Inter- and Intrarater Agreement on the Outcome of Endovascular Treatment of Aneurysms Using MRA.
Patients treated with coiling are often followed by MR angiography. Our objective was to assess the inter- and intraobserver agreement in diagnosing aneurysm remnants and recurrences by using multimodality imaging, including TOF MRA. A portfolio composed of 120 selected images from 56 patients was sent to 15 neuroradiologists from 10 institutions. For each case, raters were asked to classify angiographic results (3 classes) of 2 studies (32 MRA-MRA and 24 DSA-MRA pairs) and to provide a final judgment regarding the presence of a recurrence (no, minor, major). Six raters were asked to independently review the portfolio twice. A second study, restricted to 4 raters having full access to all images, was designed to validate the results of the electronic survey. The proportion of cases judged to have a major recurrence varied between 16.1% and 71.4% (mean, 35.0% ± 12.7%). There was moderate agreement overall (κ = 0.474 ± 0.009), increasing to nearly substantial (κ = 0.581 ± 0.014) when the judgment was dichotomized (presence or absence of a major recurrence). Agreement on cases followed-up by MRA-MRA was similarly substantial (κ = 0.601 ± 0.018). The intrarater agreement varied between fair (κ = 0.257 ± 0.093) and substantial (κ= 0.699 ± 0.084), improving with a dichotomized judgment concerning MRA-MRA comparisons. Agreement was no better when raters had access to all images. There is an important variability in the assessment of angiographic outcomes of endovascular treatments. Agreement on the presence of a major recurrence when comparing 2 MRA studies or the MRA with the last catheter angiographic study can be substantial.


Ultra-processed food consumption and excess weight among US adults.
Ultra-processed foods provide 58 % of energy intake and 89 % of added sugars in the American diet. Nevertheless, the association between ultra-processed foods and excess weight has not been investigated in a US sample. The present investigation therefore aims to examine the association between ultra-processed foods and excess weight in a nationally representative sample of US adults. We performed a cross-sectional analysis of anthropometric and dietary data from 15 977 adults (20-64 years) participating in the National Health and Nutrition Examination Survey 2005-2014. Dietary data were collected by 24-h recall. Height, weight and waist circumference (WC) were measured. Foods were classified as ultra-processed/non-ultra-processed according to the NOVA classification. Multivariable linear and logistic regression was used to evaluate the association between ultra-processed food consumption (% energy) and BMI, WC and odds of BMI≥25 kg/m2, BMI≥30 kg/m2 and abdominal obesity (men: WC≥102 cm, women: WC≥88 cm). Prevalence of BMI≥25 kg/m2, BMI≥30 kg/m2 and abdominal obesity was 69·2, 36·1 and 53·0 %, respectively. Consuming ≥74·2 v. ≤36·5 % of total energy from ultra-processed foods was associated with 1·61 units higher BMI (95 % CI 1·11, 2·10), 4·07 cm greater WC (95 % CI 2·94, 5·19) and 48, 53 and 62 % higher odds of BMI≥25 kg/m2, BMI≥30 kg/m2 and abdominal obesity, respectively (OR 1·48; 95 % CI 1·25, 1·76; OR 1·53; 95 % CI 1·29, 1·81; OR 1·62; 95 % CI 1·39, 1·89, respectively; P for trend<0·001 for all). A significant interaction between being female and ultra-processed food consumption was found for BMI (F 4,79=4·89, P=0·002), WC (F 4,79=3·71, P=0·008) and BMI≥25 kg/m2 (F 4,79=5·35, P<0·001). As the first study in a US population, our findings support that higher consumption of ultra-processed food is associated with excess weight, and that the association is more pronounced among women.


