sleep homeostasis, but are not impaired by sleep deprivation. We then show that mns flies carry a point mutation in a conserved domain of the Shaker gene. Moreover, after crossing out genetic modifiers accumulated over many generations, other Shaker alleles also become short sleepers and fail to complement the mns phenotype. Finally, we show that short-sleeping Shaker flies have a reduced lifespan. Shaker, which encodes a voltage-dependent potassium channel controlling membrane repolarization and transmitter release, may thus regulate sleep need or efficiency.


Diabody-based recombinant formats of humanized IgG-like bispecific antibody with effective retargeting of lymphocytes to tumor cells.
Recently, recombinant antibodies have been dissected into antigen-binding regions and rebuilt into multivalent high-avidity formats. These new structural designs are expected to improve in vivo pharmacokinetics and efficacy in clinical use. Here, we designed effective recombinant bispecific antibody (BsAb) formats based on hEx3, a humanized bispecific diabody with epidermal growth factor receptor and CD3 retargeting. The bispecific and bivalent IgG-like antibodies engineered from hEx3 (or its single-chain form, hEx3-scDb) and the human Fc region showed stronger binding to each target cell than did monovalent diabody formats, and their affinity was identical to that of the corresponding parent IgG. The bivalent effect of the constructed IgG-like BsAbs resulted in cell cytotoxicity 10 times that of monovalent diabodies, and further, the fusion of Fc portion contributed intense cytotoxicity in peripheral blood mononuclear cells by the induction of the antibody-dependent cellular cytotoxicity. The growth-inhibition effects of IgG-like BsAbs were superior to those of the approved therapeutic antibody cetuximab, which recognizes the same epidermal growth factor receptor antigen, even when peripheral blood mononuclear cells were used as effector cells. We thus demonstrated a critical improvement in the effect of hEx3 by the bottom-up construction of IgG-like BsAbs; in adoptive immunotherapy, monotherapy without supplemental molecules may be able to induce antibody-dependent cellular cytotoxicity.


Low-dose amphotericin B lipid complex vs. conventional amphotericin B for empirical antifungal therapy of neutropenic fever in patients with hematologic malignancies--a randomized, controlled trial.
Conventional amphotericin B (c-AmB) remains the empirical antifungal treatment of choice for neutropenic patients with persistent fever of unknown origin (FUO). Unfortunately, empirical treatment with c-AmB is hampered by its safety profile, with frequent infusion-related adverse events (IRAEs) and renal toxicity. Amphotericin B lipid complex (ABLC) has been investigated for this indication due to its low toxicity profile. The recommended dose of ABLC is 5 mg/kg/d, which is five to seven times higher than the recommended dose of c-AmB. This randomized, controlled trial includes 105 adult patients with hematologic malignancies and with FUO after receiving chemotherapy or autologous stem cell transplantation. Patients were randomly allocated to receive ABLC at 1 mg/kg/d or c-AmB at 0.6 mg/kg/d for empirical antifungal therapy. The incidence of renal toxicity was significantly lower in the ABLC group, compared with c-AmB group: 8% vs. 32%, respectively (P = 0.003). The rates of IRAEs were similar in both groups (73% for ABLC vs. 77% for c-AmB). The overall response rate was 72% for ABLC compared with 48% for c-AmB (P = 0.018). This difference was mainly due to the significantly higher renal toxicity in the c-AmB group. The number of emergent fungal infections and overall mortality were similar in both groups. This randomized trial suggests that ABLC at 1 mg/kg/d produces less nephrotoxicity than c-AmB, without differences in the incidence of IRAEs and with similar efficacy.


Psychiatric malpractice case analysis: striving for objectivity.
Forensic psychiatrists, acting as expert witnesses, must be able to perform objective analyses of psychiatric malpractice cases. Accurate malpractice case analysis requires careful attention to relevant legal concepts and consideration of potential biasing influences. If forensic psychiatrists are to avoid a reliance on "experts policing experts," individual forensic psychiatrists must be fully prepared to police themselves by recognizing and avoiding certain errors in malpractice case analysis. Any effort to improve objectivity must include a clear understanding of the confounding variables. In this article, the authors discuss some potential impediments to objective analysis of malpractice cases such as the use of the wrong standard, causation, hindsight bias, and contributory negligence.


Retaining rural and remote area nurses. The Queensland, Australia experience.
Because higher-than-average turnover rates for nurses who work in remote and rural areas are the norm, the authors conducted a study to identify professional and personal factors that influenced rural nurses' decisions to resign. Using a mail survey, the authors gathered qualitative and quantitative data from nurses who had resigned from rural and remote areas in Queensland, Australia. Their findings, categorized into professional and rural influences, highlight the importance of work force planning strategies that capitalize on the positive aspects of rural and remote area practice, to retain nurses in nonmetropolitan areas.


Exploration of the Associations of lncRNA Expression Patterns with Tumor Mutation Burden and Prognosis in Colon Cancer.
Tumor mutation burden (TMB) is emerging as a new biomarker to monitor the response of cancer patients to immunotherapy. Long non-coding RNAs (lncRNAs) are critical in regulating gene expression and play a significant role in cancer-associated immune responses. However, the association between lncRNA expression patterns and TMB levels and survival outcomes remains unknown in colon cancer. In colon cancer patients from The Cancer Genome Atlas Program (TCGA), a multi-lncRNAs based classifier for predicting TMB levels was established using the least absolute shrinkage and selection operator (LASSO) method. The association between classifier index and immune-related characteristics of patients was also investigated. Quantitative polymerase chain reaction (qPCR) was used to verify the expression levels of these lncRNAs in normal and CRC cell lines. The multi-lncRNAs based classifier had ability to predict TMB level of patients with accuracy (AUC= 0.70), and the general applicability of this classifier was proved in the validation set (AUC= 0.71) and the pooled set (AUC= 0.70). The classifier index was related to three immune checkpoints (PD1, PD-L1, and CTLA-4), the infiltration level of immune cells, and immune response-related score (IFN-γ score, gene expression profiles (GEP) score, cytolytic activity (CYT) score and MHC score). A nomogram, which integrates classifier and some common clinical information, was able to predict the overall survival of colon cancer patients accurately. LncRNA expression patterns are associated with TMB, which may serve as a classifier to predict the TMB in colon cancer patients. The nomogram could potentially evaluate survival outcomes and provide a reference to better manage colon cancer patients.


Expression of DISC1-interactome members correlates with cognitive phenotypes related to schizophrenia.
Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies have implicated Disrupted-in-Schizophrenia 1 (DISC1), a leading candidate gene for schizophrenia and related psychiatric conditions, in cognitive function. Altered expression of DISC1 and DISC1-interactors has been identified in schizophrenia. Dysregulated expression of DISC1-interactome genes might, therefore, contribute to schizophrenia susceptibility via disruption of molecular systems required for normal cognitive function. Here, the blood RNA expression levels of DISC1 and DISC1-interacting proteins were measured in 63 control subjects. Cognitive function was assessed using neuropsychiatric tests and functional magnetic resonance imaging was used to assess the activity of prefrontal cortical regions during the N-back working memory task, which is abnormal in schizophrenia. Pairwise correlations between gene expression levels and the relationship between gene expression levels and cognitive function and N-back-elicited brain activity were assessed. Finally, the expression levels of DISC1, AKAP9, FEZ1, NDEL1 and PCM1 were compared between 63 controls and 69 schizophrenic subjects. We found that DISC1-interactome genes showed correlated expression in the blood of healthy individuals. The expression levels of several interactome members were correlated with cognitive performance and N-back-elicited activity in the prefrontal cortex. In addition, DISC1 and NDEL1 showed decreased expression in schizophrenic subjects compared to healthy controls. Our findings highlight the importance of the coordinated expression of DISC1-interactome genes for normal cognitive function and suggest that dysregulated DISC1 and NDEL1 expression might, in part, contribute to susceptibility for schizophrenia via disruption of prefrontal cortex-dependent cognitive functions.


Nonequilibrium statistical mechanics of the heat bath for two Brownian particles.
We propose a new look at the heat bath for two Brownian particles, in which the heat bath as a "system" is both perturbed and sensed by the Brownian particles. Nonlocal thermal fluctuations give rise to bath-mediated static forces between the particles. Based on the general sum rule of the linear response theory, we derive an explicit relation linking these forces to the friction kernel describing the particles' dynamics. The relation is analytically confirmed in the case of two solvable models and could be experimentally challenged. Our results point out that the inclusion of the environment as a part of the whole system is important for micron- or nanoscale physics.


Menstrual cycle and protein requirements of women.
A nitrogen balance study was done to determine the protein requirement of healthy young women and to evaluate the impact of the menstrual cycle on nitrogen utilization. Six healthy young women were fed a defined formula diet with progressively decreasing levels of egg white protein: 4 mg nitrogen/basal kcal for 42 days, 3 mg nitrogen/basal kcal for 28 days and 2.5 mg nitrogen/basal kcal for 22 days. Dietary energy was fixed at about 38 kcal/kg body weight and exercise was standardized. Excreta, menstrual fluids, and integumentary losses were collected. A statistically significant (P less than .001) biphasic cycle in urinary nitrogen excretion was found in every subject. Linear regression analysis predicted nitrogen requirement to be 73 +/- 20 mg nitrogen/kg body weight. When expressed per kilogram of body weight, there appears to be no significant difference in protein requirement between women and men. The urinary nitrogen cycle, however, was found to be unique to women, implying a hormonal regulation of nitrogen utilization. The failure to account for this cycle in women could lead to erroneous estimates of nitrogen requirement or large coefficients of variation.