Hyper-fractionated radiotherapy for soft tissue sarcoma: results of the second study of hyper-fractionated radiotherapy.
Purpose and Method. Hyper-fractionated radiotherapy for treatment of soft tissue sarcomas is designed to deliver a higher total dose of radiation without an increase in late normal tissue damage. In a previous study at the Royal Marsden Hospital, a total dose of 75 Gy using twice daily 1.25 Gy fractions resulted in a higher incidence of late damage than conventional radiotherapy using 2 Gy daily fractions treating to a total of 60 Gy. The current trial therefore used a lower dose per fraction of 1.2 Gy and lower total dose of 72 Gy, with 60 fractions given over a period of 6 weeks.Subjects. A total of 37 patients (22 males and 15 females) with a median age of 56 years (range 19-88 years) were treated.Results. Of eight patients treated pre-operatively, six showed a partial response and in two the tumour was static. The maximum acute toxicities were grade 1 in eight, grade 2 in 14 and grade 3 in 15 patients. Late toxicities of the skin were graded 1 in 10 and grade 2 in nine patients. Five patients complained of pain in the irradiated bone and soft tissues, which was of moderate severity (grade 2). Stiffness was graded 2 in three patients and severe (grade 3) in one.Three patients had moderate and one patient had severe lymphoedema following treatment. The 5-year recurrence-free survival probability of patients treated radically was 76%. Following excision of local recurrences the study group had a disease-free survival probability of 86% at 5 years.Discussion. The regime is well tolerated with comparable local control and late complication rates to standard daily fractionated therapy.The potential benefit of this regime needs to be defined in a prospective randomized trial.


The word class effect in the picture-word interference paradigm.
The word class effect in the picture-word interference paradigm is a highly influential finding that has provided some of the most compelling support for word class constraints on lexical selection. However, methodological concerns called for a replication of the most convincing of those effects. Experiment 1 was a direct replication of Pechmann and Zerbst (2002; Experiment 4). Participants named pictures of objects in the context of noun and adverb distractors. Naming took place in bare noun and sentence frame contexts. A word class effect emerged in both bare noun and sentence frame naming conditions, suggesting a semantic origin of the effect. In Experiment 2, participants named objects in the context of noun and verb distractors whose word class relationship to the target and imageability were orthogonally manipulated. As before, naming took place in bare noun and sentence frame naming contexts. In both naming contexts, distractor imageability but not word class affected picture naming latencies. These findings confirm the sensitivity of the picture-word interference paradigm to distractor imageability and suggest the paradigm is not sensitive to distractor word class. The results undermine the use of the word class effect in the picture-word interference paradigm as supportive of word class constraints during lexical selection.


On the role of intermolecular vibrational motions for ice polymorphs. II. Atomic vibrational amplitudes and localization of phonons in ordered and disordered ices.
We investigate the vibrational amplitudes and the degree of the phonon localization in 19 ice forms, both crystalline and amorphous, by a quasi-harmonic approximation with a reliable classical intermolecular interaction model for water. The amplitude in the low pressure ices increases with compression, while the opposite trend is observed in the medium and high pressure ices. The amplitude of the oxygen atom does not differ from that of hydrogen in low pressure ices apart from the contribution from the zero-point vibrations. This is accounted for by the coherent but opposite phase motions in the mixed translational and rotational vibrations. A decoupling of translation-dominant and rotation-dominant motions significantly reduces the vibrational amplitudes in any ice form. The amplitudes in ice III are found to be much larger than any other crystalline ice form. In order to investigate the vibrational mode characteristics, the moment ratio of the atomic displacements for individual phonon modes, called the inverse participation ratio, is calculated and the degree of the phonon localization in crystalline and amorphous ices is discussed. It is found that the phonon modes in the hydrogen-ordered ice forms are remarkably spread over the entire crystal having propagative or diffusive characteristic, while many localized modes appear at the edges of the vibrational bands, called dissipative modes, in the hydrogen-disordered counterparts. The degree of localization is little pronounced in low density amorphous and high density amorphous due to disordering of oxygen atoms.


Trauma, PTSD, and complex PTSD in the Republic of Ireland: prevalence, service use, comorbidity, and risk factors.
This study represents the first assessment of the prevalence of trauma exposure, and Posttraumatic Stress Disorder (PTSD) and Complex PTSD (CPTSD), ever conducted in the general population of the Republic of Ireland. Additionally, prevalence of past-year mental health service use, comorbidity with major depression and generalized anxiety, and risk factors associated with PTSD and CPTSD were assessed. A nationally representative sample of non-institutionalized Irish adults (N = 1020) completed self-report measures of trauma history, trauma-related psychopathology, mental health service use, and concurrent mental health problems. Lifetime exposure to one or more traumatic events was 82.3%, and 67.8% reported experiencing two or more traumatic events. Males and females significantly differed in their frequency of exposure to eight of 16 traumatic events. The past-month prevalence for PTSD was 5.0% (95% CI 3.7%, 6.3%) and 7.7% (95% CI 6.1%, 9.4%) for CPTSD. Of those who screened positive for PTSD or CPTSD, 48.6% accessed mental health care in the past year. Comorbidity with major depression and generalized anxiety was high, especially among those with CPTSD. Several unique and shared risk factors for PTSD and CPTSD were identified. Approximately one-in-eight Irish adults met diagnostic requirements for PTSD or CPTSD, and comorbidity with other disorders was high. History of interpersonal trauma and exposure to multiple types of trauma in different developmental periods were associated with CPTSD. Many individuals did not access mental health care revealing a substantial mental health treatment gap.


[Genetic findings in obsessive-compulsive disorder in childhood and adolescence and in adulthood].
Obsessive-compulsive disorders (OCD) are on the rise, and affected children, 1-2% of the general population, often are seriously impaired in their development. OCD is characterized by recurrent, intrusive and disturbing thoughts as well as by repetitive stereotypic behaviours. Depending on their age and developmental status, patients usually try unsuccessfully to suppress the obsessive thoughts and compulsive behaviours. The current state of genetic research on OCD and early-onset OCD is presented and discussed. OCD, especially early-onset OCD, has been shown to be familial. Convincing evidence indicates that both environmental and genetic factors substantially influence OCD. Various approaches, including linkage and association studies, yielded conflicting results as well as the notion that multiple genes of modest effect sizes, in interaction with environmental factors, cause vulnerability to the disorder. The phenotypic and genetic heterogeneity of OCD complicate the identification of specific genetic factors. Further studies have to be designed in consideration of subtypes, e.g. age at onset, symptom dimensions, or comorbid disorders.


Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma.
A low mutation rate seems to be a general feature of pediatric cancers, in particular in oncofusion gene-driven tumors. Genetically, Ewing sarcoma is defined by balanced chromosomal EWS/ETS translocations, which give rise to oncogenic chimeric proteins (EWS-ETS). Other contributing somatic mutations involved in disease development have only been observed at low frequency. Tumor samples of 116 Ewing sarcoma patients were analyzed here. Whole-genome sequencing was performed on two patients with normal, primary, and relapsed tissue. Whole-exome sequencing was performed on 50 Ewing sarcoma and 22 matched normal tissues. A discovery dataset of 14 of these tumor/normal pairs identified 232 somatic mutations. Recurrent nonsynonymous mutations were validated in the 36 remaining exomes. Transcriptome analysis was performed in a subset of 14 of 50 Ewing sarcomas and DNA copy number gain and expression of FGFR1 in 63 of 116 Ewing sarcomas. Relapsed tumors consistently showed a 2- to 3-fold increased number of mutations. We identified several recurrently mutated genes at low frequency (ANKRD30A, CCDC19, KIAA0319, KIAA1522, LAMB4, SLFN11, STAG2, TP53, UNC80, ZNF98). An oncogenic fibroblast growth factor receptor 1 (FGFR1) mutation (N546K) was detected, and the FGFR1 locus frequently showed copy number gain (31.7%) in primary tumors. Furthermore, high-level FGFR1 expression was noted as a characteristic feature of Ewing sarcoma. RNA interference of FGFR1 expression in Ewing sarcoma lines blocked proliferation and completely suppressed xenograft tumor growth. FGFR1 tyrosine kinase inhibitor (TKI) therapy in a patient with Ewing sarcoma relapse significantly reduced 18-FDG-PET activity. FGFR1 may constitute a promising target for novel therapeutic approaches in Ewing sarcoma.