Stimulating role of potassium ions and ouabain on glycogen synthesis in adipose tissue.
1. Exposure of fat-pads to increasing concentrations of K+ in the presence of insulin stimulates the incorporation of labelled glucose into glycogen. In the absence of hormone, only a slight incorporation of glucose into glycogen and slight glucose oxidation were detectable. 2. Ouabain alone, up to 100 microM, had no effect on synthesis of glycogen. Ouabain reinforced the effect of insulin on the conversion of glucose into glycogen in a Na+ medium and in a equimolar Na+-K+ medium, but not in a K+ medium. In addition, ouabain modified the optimal K+/Na+ ratio for glycogen synthesis. 3. The proportion of glycogen synthase in the active form was increased in a K+ medium, and a faster rate of conversion of synthase b into a was observed under these conditions. No difference was detected in the rate of inactivation of phosphorylase in a K+ or a Na+ medium. 4. Even though these results, taken together, are consistent with the proposed role of phosphorylase a in the regulation of synthase activation, the molecular mechanism of action of K+ in adipose tissue in increasing synthesis of glycogen cannot be explained simply by a faster inactivation of phosphorylase a. It is concluded that some undetermined effector(s) or signal could itself be a primary determinant for the greater activation of synthase observed in a K+ medium.


Materiel executives and the managed cost continuum in a capitated environment.
Strategies that involve supplier partnerships and pose high risk for both hospitals and suppliers are an increasing trend. The materiel management professional who is proactive and able to assess risks in a managed care contractual environment will be the winner as materiel management becomes a network function rather than individual hospital function.


White-spot lesions and gingivitis microbiotas in orthodontic patients.
White-spot lesions (WSL) associated with orthodontic appliances are a cosmetic problem and increase risk for cavities. We characterized the microbiota of WSL, accounting for confounding due to gingivitis. Participants were 60 children with fixed appliances, aged between 10 and 19 yrs, half with WSL. Plaque samples were assayed by a 16S rRNA-based microarray (HOMIM) and by PCR. Mean gingival index was positively associated with WSL (p = 0.018). Taxa associated with WSL by microarray included Granulicatella elegans (p = 0.01), Veillonellaceae sp. HOT 155 (p < 0.01), and Bifidobacterium Cluster 1 (p = 0.11), and by qPCR, Streptococcus mutans (p = 0.008) and Scardovia wiggsiae (p = 0.04) Taxa associated with gingivitis by microarray included: Gemella sanguinis (p = 0.002), Actinomyces sp. HOT 448 (p = 0.003), Prevotella cluster IV (p = 0.021), and Streptococcus sp. HOT 071/070 (p = 0.023); and levels of S. mutans (p = 0.02) and Bifidobacteriaceae (p = 0.012) by qPCR. Species' associations with WSL were minimally changed with adjustment for gingivitis level. Partial least-squares discriminant analysis yielded good discrimination between children with and those without WSL. Granulicatella, Veillonellaceae and Bifidobacteriaceae, in addition to S. mutans and S. wiggsiae, were associated with the presence of WSL in adolescents undergoing orthodontic treatment. Many taxa showed a stronger association with gingivitis than with WSL.


Mitochondria: multifaceted regulators of aging.
Aging is accompanied by a time-dependent progressive deterioration of multiple factors of the cellular system. The past several decades have witnessed major leaps in our understanding of the biological mechanisms of aging using dietary, genetic, pharmacological, and physical interventions. Metabolic processes, including nutrient sensing pathways and mitochondrial function, have emerged as prominent regulators of aging. Mitochondria have been considered to play a key role largely due to their production of reactive oxygen species (ROS), resulting in DNA damage that accumulates over time and ultimately causes cellular failure. This theory, known as the mitochondrial free radical theory of aging (MFRTA), was favored by the aging field, but increasing inconsistent evidence has led to criticism and rejection of this idea. However, MFRTA should not be hastily rejected in its entirety because we now understand that ROS is not simply an undesired toxic metabolic byproduct, but also an important signaling molecule that is vital to cellular fitness. Notably, mitochondrial function, a term traditionally referred to bioenergetics and apoptosis, has since expanded considerably. It encompasses numerous other key biological processes, including the following: (i) complex metabolic processes, (ii) intracellular and endocrine signaling/communication, and (iii) immunity/inflammation. Here, we will discuss shortcomings of previous concepts regarding mitochondria in aging and their emerging roles based on recent advances. We will also discuss how the mitochondrial genome integrates with major theories on the evolution of aging. [BMB Reports 2019; 52(1): 13-23].


Sleep disorders and ADHD symptoms in children and adolescents with typical absence seizures: An observational study.
To assess the occurrence of sleep disorders (SD) and attention deficit hyperactivity disorder (ADHD) symptoms in children with typical absence seizures (TAS) compared to control children and to evaluate the impact of epilepsy-related factors on sleep and attention in children with TAS. The Sleep Disturbance Scale for Children (SDSC) and the ADHD rating scale were filled in by parents of a cohort composed by 82 children aged from 5 to 15.6 years, 49% of boys (41 with TAS with a syndromic diagnosis of childhood absence epilepsy and 41 controls). For children with TAS, the Pediatric Epilepsy Side Effects Questionnaire was completed. Statistical analyses were conducted in order to compare sleep and attention scores between groups. In children with TAS, a correlation was computed between these scores. Logistics regression models were conducted to identify predictors of excessive diurnal sleepiness and inattention in children with TAS. Compared to controls, children with TAS had higher total scores for subjective sleep (mean 42.9 vs 38.3, p = 0.05) and attention disorders (mean 16.8 vs 11.6, p = 0.01), especially for excessive diurnal sleepiness (mean 3.9 vs 3.2, p = 0.02) and inattention (mean 9.3 vs 5.6, p = 0.003) components. In children with TAS, sleep problems were significantly under-reported by parents. Sleep disorders symptoms as breathing-related sleep disturbance, excessive diurnal sleepiness or naps at or after 7 years of age were reported. Subjective sleep and attention disorders were significantly correlated (r = 0.43, p = 0.01). Subjective excessive diurnal sleepiness may be the result of a polytherapy (p = 0.05) or a side effect of anti-seizure medication (ASM) (p = 0.03) but children without medication side effects also reported subjective SD. In children with TAS, the risk of inattention symptoms was increased in boys (p = 0.02), with a high BMI (p = 0.05), or with ASM side effects (p = 0.03). This study demonstrates that children with TAS are at risk of sleep and attention disorder symptoms. If attention disorders in a context of epilepsy are now widely assessed and identified, sleep disorders are still under-estimated. An accurate identification and management of sleep disorders could improve academic performances, quality of life, and seizure management in children with TAS.


The development of cowpea mosaic virus as a potential source of novel vaccines.
Epitopes from human rhinovirus 14 (HRV-14) and human immunodeficiency virus type (HIV-1) have been expressed on the surface of particles of the plant virus, cowpea mosaic virus (CPMV). The chimaeras retain their ability to grow in plants and large quantities of virions can be easily purified. Immunological studies have shown that purified particles have the antigenic properties of the insert, and, in the case of the HIV-1 chimaera, can elicit the production of neutralising antibodies in mice. The chimaera containing the epitope from HRV-14 has been crystallised and the crystals shown to diffract to atomic resolution.


Outcome of acute ST-segment elevation myocardial infarction in patients with prior coronary artery bypass surgery receiving thrombolytic therapy.
Patients with prior coronary bypass surgery with acute ST-segment elevation myocardial infarction (MI) pose an increasingly common clinical problem. We assessed the characteristics and outcomes of such patients undergoing thrombolysis for acute MI. We compared the characteristics and outcomes of patients in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial (GUSTO-I) who had had prior bypass (n = 1784, 4% of the population) with those without prior coronary artery bypass grafting (CABG), all of whom were randomized to receive one of four thrombolytic strategies. Patients with prior bypass were older with significantly more prior MI and angina. Overall, 30-day mortality was significantly higher in patients with prior bypass (10.7% vs 6.7% for no prior bypass, P <.001); these patients also had significantly more pulmonary edema, sustained hypotension, or cardiogenic shock. Patients with prior bypass showed a 12.5% relative reduction (95% confidence interval, 0% to 41.9%) in 30-day mortality with accelerated alteplase over the streptokinase monotherapies. In the 62% of patients with prior CABG who underwent coronary angiography, the infarct-related vessel was a native coronary artery in 61.9% and a bypass graft in 38.1% of cases. The Thrombolysis in Myocardial Infarction (TIMI) 3 flow rate was 30.5% for culprit native coronary arteries and 31.7% for culprit bypass grafts. Patients with prior bypass had more severe infarct-vessel stenoses (99% [90%, 100%] vs 90% [80%, 99%], P <.001). The 30-day mortality in patients with prior CABG was significantly higher than that for patients without prior CABG. As in the overall trial, these patients derived an incremental survival benefit from treatment with accelerated alteplase, but mortality remained high (16.7%) at 1 year. These results are at least partially explained by the higher baseline risk of these patients and by the lower rate of patency of the infarct-related artery.