53BP1 exchanges slowly at the sites of DNA damage and appears to require RNA for its association with chromatin.
53BP1 protein is re-localized to the sites of DNA damage after ionizing radiation (IR) and is involved in DNA-damage-checkpoint signal transduction. We examined the dynamics of GFP-53BP1 in living cells. The protein starts to accumulate at the sites of DNA damage 2-3 minutes after damage induction. Fluorescence recovery after photobleaching experiments showed that GFP-53BP1 is highly mobile in non-irradiated cells. Upon binding to the IR-induced nuclear foci, the mobility of 53BP1 reduces greatly. The minimum (M) domain of 53BP1 essential for targeting to IR induced foci consists of residues 1220-1703. GFP-M protein forms foci in mouse embryonic fibroblast cells lacking functional endogenous 53BP1. The M domain contains a tandem repeat of Tudor motifs and an arginine- and glycine-rich domain (RG stretch), which are often found in proteins involved in RNA metabolism, the former being essential for targeting. RNase A treatment dissociates 53BP1 from IR-induced foci. In HeLa cells, dissociation of the M domain without the RG stretch by RNase A treatment can be restored by re-addition of nuclear RNA in the early stages of post-irradiation. 53BP1 immunoprecipitates contain some RNA molecules. Our results suggest a possible involvement of RNA in the binding of 53BP1 to chromatin damaged by IR.


Phase 2b Controlled Trial of M72/AS01E Vaccine to Prevent Tuberculosis.
A vaccine to interrupt the transmission of tuberculosis is needed. We conducted a randomized, double-blind, placebo-controlled, phase 2b trial of the M72/AS01E tuberculosis vaccine in Kenya, South Africa, and Zambia. Human immunodeficiency virus (HIV)-negative adults 18 to 50 years of age with latent M. tuberculosis infection (by interferon-γ release assay) were randomly assigned (in a 1:1 ratio) to receive two doses of either M72/AS01E or placebo intramuscularly 1 month apart. Most participants had previously received the bacille Calmette-Guérin vaccine. We assessed the safety of M72/AS01E and its efficacy against progression to bacteriologically confirmed active pulmonary tuberculosis disease. Clinical suspicion of tuberculosis was confirmed with sputum by means of a polymerase-chain-reaction test, mycobacterial culture, or both. We report the primary analysis (conducted after a mean of 2.3 years of follow-up) of the ongoing trial. A total of 1786 participants received M72/AS01E and 1787 received placebo, and 1623 and 1660 participants in the respective groups were included in the according-to-protocol efficacy cohort. A total of 10 participants in the M72/AS01E group met the primary case definition (bacteriologically confirmed active pulmonary tuberculosis, with confirmation before treatment), as compared with 22 participants in the placebo group (incidence, 0.3 cases vs. 0.6 cases per 100 person-years). The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P=0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P=0.03). There were more unsolicited reports of adverse events in the M72/AS01E group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. M72/AS01E provided 54.0% protection for M. tuberculosis-infected adults against active pulmonary tuberculosis disease, without evident safety concerns. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598 .).


Discovery of potential scaffolds for glutaminyl cyclase inhibitors: Virtual screening, synthesis, and evaluation.
Glutaminyl cyclase (QC) plays a crucial role in the early stages of Alzheimer's disease (AD), thus inhibition of QC may be a promising strategy for the treatment of early AD. Therefore, QC inhibitors with novel chemical scaffolds may contribute to the development of additional anti-AD agents. We conducted a virtual screening of 3 million compounds from the Chemdiv and Enamine databases, to discover potential scaffolds for QC inhibitors. Three scaffolds, 120974, 147706, and 141449, were selected from this structure-based virtual screening through a combination of pharmacophore modeling, a receptor-ligand pharmacophore model, and the GALAHAD model, and furtherly filtered by chelation with zinc ion and docking properties. Consequently, three compounds, 1, 2, and 3, were designed and synthesized based on these three scaffolds, respectively. The IC50 of compounds 1 and 3 against QC were 14.19 ± 4.21 and 4.34 ± 0.35 μM, respectively. Our results indicate that the new scaffolds selected using a virtual screening process exhibit potential as novel QC inhibitors.


Cardiovascular determinants of prognosis in normotensive hemodialysis patients.
Normotension has been hold to be the goal of hemodialysis. It remains obscure which cardiovascular parameter determines the prognosis in these normotensive hemodialysis patients. We prospectively enrolled 145 hemodialysis patients, who had attained normotension without anti-hypertensive medications, and followed them for 72.6 ± 28.5 months. Important cardiovascular parameters were obtained at enrollment. Predictors for all-cause and cardiovascular mortalities were identified with the Cox model. There were 45 (18 cardiovascular/27 non-cardiovascular) deaths occurred during follow-up. Age, diabetes, left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF), carotid intima-media thickness (CIMT), and aortic pulse wave velocity (PWV) were significant predictors for all-cause and cardiovascular mortalities. After adjustment for age and diabetes, only LVEF was significantly associated with all-cause mortality. LVEF was significantly associated with cardiovascular mortality. LVEF remained as a significant independent predictor of cardiovascular death after adjusting for age, diabetes, LVMI, CIMT, or PWV, respectively. LVEF is the independent predictor for all-cause and cardiovascular mortalities in the normotensive hemodialysis patients.


Developmental neurotoxicity of industrial chemicals.
Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.


Mapping local variation in household overcrowding across Africa from 2000 to 2018: a modelling study.
Household overcrowding is a serious public health threat associated with high morbidity and mortality. Rapid population growth and urbanisation contribute to overcrowding and poor sanitation in low-income and middle- income countries, and are risk factors for the spread of infectious diseases, including COVID-19, and antimicrobial resistance. Many countries do not have adequate surveillance capacity to monitor household overcrowding. Geostatistical models are therefore useful tools for estimating household overcrowding. In this study, we aimed to estimate household overcrowding in Africa between 2000 and 2018 by combining available household survey data, population censuses, and other country-specific household surveys within a geostatistical framework. We used data from household surveys and population censuses to generate a Bayesian geostatistical model of household overcrowding in Africa for the 19-year period between 2000 and 2018. Additional sociodemographic and health-related covariates informed the model, which covered 54 African countries. We analysed 287 surveys and population censuses, covering 78 695 991 households. Spatial and temporal variability arose in household overcrowding estimates over time. In 2018, the highest overcrowding estimates were observed in the Horn of Africa region (median proportion 62% [IQR 57-63]); the lowest regional median proportion was estimated for the north of Africa region (16% [14-19]). Overall, 474·4 million (95% uncertainty interval [UI] 250·1 million-740·7 million) people were estimated to be living in overcrowded conditions in Africa in 2018, a 62·7% increase from the estimated 291·5 million (180·8 million-417·3 million) people who lived in overcrowded conditions in the year 2000. 48·5% (229·9 million) of people living in overcrowded conditions came from six African countries (Nigeria, Ethiopia, Democratic Republic of the Congo, Sudan, Uganda, and Kenya), with a combined population of 538·3 million people. This study incorporated survey and population censuses data and used geostatistical modelling to estimate continent-wide overcrowding over a 19-year period. Our analysis identified countries and areas with high numbers of people living in overcrowded conditions, thereby providing a benchmark for policy planning and the implementation of interventions such as in infectious disease control. UK Department of Health and Social Care, Wellcome Trust, Bill & Melinda Gates Foundation.