Improved glucose regulation on a low carbohydrate diet in diabetic rats transplanted with macroencapsulated porcine islets.
Islet xenografts from porcine donors can reverse diabetes in experimental animal models and may be an alternative to human islet transplantation. We have recently reported the ability of porcine islets encapsulated in a double layer of hydrophilic agarose to maintain in vitro functional ability for >6 months. Although beta-cells are capable of adapting their secretory capacity in response to glucose levels, evidence has shown that prolonged hyperglycemia can compromise this ability. The aim of the present study was to determine the effects of diet manipulation on the long-term regulation of blood glucose levels, and the preservation of functional islet in the macrobeads. Twenty-one streptozotocin-induced diabetic Wistar-Furth male rats were randomly assigned to two diets containing 64% carbohydrate (CHO) or 20% CHO. Groups of five to six animals assigned to either diet were implanted with either empty (EM) or porcine islet-containing macrobeads (PIM) and followed for 333 days. Observations included general condition, body weight, blood glucose, and food and water intakes. Monthly blood samples were collected for insulin and C-peptide analysis. The 20% CHO diet significantly lowered blood glucose values when compared with those of the 64% CHO groups for both the empty (14.94 +/- 0.41 vs. 16.26 +/- 0.42 mmol/L, respectively, p < 0.001) and islet macrobead recipients (12.88 +/- 0.39 vs. 15.57 +/-0.85 mmol/L, respectively, p <0.001). The different diets, however, had no statistically significant effects on the preservation of islet mass in the macrobead. Serum porcine C-peptide was detected throughout the experiment in animals receiving porcine islet macrobeads, regardless of diet. Diabetic rats fed a low carbohydrate level diet and transplanted with porcine islet macrobeads had improved total tissue glucose disposal and improved clinical parameters associated with diabetes.


Nutritionally altering weight gain patterns of pregnant heifers and young cows changes the time that feed resources are offered without any differences in production.
We hypothesized that feed resources could be deferred to a later time in the production cycle without a decrease in fertility or weight of calf produced in heifers and young cows. One-hundred and thirty-one MARC III (four breed composite: (1/4) Hereford, (1/4) Angus, (1/4) Red Poll, and (1/4) Pinzgauer) heifers were divided into three treatments: M-M-M-M (n = 46), L-H-M-M (n = 41), and L-L-L-H (n = 44). The experiment consisted of four feeding periods. Period 1 was 94 to 186 d of gestation, and heifers were fed a moderate (M) or low (L) level of feed. Period 2 was 187 d of gestation to parturition, and heifers were fed moderate, high (H), or low levels of feed. Period 3 was from parturition through 27 d of lactation, and heifers were fed moderate or low levels of feed. Period 4 was from 28 d to approximately 63 d of lactation, and heifers were fed moderate or high levels of feed. Females remained within treatments through their first parity (heifers) and second parity (cows). Feed intake of L-H-M-M and M-M-M-M treatments did not differ from each other either as heifers (P = 0.23) or as second-parity cows (P > 0.59). The L-L-L-H heifers ate less feed than L-H-M-M and M-M-M-M heifers (P < 0.001), and second-parity L-L-L-H cows ate less feed than second-parity L-H-M-M and M-M-M-M cows (P < 0.002). In the first parity, treatments did not differ in the percentage of calves weaned (P = 0.11), weight of calf weaned (P = 0.50), or percentage of cows diagnosed pregnant (P = 0.29) with a second calf. In the second parity, treatments did not differ in the percentage of calves weaned (P = 0.77), weight of calf weaned (P = 0.63), or percentage of cows expressing a corpus luteum at the start of breeding for their third calf (P = 0.21). Our findings suggest that timing nutrient availability to heifers and primiparous cows can be used to change the time that feed resources are used.


Synergy among differentially regulated repressors of the ribonucleotide diphosphate reductase genes of Saccharomyces cerevisiae.
The Ssn6/Tup1 general repression complex represses transcription of a number of regulons through recruitment by regulon-specific DNA-binding repressors. Rox1 and Mot3 are Ssn6/Tup1-recruiting, DNA-binding proteins that repress the hypoxic genes, and Rfx1 is a Ssn6/Tup1-recruiting, a DNA-binding protein that represses the DNA damage-inducible genes. We previously reported that Rox1 and Mot3 functioned synergistically to repress a subset of the hypoxic genes and that this synergy resulted from an indirect interaction through Ssn6. We report here cross-regulation between Rox1 and Mot3 and Rfx1 in the regulation of the RNR genes encoding ribonucleotide diphosphate reductase. Using a set of strains containing single and multiple mutations in the repressor encoding genes and lacZ fusions to the RNR2 to -4 genes, we demonstrated that Rox1 repressed all three genes and that Mot3 repressed RNR3 and RNR4. Each repressor could act synergistically with the others, and synergy required closely spaced sites. Using artificial constructs containing two repressor sites, we confirmed that all three proteins could function synergistically but that two Rox1 sites or two Rfx1 sites could not. The significance of this synergy lies in the ability to repress gene transcription strongly under normal growth conditions, and yet allow robust induction under conditions that inactivate only one of the repressors. Since the interaction between the proteins is indirect, the evolution of dually regulated genes requires only the acquisition of closely spaced repressor sites.


Birth weight, childhood body mass index, and height in relation to mammographic density and breast cancer: a register-based cohort study.
High breast density, a strong predictor of breast cancer may be determined early in life. Childhood anthropometric factors have been related to breast cancer and breast density, but rarely simultaneously. We examined whether mammographic density (MD) mediates an association of birth weight, childhood body mass index (BMI), and height with the risk of breast cancer. 13,572 women (50 to 69 years) in the Copenhagen mammography screening program (1991 through 2001) with childhood anthropometric measurements in the Copenhagen School Health Records Register were followed for breast cancer until 2010. With logistic and Cox regression models, we investigated associations among birth weight, height, and BMI at ages 7 to 13 years with MD (mixed/dense or fatty) and breast cancer, respectively. 8,194 (60.4%) women had mixed/dense breasts, and 716 (5.3%) developed breast cancer. Childhood BMI was significantly inversely related to having mixed/dense breasts at all ages, with odds ratios (95% confidence intervals) ranging from 0.69 (0.66 to 0.72) at age 7 to 0.56 (0.53 to 0.58) at age 13, per one-unit increase in z-score. No statistically significant associations were detected between birth weight and MD, height and MD, or birth weight and breast cancer risk. BMI was inversely associated with breast cancer, with hazard ratios of 0.91 (0.83 to 0.99) at age 7 and 0.92 (0.84 to 1.00) at age 13, whereas height was positively associated with breast cancer risk (age 7, 1.06 (0.98 to 1.14) and age 13, 1.08 (1.00 to 1.16)). After additional adjustment for MD, associations of BMI with breast cancer diminished (age 7, 0.97 (0.88 to 1.06) and age 13, 1.01 (0.93 to 1.11)), but remained with height (age 7, 1.06 (0.99 to 1.15) and age 13, 1.09 (1.01 to 1.17)). Among women 50 years and older, childhood body fatness was inversely associated with the breast cancer risk, possibly via a mechanism mediated by MD, at least partially. Childhood tallness was positively associated with breast cancer risk, seemingly via a pathway independent of MD. Birth weight was not associated with MD or breast cancer in this age group.


Extra terrestrials: drought creates niche space for rare invertebrates in a large-scale and long-term field experiment.
Freshwater habitats are drying more frequently and for longer under the combined pressures of climate change and overabstraction. Unsurprisingly, many aquatic species decline or become locally extinct as their benthic habitat is lost during stream droughts, but less is known about the potential 'winners': those terrestrial species that may exploit emerging niches in drying riverbeds. In particular, we do not know how these transient ecotones will respond as droughts become more extreme in the future. To find out we used a large-scale, long-term mesocosm experiment spanning a wide gradient of drought intensity, from permanent flows to full streambed dewatering, and analysed terrestrial invertebrate community assembly after 1 year. Droughts that caused stream fragmentation gave rise to the most diverse terrestrial invertebrate assemblages, including 10 species with UK conservation designations, and high species turnover between experimental channels. Droughts that caused streambed dewatering produced lower terrestrial invertebrate richness, suggesting that the persistence of instream pools may benefit these taxa as well as aquatic biota. Particularly intense droughts may therefore yield relatively few 'winners' among either aquatic or terrestrial species, indicating that the threat to riverine biodiversity from future drought intensification could be more pervasive than widely acknowledged.


Discovery of N-[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides as Novel AXL Kinase Inhibitors.
The overexpression of AXL kinase has been described in many types of cancer. Due to its role in proliferation, survival, migration, and resistance, AXL represents a promising target in the treatment of the disease. In this study we present a novel compound family that successfully targets the AXL kinase. Through optimization and detailed SAR studies we developed low nanomolar inhibitors, and after further biological characterization we identified a potent AXL kinase inhibitor with favorable pharmacokinetic profile. The antitumor activity was determined in xenograft models, and the lead compounds reduced the tumor size by 40% with no observed toxicity as well as lung metastasis formation by 66% when compared to vehicle control.