Individual flowering phenology, plant size, and reproductive success in Linanthus androsaceus, a California annual.
For natural selection to shape population flowering phenologies, individual phenological variation must be correlated with variation in reproductive success. I therefore marked and followed individual plants of Linanthus androsaceus (a California grassland annual) throughout the flowering season, recording individual flowering phenology, flower number, mortality, and seed production. Although date of first flowering was unrelated to number of flowers, plants first flowering during an intermediate interval had a greater probability of setting seed, and a stronger relationship between seed number and flower number, than plants first flowering early or late in the season. The actual distribution of first flowering date in the population was clustered around this intermediate interval. In contrast with first flowering date, flowering duration was correlated with flower number, with a positively skewed distribution that reflected the skewed size structure of the population. The combined distributions of individual flowering dates and furations resulted in an overall population flowering curve that was skewed to the right. Within individual quadrats, Linanthus density was positively correlated with skewness if the quadrat flowering phenology curve, and negatively correlated with the percentage of plants in bloom at flowering peak. Thus, although individual variation in first flowering date was related to reproductive success in L. androsaceus, the size dependence of flowering duration provides a mechanism whereby ecological factors can shape population flowering phenologies without evolutionary change.


Supporting the health care transition from adolescence to adulthood in the medical home.
Optimal health care is achieved when each person, at every age, receives medically and developmentally appropriate care. The goal of a planned health care transition is to maximize lifelong functioning and well-being for all youth, including those who have special health care needs and those who do not. This process includes ensuring that high-quality, developmentally appropriate health care services are available in an uninterrupted manner as the person moves from adolescence to adulthood. A well-timed transition from child- to adult-oriented health care is specific to each person and ideally occurs between the ages of 18 and 21 years. Coordination of patient, family, and provider responsibilities enables youth to optimize their ability to assume adult roles and activities. This clinical report represents expert opinion and consensus on the practice-based implementation of transition for all youth beginning in early adolescence. It provides a structure for training and continuing education to further understanding of the nature of adolescent transition and how best to support it. Primary care physicians, nurse practitioners, and physician assistants, as well as medical subspecialists, are encouraged to adopt these materials and make this process specific to their settings and populations.


DETECTION OF LACTOBACILLI IN MONTHLY MAIL-IN STOOL SAMPLES FROM 3-18 MONTHS OLD INFANTS AT GENETIC RISK FOR TYPE 1 DIABETES.
The feasibility to detect lactobacilli in mail-in infant stools collected monthly from 3-18 months old children was investigated. The aim was to determine total lactobacilli and Lactobacillus plantarum (L. plantarum) content (ng/g feces) in 50 infants each from Colorado (648 samples), Finland (624 samples) and Sweden (685 samples) who participated in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. Total lactobacilli content varied markedly between 5 and 16,800 ng/g feces in the three clinical sites within and between individuals especially in infants. L.plantarum also varied markedly intra- and inter-individually from <0.5 - 736 ng/g feces. A higher variability of total lactobacilli was found before 10 months of age than after in the three different clinical sites. Sweden had the lowest total lactobacilli content compared to Colorado and Finland while the L.plantarum content was higher in Sweden. Mail-in stool samples from infants should prove useful in analyzing probiotics in childhood.


The evolutionary history of prosaposin: two successive tandem-duplication events gave rise to the four saposin domains in vertebrates.
Prosaposin is a multifunctional protein encoded by a single-copy gene. It contains four saposin domains (A, B, C, and D) occurring as tandem repeats connected by linker sequences. Because the saposin domains are similar to one another, it is deduced that they were created by sequential duplications of an ancestral domain. There are two types of evolutionary scenarios that may explain the creation of the four-domain gene: (1) two rounds of tandem internal gene duplication and (2) three rounds of duplications. An evolutionary and phylogenetic analysis of saposin DNA and amino acid sequences from human, mouse, rat, chicken, and zebrafish indicates that the first evolutionary scenario is the most likely. Accordingly, an ancestral saposin-unit duplication produced a two-domain gene, which, subsequently, underwent a second complete tandem duplication to give rise to the present four-domain structure of the prosaposin gene.