Targeting the endocannabinod system to limit myocardial and cerebral ischemic and reperfusion injury.
Coronary and carotid arterial occlusion due to thrombosis after atherosclerotic plaque rupture is the major cause of myocardial and cerebral infarction. Together these acute events represent the leading cause of death worldwide. Early reperfusion is the best method to salvage the ischemic organ; however, it leads to additional damage known as reperfusion injury. A large number of experimental studies has been performed in the past aimed at targeting individual mediators of reperfusion injury such as treatment with anti-oxidants or anti-inflammatory agents. Although many agents proved beneficial in animal models of myocardial or cerebral ischemia/reperfusion, the attempts to translate these protective effects into clinical practice were mostly disappointing. Elucidating the complex cellular and molecular mechanisms involved in ischemic cell death is crucial for the development of more efficient drugs in order to improve current treatment strategies. The aim of this review is to discuss cannabinoid and endocannabinoid-mediated effects in the pathogenesis of myocardial infarction and reperfusion injury, post-myocardial infarction remodeling, as well as ischemic stroke and reperfusion injury. We report experimental evidence suggesting that targeting the endocannabinoid system might evolve as a novel therapeutic concept to limit the devastating consequences of these acute vascular events through a wide variety of mechanisms, including lowering inflammation, oxidative stress, fibrosis, and excitotoxicity, and enhanced blood flow.


Salmonella Typhimurium phage type DT160 infection in two Moluccan cockatoos (Cacatua moluccensis): clinical presentation and pathology.
This paper reports on two fatal cases of Salmonella Typhimurium phage type DT160 infection in Moluccan cockatoos (Cacatua moluccensis) from a zoological collection in Italy. No previous clinical signs were observed in birds before death, except for anorexia and mild diarrhea in one bird. At post mortem, necrotic foci surrounded by a hyperemic halo were observed in lungs, heart, liver, spleen, kidneys, and intestine. Microscopically, heterophils and macrophages with rare lymphocyte infiltration associated with gram-negative, rod-shaped bacteria aggregates were detected in necrotic foci. Bacteriology confirmed the presence of Salmonella Typhimurium phage type DT160 in the tissues of birds. The source of Salmonella Typhimurium in these birds remains unknown, but the authors emphasize the need to better control Salmonella infections in these avian species because they are important zoonotic agents and responsible for disease in animals and humans. This is the first documentation of Salmonella Typhimurium phage type DT160 infection in Moluccan cockatoos.


Peanut allergy diagnosis: A 2020 practice parameter update, systematic review, and GRADE analysis.
Given the burden of disease and the consequences of a diagnosis of peanut allergy, it is important that peanut allergy be accurately diagnosed so that an appropriate treatment plan can be developed. However, a test that indicates there is peanut sensitization present (eg, a "positive" test) is not always associated with clinical reactivity. This practice parameter addresses the diagnosis of IgE-mediated peanut allergy, both in children and adults, as pertaining to 3 fundamental questions, and based on the systematic reviews and meta-analyses, makes recommendations for the clinician who is evaluating a patient for peanut allergy. These questions relate to when diagnostic tests should be completed, which diagnostic tests to utilize, and the utility (or lack thereof) of diagnostic testing to predict the severity of a future allergic reaction to peanut.


Distinctive features arising in maximally random jammed packings of superballs.
Dense random packings of hard particles are useful models of granular media and are closely related to the structure of nonequilibrium low-temperature amorphous phases of matter. Most work has been done for random jammed packings of spheres and it is only recently that corresponding packings of nonspherical particles (e.g., ellipsoids) have received attention. Here we report a study of the maximally random jammed (MRJ) packings of binary superdisks and monodispersed superballs whose shapes are defined by |x1|2p+...+|xd|2p<or=1 with d=2 and 3, respectively, where p is the deformation parameter with values in the interval (0,infinity). As p increases from zero, one can get a family of both concave (0<p<0.5) and convex (p>or=0.5) particles with square symmetry (d=2), or octahedral and cubic symmetry (d=3). In particular, for p=1 the particle is a perfect sphere (circular disk) and for p-->infinity the particle is a perfect cube (square). We find that the MRJ densities of such packings increase dramatically and nonanalytically as one moves away from the circular-disk and sphere point (p=1). Moreover, the disordered packings are hypostatic, i.e., the average number of contacting neighbors is less than twice the total number of degrees of freedom per particle, and yet the packings are mechanically stable. As a result, the local arrangements of particles are necessarily nontrivially correlated to achieve jamming. We term such correlated structures "nongeneric." The degree of "nongenericity" of the packings is quantitatively characterized by determining the fraction of local coordination structures in which the central particles have fewer contacting neighbors than average. We also show that such seemingly "special" packing configurations are counterintuitively not rare. As the anisotropy of the particles increases, the fraction of rattlers decreases while the minimal orientational order as measured by the tetratic and cubatic order parameters increases. These characteristics result from the unique manner in which superballs break their rotational symmetry, which also makes the superdisk and superball packings distinctly different from other known nonspherical hard-particle packings.


Immunohistochemical demonstration of VIP, [Met5]-and [Leu5]-enkephalin immunoreactive nerve fibres in the human prostate and seminal vesicles.
The distribution of nerves containing immunoreactivity for the VIP and enkephalins has been demonstrated in the human prostate and seminal vesicles using the immunoperoxidase bridge. VIP-containing nerves were detected in both organs studied mainly in association with the epithelium, while nerves containing ELI seemed to be related to smooth muscle. Compared with the distribution of adrenergic and cholinergic nerves in the prostate marked differences in the density of the innervation were detected. The possible nature of these peptide-containing nerves is discussed.


Sensitivity and reproducibility of accelerometry and heart rate in physical strain assessment during prosthetic gait.
Accelerometry and heart rate (HR) are frequently used indicators of physical strain during normal daily life. The present study focused on the sensitivity and reproducibility of accelerometry (body motility, the intensity of body movement measured with accelerometry) and HR (percentage maximal heart rate reserve, %HRR(max)) in the assessment of physical strain during walking in persons with a lower leg amputation, using persons without an amputation as reference. Ten patients with an amputation of the leg and ten comparison subjects performed, at an interval of 1 month, the same walking protocol three times. Subjects walked at a preferred speed and at fixed speeds. At their preferred walking speed, speed (0.63 vs 1.31 m s(-1), P=0.001), body motility [0.53 vs 0.91 (arbitrary unit), P=0.001] and %HRR(max) (42.5 vs 27.6, P=0.02) differed between the amputation group and the comparison group. At fixed walking speeds, only %HRR(max) differed between groups ( P</=0.002) and showed a session effect ( P=0.02). The relationship between body motility and %HRR(max) in the patient group was significantly different from that in the comparison group. It can be concluded that accelerometry is strongly related with walking speed, but not sensitive to differences and changes in economy, contrary to %HRR(max). The use of accelerometry as an indicator of the level of physical strain in persons with an amputation is not feasible. The added value of a calibration procedure has to be studied.


Stimulation of glycolysis as an activation signal in rat peritoneal macrophages. Effect of glucocorticoids on this process.
1. Peritoneal macrophages were prepared from control, Escherichia coli-treated and triamcinolone acetonide-treated rats. Control and E. coli-treated rats produced resident and activated macrophages respectively. Glycolysis in these cells was studied by the fructose 2,6-bisphosphate (Fru-2,6-P2) content, lactate release and 6-phosphofructo-1-kinase (PFK-1) and 6-phosphofructo-2-kinase (PFK-2) activities. 2. In activated macrophages, lactate release and Fru-2,6-P2 content were increased several-fold compared with those in resident cells. Moreover, the response of these parameters to phorbol 12-myristate 13-acetate in activated macrophages was greater than for resident cells. 3. PFK-2 activity was moderately increased (about 3-fold), but PFK-1 activity was increased 5-fold in activated macrophages compared with resident cells. Partially purified preparations of PFK-1 were sensitive to Fru-2,6-P2, with K0.5 about 0.25 microM in both control and activated cells. However, the Vmax. of PFK-1 from activated cells was increased. In addition, AMP stimulated PFK-1, but the kinetic pattern was different from that described for Fru-2,6-P2. Moreover there was no difference in the stimulation by AMP of PFK-1 from resident and activated cells. 4. Fru-2,6-P2 content and lactate release in macrophages from triamcinolone acetonide-treated rats were decreased in both resident and activated cells. Also, the glucocorticoid inhibited PFK-1 and PFK-2 activities in both resident and activated macrophages. PFK-1 from triamcinolone acetonide-treated rats was not stimulated by Fru-2,6-P2, whereas the effect of AMP was unchanged. The effects of glucocorticoid seem to be specific for phagocytic cells, since the glucocorticoid treatment increased PFK-1 and PFK-2 activities in liver.


Calcium influence on neurotensin and beta-endorphin enhancement of ethanol sensitivity in selectively bred mouse lines.
Intracerebroventricular (icv) administration of neurotensin produced a dose-dependent increase in ethanol sensitivity as measured by blood ethanol concentration at loss of righting reflex in SS/Ibg (SS) but not in LS/Ibg (LS) mice. Central administration of calcium also enhanced ethanol sensitivity of SS and to a lesser extent LS mice. Concurrent icv administration of calcium and neurotensin resulted in an additional enhancement of sensitivity to ethanol over that seen with either substance alone in both mouse lines. A dose-dependent increase in ethanol sensitivity was also produced in response to central administration of beta-endorphin in SS mice. No additional increase in sensitivity was noted following administration of beta-endorphin plus calcium. These results suggest a specific interaction of calcium and neurotensin may be involved in the mechanism through which ethanol elicits intoxication. The difference in response of LS and SS mice to neuropeptide and calcium-induced alterations in ethanol sensitivity may be related to the genetically selected differences to the acute narcotic actions of ethanol in these mice.


Initialization for robust inverse synthesis of phase-shifting masks in optical projection lithography.
The continuous shrinkage of minimum feature size in integrated circuit (IC) fabrication incurs more and more serious distortion in the optical projection lithography process, generating circuit patterns that deviate significantly from the desired ones. Conventional resolution enhancement techniques (RETs) are facing critical challenges in compensating such increasingly severe distortion. In this paper, we adopt the approach of inverse lithography in the mask design, which is a branch of design methodology to treat it as an inverse mathematical problem. We focus on using pixel-based algorithms to design alternating phase-shifting masks with minimally distorted output, with the goal that the patterns generated should have high contrast and low dose sensitivity. This is achieved with a dynamic-programming-based initialization scheme to pre-assign phases to the layout when alternating phase-shifting masks are used. Pattern fidelity and worst case slopes are shown to improve with this initialization scheme, which are important for robustness considerations.


Flexible and Wearable Fiber Microsupercapacitors Based on Carbon Nanotube-Agarose Gel Composite Electrodes.
Fiber electrodes provide interesting opportunities for energy storage by providing both mechanical flexibility and the opportunity to impart multifunctionality to fabrics. We show here carbon nanotube (CNT)-embedded agarose gel composite fiber electrodes, with a diameter of ∼120 μm, consisting of 60 wt % CNTs that can serve as the basis for flexible and wearable fiber microsupercapacitors (mSCs). Via an extrusion process, CNT bundles are induced to align in an agarose filament matrix. Due to the shear alignment of the CNT bundles, the dehydrated filaments have an electrical conductivity as high as 8.3 S cm-1. The composite fiber electrodes are mechanically stable, enabling formation of twisted two-ply fiber mSCs integrated with a solid electrolyte. The fiber mSC shows a high capacitance (∼1.2 F cm-3), good rate retention (∼90%) at discharge current densities ranging from 5.1 to 38 mA cm-3, long cycle life under repeated charging/discharging (10% fade after 10 000 cycles) and good performance after at least 1000 cycles of deformation, with a radius of curvature of 12.3 mm (90° bend). After being coated with a thin layer of poly(dimethylsiloxane), the fiber mSCs could be cycled over 10 000 times under water. Impedance studies indicate that the superior performance is due to the high electrical conductivity along the aligned CNTs and the large electrode surface area that is accessible through the ion-conducting agarose.


Exciting chaos with noise: unexpected dynamics in epidemic outbreaks.
In this paper, we identify a mechanism for chaos in the presence of noise. In a study of the SEIR model, which predicts epidemic outbreaks in childhood diseases, we show how chaotic dynamics can be attained by adding stochastic perturbations at parameters where chaos does not exist apriori. Data recordings of epidemics in childhood diseases are still argued as deterministic chaos. There also exists noise due to uncertainties in the contact parameters between those who are susceptible and those who are infected, as well as random fluctuations in the population. Although chaos has been found in deterministic models, it only occurs in parameter regions that require a very large population base or other large seasonal forcing. Our work identifies the mechanism whereby chaos can be induced by noise for realistic parameter regions of the deterministic model where it does not naturally occur.


The effectiveness of dried cranberries ( Vaccinium macrocarpon) in men with lower urinary tract symptoms.
Lower urinary tract symptoms (LUTS) are a common condition in older men. The objective of the present study was to evaluate the efficacy and tolerability of cranberry (Vaccinium macrocarpon) powder in men at risk of prostate disease with LUTS, elevated prostate-specific antigen (PSA), negative prostate biopsy and clinically confirmed chronic non-bacterial prostatitis. Forty-two participants received either 1500 mg of the dried powdered cranberries per d for 6 months (cranberry group; n 21) or no cranberry treatment (control group; n 21). Physical examination, International Prostate Symptom Score, quality of life (QoL), five-item version of the International Index of Erectile Function (IIEF-5), basic clinical chemistry parameters, haematology, Se, testosterone, PSA (free and total), C-reactive protein (CRP), antioxidant status, transrectal ultrasound prostate volume, urinary flow rate, ultrasound-estimated post-void residual urine volume at baseline, and at 3 and 6 months, and urine ex vivo anti-adherence activity were determined in all subjects. In contrast to the control group, patients in the cranberry group had statistically significant improvement in International Prostate Symptom Score, QoL, urination parameters including voiding parameters (rate of urine flow, average flow, total volume and post-void residual urine volume), and lower total PSA level on day 180 of the study. There was no influence on blood testosterone or serum CRP levels. There was no statistically significant improvement in the control group. The results of the present trial are the first firm evidence that cranberries may ameliorate LUTS, independent of benign prostatic hyperplasia or C-reactive protein level.


Efficacy and cost effectiveness of rapid on site examination (ROSE) in management of patients with mediastinal lymphadenopathies.
The diagnostic and staging approach for the mediastinal lymphadenopathies, with or whithout pulmonary lesions endoscopically visible, is based on transbronchial needle aspiration (TBNA) during fiberoptic bronchoscopy and on mediastinoscopy. One important factor impacting on TBNA sensitivity is the rapid on site cytological examination (ROSE). The aim of this study was to evaluate the economic impact of TBNA and TBNA + ROSE, in the diagnosis of these lesions. 120 patients, affected by mediastinal lymphadenopathies suspected for lung cancer, underwent TBNA during fiberoptic bronchoscopy: 60 patients without ROSE (group A) and other 60 with ROSE (group B). Whenever needle aspirations failed to provide diagnosis, the patient underwent mediastinoscopy. The economic impact of the diagnostic process was performed. In group A, 39 patients (65%) obtained a diagnosis with TBNA while 21 patients (35%) required mediastinoscopy. In group B, 48 patients (80%) obtained a diagnosis with TBNA + ROSE, while 12 patients (20%) required mediastinoscopy. With regards to the costs of the procedures performed in the diagnostic process, the use of TBNA with ROSE as first diagnostic approach has saved a considerable amount of euros (19,413) compared to the use of TBNA without ROSE and the combined procedure increased (p < 0.02; chi square test) the sensitivity of TBNA by 15%. ROSE significantly impacts on the diagnostic yield, as well as on the overall management costs of patients with mediastinal lymphadenopathy, suspected for lung cancer.


Bone remodeling after supracondylar humeral fracture in children.
The aim of this study was to evaluate bone remodeling in treated supracondylar humeral fractures in children. The study was carried out at the Department of Pediatric Surgery of University Hospital Rijeka on 58 patients with an average of 6.2 years, followed up during 1 to 7 years. The Baumann angle of the humerus was measured by five observers on the anteroposterior radiographs of the injured elbow right after the surgery, and on routine follow-up. The results obtained were compared with the results of the Baumann angle on the healthy arm, and statistically processed. There was a significant difference in number of cases that showed an increase of Baumann angle, when related to cases with no change of the angle or its decrease. The mean value change of Baumann angle in cases of its increase was 4.22 degrees and in cases of its decrease 2.65 degrees. Because of relatively low mean values of the angles of remodelation, we concluded that an adequate reduction is essential to prevent malunion in supracondylar humeral fractures.


Upregulation of leukocyte immunoglobulin-like receptor B4 on interstitial macrophages in COPD; their possible protective role against emphysema formation.
Leukocyte immunoglobulin-like receptor B4 (LILRB4) is one of the inhibitory receptors in various types of immune cells including macrophages. Previous reports suggested that LILRB4 could be involved in a negative feedback system to prevent excessive inflammatory responses. However, its role has been unclear in chronic obstructive pulmonary disease (COPD), in which macrophages play a crucial role in the pathogenesis. In this study, we aimed to examine the changes of LILRB4 on macrophages both in the lung specimens of COPD patients and the lungs of a mouse emphysema model. We then tried to compare the differences in both inflammation and emphysematous changes of the model between wild-type and LILRB4-deficient mice in order to elucidate the role of LILRB4 in the pathogenesis of COPD. We prepared single-cell suspensions of resected lung specimens of never-smokers (n = 21), non-COPD smokers (n = 16), and COPD patients (n = 14). The identification of LILRB4-expressing cells and the level of LILRB4 expression were evaluated by flow cytometry. We analyzed the relationships between the LILRB4 expression and clinical characteristics including respiratory function. In the experiments using an elastase-induced mouse model of emphysema, we also analyzed the LILRB4 expression on lung macrophages. We compared inflammatory cell accumulation and emphysematous changes induced by elastase instillation between wild-type and LILRB4-deficient mice. The levels of surface expression of LILRB4 are relatively high on monocyte linage cells including macrophages in the human lungs. The percentage of LILRB4+ cells in lung interstitial macrophages was increased in COPD patients compared to non-COPD smokers (p = 0.018) and correlated with the severity of emphysematous lesions detected by CT scan (rs = 0.559, p < 0.001), whereas the amount of smoking showed no correlation with LILRB4 expression. Increased LILRB4 on interstitial macrophages was also observed in elastase-treated mice (p = 0.008). LILRB4-deficient mice showed severer emphysematous lesions with increased MMP-12 expression in the model. LILRB4 on interstitial macrophages was upregulated both in human COPD lungs and in a mouse model of emphysema. This upregulated LILRB4 may have a protective effect against emphysema formation, possibly through decreasing MMP-12 expression in the lungs.


Melanoma with rhabdomyosarcomatous features: a potential diagnostic pitfall.
Malignant melanoma is well-known for phenotypic plasticity, and rare cases of divergent differentiation have been described. This case report is of a tumour diagnosed as 'rhabdomyosarcoma' on the face of a man in his 80s. However, given the recent excision of an ulcerated melanoma (Breslow thickness 5.8 mm) from the same site, the more likely diagnosis would be recurrent melanoma with rhabdomyosarcomatous differentiation. This highlights a rare form of divergent differentiation and a potential diagnostic pitfall.


An observational study of pain severity, cannabis use, and benefit expenditures in work disability.
This study pools two cohorts of workers in Ontario interviewed 18 months following a disabling work-related injury to estimate the association between pain severity, cannabis use, and disability benefit expenditures. Among 1650 workers, disability benefit expenditures obtained from administrative records were combined with self-reported measures of pain symptoms and cannabis use. Disability benefit expenditures comprised wage replacement benefits and expenditures on healthcare services. Past-year cannabis use was reported by 31% of participants, with approximately one third of cannabis use attributed to the treatment of conditions arising from the work-related injury. Condition-related cannabis use was elevated among the 34% of participants reporting severe pain symptoms. In regression models adjusted for age, sex, nature of injury, opioid prescription, and pre-injury chronic conditions, participants reporting condition-related cannabis use had equivalent wage replacement benefit expenditures (β = 0.254, ns) and higher healthcare benefit expenditures (β = 0.433, p = 0.012) compared to participants who did not use cannabis. Participants reporting cannabis use unrelated to conditions arising from their work-related injury had lower wage replacement benefit expenditures (β = - 0.309, p = 0.002) and equivalent healthcare benefit expenditures (β = - 0.251, ns) compared to participants not using cannabis. This novel study of workers' compensation claimants interviewed at 18 months post-injury did not observe a substantial relationship between cannabis use and disability benefit expenditures, suggesting that neither harm nor significant benefit is associated with cannabis use. These findings contribute to understanding the potential benefits and risks associated with cannabis use in settings that have legalized cannabis use.


LATE IMPACT OF THE LAPAROSCOPIC TREATMENT OF DEEP INFILTRATING ENDOMETRIOSIS WITH SEGMENTAL COLORECTAL RESECTION.
Deep infiltrating colorectal endometriosis may severely affect the quality of life and fertility of patients. Although segmental resection is a therapeutic option that provides positive outcomes in the management of symptoms, its functional effects are still unproven. Assess the late impact of the laparoscopic approach in treating deep infiltrating endometriosis with segmental colorectal resection. Prospective case series of 46 patients submitted to laparoscopic treatment of deep infiltrating endometriosis with segmental colorectal resection between 2013 and 2016. Fertility, gynecological and bowel symptoms were assessed at the preoperative period and at three and 12 months (or more) after the procedure. Preoperative interview assessed the prevalence of infertility (45.6%), gynecological (87%) and intestinal (80.4%) symptoms. At the third month after the procedure a significant reduction in the prevalence of gynecological symptoms (p<0,001), tenesmus (p=0,001) and dysquesia (p=0,002) was observed. After a period of 12 months or more following the procedure a significant reduction in the prevalence persisted for dysmenorrhea (p=0,001), deep dyspareunia (p=0,041), chronic pelvic pain (p=0,011) and dysquesia (p=0,001), as compared to the preoperative period. Total pregnancy rate was 57.1% and spontaneous pregnancy 47.6%. The treatment of deep infiltrating endometriosis using segmental colorectal resection has provided early and late relief of gynecological and bowel symptoms. The outcomes also indicate a positive impact on the fertility of infertile patients.


Molecular evolution of B6 enzymes: binding of pyridoxal-5'-phosphate and Lys41Arg substitution turn ribonuclease A into a model B6 protoenzyme.
The pyridoxal-5'-phosphate (PLP)-dependent or vitamin B6-dependent enzymes that catalyze manifold reactions in the metabolism of amino acids belong to no fewer than four evolutionarily independent protein families. The multiple evolutionary origin and the essential mechanistic role of PLP in these enzymes argue for the cofactor having arrived on the evolutionary scene before the emergence of the respective apoenzymes and having played a dominant role in the molecular evolution of the B6 enzyme families. Here we report on an attempt to re-enact the emergence of a PLP-dependent protoenzyme. The starting protein was pancreatic ribonuclease A (RNase), in which active-site Lys41 or Lys7 readily form a covalent adduct with PLP. We screened the PLP adduct of wild-type RNase and two variant RNases (K7R and K41R) for catalytic effects toward L- and D-amino acids. RNase(K41R)-PLP, in which the cofactor is bound through an imine linkage to Lys7, qualifies for a model proto-B6 enzyme by the following criteria: (1) covalent linkage of PLP (internal aldimine); (2) catalytic activity toward amino acids that depends on formation of an imine linkage with the substrate (external aldimine); (3) adjoining binding sites for the cofactor and amino acid moiety that facilitate the transimination reaction of the internal to the external aldimine and stabilize the resulting noncovalent complex of the coenzyme-substrate adduct with the protein; (4) reaction specificity, the only detectable reactions being racemization of diverse amino acids and beta-decarboxylation of L-aspartate; (5) acceleration factors for racemization and beta-decarboxylation of >103 over and above that of PLP alone; (6) ribonuclease activity that is 103-fold lower than that of wild-type RNase, attenuation of a pre-existing biological activity being indispensable for the further evolution as a PLP-dependent protoenzyme. A single amino acid substitution (Lys41Arg) and covalent binding of PLP to active-site Lys7 suffice to turn pancreatic ribonuclease A into a protein catalyst that complies with all plausible criteria for a proto-B6 enzyme. The study thus retraces in a model system what may be considered the committed step in the molecular evolution of a potential ancestor of a B6 enzyme family.


L- and P-selectin and CD11/CD18 in intracapillary neutrophil sequestration in rabbit lungs.
Infusion of complement fragments induces rapid sequestration of neutrophils within pulmonary capillaries. This study examined the mechanisms through which this sequestration occurs, as well as the effect of complement fragments on the expression of L-selectin and CD11/CD18 using ultrastructural immunohistochemistry. Studies using anti-P-selectin antibodies, fucoidin, L-selectin-depleted neutrophils, and anti-CD18 antibodies showed that selectins and CD18 were not required for neutrophil sequestration. However, maintaining the sequestered neutrophils within the pulmonary capillaries required both L-selectin and CD11/CD18. Neutrophils in the pulmonary capillaries of rabbits given complement fragments expressed 72% less L-selectin and 98% more CD11/CD18 than did those in rabbits given saline. Shedding of L-selectin occurred preferentially from the microvillar processes of the plasma membrane rather than from the flat intervening regions. About 28% of L-selectin still remained on intracapillary neutrophil membranes after 15 min and was likely available for binding. Shedding of L-selectin appeared slower in vivo than in vitro. These studies indicate that neutrophil sequestration induced by complement fragments requires at least two sequential steps, one that does not require recognized adhesion molecules followed by a second that requires L-selectin and CD11/ CD18.


Efficient and improved prediction of the band offsets at semiconductor heterojunctions from meta-GGA density functionals: A benchmark study.
Accurate theoretical prediction of the band offsets at interfaces of semiconductor heterostructures can often be quite challenging. Although density functional theory has been reasonably successful to carry out such calculations, efficient, accurate semilocal functionals are desirable to reduce the computational cost. In general, the semilocal functionals based on the generalized gradient approximation (GGA) significantly underestimate the bulk bandgaps. This, in turn, results in inaccurate estimates of the band offsets at the heterointerfaces. In this paper, we investigate the performance of several advanced meta-GGA functionals in the computational prediction of band offsets at semiconductor heterojunctions. In particular, we investigate the performance of r2SCAN (two times revised strongly constrained and appropriately normed functional), rMGGAC (revised semilocal functional based on cuspless hydrogen model and Pauli kinetic energy density functional), mTASK (modified Aschebrock and Kümmel meta-GGA functional), and local modified Becke-Johnson exchange-correlation functionals. Our results strongly suggest that these meta-GGA functionals for supercell calculations perform quite well, especially, when compared to computationally more demanding GW calculations. We also present band offsets calculated using ionization potentials and electron affinities, as well as band alignment via the branch point energies. Overall, our study shows that the aforementioned meta-GGA functionals can be used within the density functional theory framework to estimate the band offsets in semiconductor heterostructures with predictive accuracy.


ACOG committee opinion. Von Willebrand's disease in gynecologic practice.
Von Willebrand's disease is one of the most common inherited bleeding disorders. Inherited and acquired disorders of coagulation and hemostasis should be considered in the differential diagnosis of menorrhagia and abnormal uterine bleeding. This Committee Opinion provides screening recommendations for von Willebrand's disease and describes treatment options.


The effect of endothelial cells on hESC-derived pancreatic progenitors in a 3D environment.
Generating transplantable β-like-cells from human embryonic stem cells (hESC) could serve as an ideal cell-based therapy for treatment of type 1 diabetes, which is characterized by the destruction of insulin-secreting pancreatic β-cells. There are several protocols for differentiating hESCs into pancreatic or endocrine precursors. However, so far, production of mature, functional β-like-cells has been achieved mainly by transplanting hESC derived pancreatic progenitors (PPs) and allowing several months for maturation to occur in vivo. One approach, believed to have potential in promoting differentiation into β-like-cells prior to transplantation, is culturing PPs alongside blood vessels. Endothelium and blood vessels have been shown to direct pancreatic development during embryogenesis and also induce endocrine differentiation in vitro. Here we designed a three-dimensional (3D) construct utilizing highly porous polymeric scaffolds that mimic natural conditions and provide cells with mechanical support, and used it in the differentiation protocol. Clusters of hESC derived pancreatic precursor cells were embedded within the scaffolds along with human endothelial cells (ECs) and fibroblasts forming vessel-like networks. Culturing these clusters with ECs for one week significantly increased the population of PPs, characterized by co-expression of the pancreatic markers Pdx1 and Nkx6.1 and also highly induced Ngn3 expression which indicates commitment to endocrine fate. The presence of fibroblasts, however, reduced this cell population. Three months upon implantation of constructs containing clusters and ECs or clusters alone, implanted mice retained normal blood glucose levels after treatment with STZ, while un-implanted mice became diabetic. These findings may lay the foundation for creating an optimal tissue-construct that will support PPs' maturation in vitro and enhance graft function upon implantation.


Anatomic and visual outcomes of scleral buckling versus primary vitrectomy in pseudophakic and aphakic retinal detachment: six-month follow-up results of a single operation--report no. 1.
To compare the anatomic and visual results and complications of conventional scleral buckling versus primary vitrectomy for management of pseudophakic and aphakic retinal detachment. Prospective, randomized, multicenter clinical trial. Two hundred twenty-five eyes of 225 patients with pseudophakic or aphakic retinal detachment. Eligible eyes were assigned randomly either to conventional scleral buckling or primary vitrectomy without any buckle. Visual results, retinal reattachment rate, proliferative vitreoretinopathy, macular pucker, cystoid macular edema, choroidal detachment, intraocular pressure, extraocular muscle dysfunction, and anisometropia. There were no statistically significant differences between the 2 treatment groups regarding the single-operation retinal reattachment rate at the 1-, 2-, 4-, and 6-month follow-up examinations. Patients in the buckle group had 28% greater likelihood of anatomic success compared with those in the vitrectomy group (odds ratio, 1.28; 95% confidence interval, 0.73-2.24), indicating no statistically significant difference. Proliferative vitreoretinopathy was the main cause of anatomic failure in both groups and occurred independent of the surgical technique used. Best-corrected visual acuity at the 1-, 2-, 4-, and 6-month postoperative follow-up examinations showed no statistically significant difference between the 2 groups. Six months after surgery, 12.8% of eyes in the buckle group and 11.3% of eyes in the vitrectomy group achieved visual acuity of 20/40 or better. The difference between the 2 groups was not statistically significant. Corresponding figures were 66.3% and 64.5% for visual acuity of 20/200 or better in the buckle and vitrectomy groups, respectively, again with no statistically significant difference. There were no statistically significant differences in rates of complications. Scleral buckling and primary vitrectomy without an encircling band have comparable results in pseudophakic and aphakic retinal detachment. The choice of surgical technique depends on various factors, including patient compliance, cost of surgery, experience and capability of surgeons, and availability of appropriate instrumentation.


mig-5/Dsh controls cell fate determination and cell migration in C. elegans.
Cell fate determination and cell migration are two essential events in the development of an organism. We identify mig-5, a Dishevelled family member, as a gene that regulates several cell fate decisions and cell migrations that are important during C. elegans embryonic and larval development. In offspring from mig-5 mutants, cell migrations are defective during hypodermal morphogenesis, QL neuroblast migration, and the gonad arm migration led by the distal tip cells (DTCs). In addition to abnormal migration, DTC fate is affected, resulting in either an absent or an extra DTC. The cell fates of the anchor cell in hermaphrodites and the linker cells in the male gonad are also defective, often resulting in the cells adopting the fates of their sister lineage. Moreover, 2 degrees vulval precursor cells occasionally adopt the 3 degrees vulval cell fate, resulting in a deformed vulva, and the P12 hypodermal precursor often differentiates into a second P11 cell. These defects demonstrate that MIG-5 is essential in determining proper cell fate and cell migration throughout C. elegans development.


Application of machine learning in prediction of hydrotrope-enhanced solubilisation of indomethacin.
Systematic in-vitro studies have been conducted to determine the ability of a range of 10 potential hydrotropes to improve the apparent aqueous solubility of the poorly water soluble drug, indomethacin. Solubilisation of the drug in the presence of the hydrotropes was determined experimentally using high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. These experimental data, together with various known and computed physicochemical properties of the hydrotropes were thereafter used in silico to train an artificial neural network (ANN) to allow for predictions of indomethacin solubilisation. The trained ANN was found to give highly accurate predictions of indomethacin solubilisation in the presence of hydrotropes and was thus shown to provide a valuable means by which hydrotrope efficacy could be screened computationally. Interrogation of the network connection weights afforded a quantitative assessment of the relative importance of the various hydrotrope physicochemical properties in determining the extent of the enhancement in indomethacin solubilisation. It is concluded that in-silico screening of drug/hydrotrope systems using artificial neural networks offers significant potential to reduce the need for extensive laboratory testing of these systems, and could thus provide an economy in terms of reduced costs and time in drug formulation development.


Eastern equine encephalitis transmission to emus (Dromaius novaehollandiae) in Volusia County, Florida: 1992 through 1994.
From May 1992 through October 1994, sera were collected from 204 domestic emus (Dromaius novaehollandiae) at a ranch in Volusia County, FL, and tested for antibody evidence of arboviral infection. Hemagglutination-inhibition (HI) and neutralizing (NT) antibodies to eastern equine encephalitis (EEE) virus were identified in sera collected during each year. In addition, HI and NT antibodies to St. Louis encephalitis virus were detected in 3 naturally infected emus. Isolations of EEE virus were made from emu blood and tissues collected in 1992 and 1994, when EEE-related mortality in emus was 14% and 1%, respectively. A total of 259 mosquito pools was collected and tested for arbo-viruses during the 3-year study. The EEE virus was isolated from 4 of 140 mosquito pools (2 Anopheles crucians and 2 Culex erraticus pools) in 1992 and 3 of 10 pools (all Culex nigripalpus) in 1994. Emus vaccinated against EEE virus showed evidence of short-term HI antibody acquisition. Evidence of EEE antibody transfer from naturally infected hens to their offspring is reported.


The effect of different Global Navigation Satellite System methods on positioning accuracy in elite alpine skiing.
In sport science, Global Navigation Satellite Systems (GNSS) are frequently applied to capture athletes' position, velocity and acceleration. Application of GNSS includes a large range of different GNSS technologies and methods. To date no study has comprehensively compared the different GNSS methods applied. Therefore, the aim of the current study was to investigate the effect of differential and non-differential solutions, different satellite systems and different GNSS signal frequencies on position accuracy. Twelve alpine ski racers were equipped with high-end GNSS devices while performing runs on a giant slalom course. The skiers' GNSS antenna positions were calculated in three satellite signal obstruction conditions using five different GNSS methods. The GNSS antenna positions were compared to a video-based photogrammetric reference system over one turn and against the most valid GNSS method over the entire run. Furthermore, the time for acquisitioning differential GNSS solutions was assessed for four differential methods. The only GNSS method that consistently yielded sub-decimetre position accuracy in typical alpine skiing conditions was a differential method using American (GPS) and Russian (GLONASS) satellite systems and the satellite signal frequencies L1 and L2. Under conditions of minimal satellite signal obstruction, valid results were also achieved when either the satellite system GLONASS or the frequency L2 was dropped from the best configuration. All other methods failed to fulfill the accuracy requirements needed to detect relevant differences in the kinematics of alpine skiers, even in conditions favorable for GNSS measurements. The methods with good positioning accuracy had also the shortest times to compute differential solutions. This paper highlights the importance to choose appropriate methods to meet the accuracy requirements for sport applications.


[Supernumerary penis. Report of a case].
To report the case of a newborn with a supernumerary penis. To make this extremely rare pathological entity known, although the newborn was not operated due to religious beliefs, so that histological evaluation was not performed. We report the case of a newborn that was found to have a perianal malformation at the time of birth. On call, the urologist diagnosed all the characteristics of a supernumerary penis with a blind urethral meatus and empty scrotum after physical examination. With the diagnosis of supernumerary penis on physical examination proper tests, like blood tests, X-rays and sexual chromosomes were performed, but surgery was not allowed by his parents and the patient was discharge from the hospital.


Evidence of Epstein-Barr virus heterogeneous gene expression in adult lung transplant recipients with posttransplant lymphoproliferative disorder.
Epstein-Barr virus (EBV)-driven posttransplant lymphoproliferative disorder (PTLD) is a serious complication following lung transplant. The extent to which the presence of EBV in PTLD tissue is associated with survival is uncertain. Moreover, whether the heterogeneity in expression of EBV latency programs is related to the timing of PTLD onset remains unexplored. We retrospectively performed a comprehensive histological evaluation of EBV markers at the tissue level in 34 adult lung transplant recipients with early- and late-onset PTLD. Early-onset PTLD, occurring within the first 12 months posttransplant, had higher odds to express EBV markers. The presence of EBV in PTLD was not associated with a difference in survival relative to EBV-negative tumors. However, we found evidence of heterogeneous expression of EBV latency programs, including type III, IIb, IIa, and 0/I. Our study suggests that the heterogeneous expression of EBV latency programs may represent a mechanism for immune evasion in patients with PLTD after lung transplants. The recognition of multiple EBV latency programs can be used in personalized medicine in patients who are nonresponsive to traditional types of chemotherapy and can be potentially evaluated in other types of solid organ transplants.


Electron affinity of the methyl radical: Structures of CH(3) and CH(3)-.
Ab initio self-consistent field and configuration interaction calculations are presented for the methyl radical and anion. The methyl radical is shown to be planar (D(3h)), while the anion is pyramidal (C(3v)). The methyl anion is unstable with respect to the limit of CH(3) plus an electron by 2-8 kcal/mole. Potential curves for the out-of-plane bending motions of both molecules are presented.


[My interpretation as a pediatrician of "Las Meninas"].
Las Meninas from Velázquez is one of the most important pictures in the world nevertheless, there is not an interpretation out of doubt of his meaning, in spite of all the studies written about it. After an original study of the history of Las Meninas, the persons painted, what are they doing, the Spanish culture on the time in what was painted and the historical life of the Infanta Margarita, the central personage of the picture, the author arrives to the conclusion about the possibility that she had a precocious puberty.


Men's facial masculinity: when (body) size matters.
Recent studies suggest that judgments of facial masculinity reflect more than sexually dimorphic shape. Here, we investigated whether the perception of masculinity is influenced by facial cues to body height and weight. We used the average differences in three-dimensional face shape of forty men and forty women to compute a morphological masculinity score, and derived analogous measures for facial correlates of height and weight based on the average face shape of short and tall, and light and heavy men. We found that facial cues to body height and weight had substantial and independent effects on the perception of masculinity. Our findings suggest that men are perceived as more masculine if they appear taller and heavier, independent of how much their face shape differs from women's. We describe a simple method to quantify how body traits are reflected in the face and to define the physical basis of psychological attributions.


Cryptococcus neoformans differential gene expression detected in vitro and in vivo with green fluorescent protein.
Synthetic green fluorescent protein (GFP) was used as a reporter to detect differential gene expression in the pathogenic fungus Cryptococcus neoformans. Promoters from the C. neoformans actin, GAL7, or mating-type alpha pheromone (MFalpha1) genes were fused to GFP, and the resulting reporter genes were used to assess gene expression in serotype A C. neoformans. Yeast cells containing an integrated pACT::GFP construct demonstrated that the actin promoter was expressed during vegetative growth on yeast extract-peptone-dextrose medium. In contrast, yeast cells containing the inducible GAL7::GFP or MFalpha1::GFP reporter genes expressed significant GFP activity only during growth on galactose medium or V-8 agar, respectively. These findings demonstrated that the GAL7 and MFalpha1 promoters from a serotype D C. neoformans strain function when introduced into a serotype A strain. Because the MFalpha1 promoter is induced by nutrient deprivation and the MATalpha locus containing the MFalpha1 gene has been linked with virulence, yeast cells containing the pMFalpha1::GFP reporter gene were analyzed for GFP expression in the central nervous system (CNS) of immunosuppressed rabbits. In fact, significant GFP expression from the MFalpha1::GFP reporter gene was detected after the first week of a CNS infection. These findings suggest that there are temporal, host-specific cues that regulate gene expression during infection and that the MFalpha1 gene is induced during the proliferative stage of a CNS infection. In conclusion, GFP can be used as an effective and sensitive reporter to monitor specific C. neoformans gene expression in vitro, and GFP reporter constructs can be used as an approach to identify a novel gene(s) or to characterize known genes whose expression is regulated during infection.


Curcumin blocks RON tyrosine kinase-mediated invasion of breast carcinoma cells.
We have recently shown that macrophage-stimulating protein (MSP) promotes the invasion of recepteur d'origine nantais (RON), a tyrosine kinase receptor-positive MDA-MB-231, MDA-MB-468 breast cancer cells, and also identified the regulatory elements required for RON gene expression. In this report, we have analyzed the efficacy of a chemopreventive agent, curcumin, in blocking RON tyrosine kinase-mediated invasion of breast cancer cells. Reverse transcription-PCR and Western analysis indicated the down-regulation of the RON message and protein, respectively, in MDA-MB-231 and MDA-MB-468 cells. Significantly, curcumin-mediated inhibition of RON expression resulted in the blockade of RON ligand, MSP-induced invasion of breast cancer cells. We have identified two putative nuclear factor-kappaB p65 subunit binding sites on the RON promoter. Using chromatin immunoprecipitation analysis and site-directed mutagenesis of the RON promoter, we have confirmed the binding of p65 to the RON promoter. Our data show that curcumin reduces RON expression by affecting p65 protein expression and transcriptional activity. Treatment of MDA-MB-231 cells with pyrrolidine dithiocarbamate, an inhibitor of p65, or small interfering RNA knockdown of p65, blocked RON gene expression and MSP-mediated invasion of MDA-MB-231 cells. This is the first report showing the regulation of human RON gene expression by nuclear factor-kappaB and suggests a potential therapeutic role for curcumin in blocking RON tyrosine kinase-mediated invasion of carcinoma cells.


[Teaching to inhale: better utilization of powder inhalators after counseling and instruction].
To study the effect of instruction of patients who used an dry powder device on the correct performance of the inhalation technique and whether the effect lasts. Prospective. A number of patients who used at least one drug by the dry powder devices Diskhaler or Diskus/Accuhaler were asked to demonstrate their inhalation technique in the outpatient clinic, Department of Pulmonary Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands. On a score list the receptionist recorded the correctness of every step of use of the device. Then information and instruction on the correct performance of the inhalation technique were supplied by the same receptionist until the patient mastered the inhalation technique. A simple instruction card was handed to the patient. At the next outpatient visit the effect of the instruction was measured by means of the same score list registered by the same or another receptionist. Data from 97 patients could be evaluated; 42 men and 55 women, with a mean age of 58 years (range: 16-84). The percentage of patients who performed all essential actions correctly increased from 12 to 62. Almost all actions were performed better at the second than at the first visit. Better inhaling technique was observed in the 53 patients who paid their second visit within 30 days as well as in the 44 who came later (mean: 96 days; range: 34-352). The performance of the inhalation technique with the Diskhaler and the Diskus/Accuhaler was poor. By means of instruction the inhalation technique improved. This improvement was also seen in the group checked after an average of 3 months.


Enhanced photoluminescence from mixed-valence Eu-doped nanocrystalline silicate glass ceramics.
Intense photoluminescence was observed from mixed-valence Eu-doped nanocrystalline BaAl₂Si₂O₈/LaBO₃ glass ceramics. For preparation in air, the ratio between Eu3+ and Eu2+ luminescence depends on synthesis temperature. XRD, TEM and IR absorption spectra were employed to characterize the crystallization process and structural properties of the precursor glass and corresponding glass ceramics. When annealed at 950 °C, the material exhibited photoluminescence more than ten times stronger than was found in its glassy state. Spectroscopic data indicate that during such a heat treatment, even in air, a significant part of the Eu3+ ions is reduced to Eu2+. Lifetime of the ⁵D₀ state of Eu3+ increases with increasing heat treatment temperature. Eu3+ species are largely incorporated on La3+ sites in LaBO₃ crystallites whereas Eu2+ locates on Ba2+ sites in the hexacelsian phase. A mechanism for the internal reduction of Eu3+ to Eu2+ is proposed. Spectroscopic properties of the material suggest application in additive luminescent light generation.


Characterization of the effect of quinidine on Na transport by the toad and turtle bladders.
Quinidine inhibits Na transport by the toad and turtle bladder. This effect of quinidine is thought to be mediated by an increase in cytosolic calcium. In the present study, we characterized the effect of quinidine on Na transport by the toad and turtle bladders. Quinidine induced a release of calcium by turtle liver mitochondria. Quinidine inhibited Na transport by increasing the resistance of the active pathway to Na transport without affecting the electromotive force. Amphotericin B addition to the mucosal solution partially reversed the inhibitory effect of quinidine on Na transport, thus suggesting that quinidine decreases Na transport by decreasing the permeability of luminal membrane to Na. The effect of amiloride was unaltered in the presence of quinidine. Vasopressin failed to stimulate Na transport in the presence of quinidine, suggesting that the drug interferes with the natriferetic effect in addition to interfering with the hydrosmotic effect. The effect of quinidine was not prevented by inhibition of cyclooxygenase system or mitochondrial inhibition, thus suggesting that alterations in prostaglandin release or mitochondrial function are not involved in the inhibition of Na transport by quinidine.