Expression of IL-6 receptor in pancreatic cancer: involvement in VEGF induction.
Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic growth factors and its expression is correlated with MVD (microvascular density) in malignant tumors, including pancreatic adenocarcinoma. On the other hand, serum interleukin-6 (IL-6) is elevated in many patients with pancreatic cancer in accordance with their disease progression. In this study, we examined whether IL-6 and its receptors have any involvement in the induction of VEGF in pancreatic cancer. Two human pancreatic cancer cell lines were examined for the induction of VEGF after treatment with IL-6. Thirty-two pancreatic cancer surgical specimens were stained immunohistochemically with VEGF, IL-6 and IL-6 receptor antibodies. CFPAC-1 cells expressed IL-6 receptor whereas AsPC-1 cells rarely expressed it. IL-6 treatment induced VEGF expression significantly and dose-dependently in CFPAC-1 cells, while it did not change in AsPC-1 cells. The intensity of VEGF expression in CFPAC-1 also increased time-dependently with IL-6 treatment. In 32 surgical pancreatic cancer tissues, 19 (59%) stained positive for VEGF and 26 (87%) positive for IL-6 receptor beta subunit. The correlation between IL-6 receptors and VEGF was significant (p = 0.0002 and p = 0.0019) while less correlation was seen between IL-6 and VEGF (p = 0.1937). Our results suggest that IL-6 is likely to take part in VEGF expression in both paracrine and autocrine fashion in pancreatic cancer. Induction of VEGF seems to be regulated by the extent of the IL-6 receptor expression on cancer cells.


Imaging of aberrant left gastric vein and associated pseudolesions of segments II and III of the liver and mimickers.
We present imaging findings of aberrant left gastric vein (ALGV) and associated pseudolesions and mimickers including metastases and focal nodular hyperplasia. ALGV is formed due to interrupted involution of anastomotic omental veins, and it can drain into left portal vein or segments II and III of the liver as third inflow. Focal fat, focal fat sparing, and perfusion changes can be seen due to the presence of ALGV, which can mimic metastasis in cancer patients. ALGV may also serve as a pathway for direct tumor spread into the liver in patients with gastric cancer. Magnetic resonance imaging can be used as a problem solving tool in the presence of equivocal findings on ultrasonography and computed tomography.


The long terminal repeats of human immunodeficiency virus type-1 and human T-cell leukemia virus type-I are activated by 12-O-tetradecanoylphorbol-13-acetate through different pathways.
The LTRs of HIV-1 and HTLV-I have been shown by several laboratories to be activated by 12-O-tetradecanoylphorbol-13-acetate (TPA). This agent is a potent activator of protein kinase C (PKC). However, long exposure to TPA downregulates PKC in many cell types. We demonstrated that TPA treatment of Jurkat cells for more than 24 hr resulted in a sever depletion of this enzyme. Therefore, to explore the role of PKC in the effect of TPA on these LTRs, we transfected Jurkat cells with HIV-1 LTR-CAT or HTLV-I LTR-CAT construct after 72 hr of TPA pretreatment. While this TPA pretreatment considerably reduced the HIV-1 LTR basal expression, it strongly stimulated the expression of HTLV-I LTR. Furthermore, when TPA was added after transfection, a strong stimulation of HIV-1 LTR was observed, which could be abrogated by PKC inhibitors like H7 and chelerythryn. However, under these conditions TPA stimulated HTLV-I LTR to a lesser extent than did the long-term TPA pretreatment. Moreover, this stimulation was enhanced by the PKC inhibitors. Thus our data indicate that while the effect of TPA on HIV-1 LTR is strictly dependent on PKC activity, its effect on HTLV-I LTR is exerted via a different pathway that not only does not require PKC activation but rather seems to be antagonized by the activated PKC. Using a deletion mutant of HTLV-I LTR we mapped the PKC-independent effect of TPA to the c-ets responsive region 1 (ERR-1) located in U3 of this LTR.


Self-incrimination and denial in the juvenile transfer evaluation.
Clinical evaluation of alleged juvenile delinquents regarding possible transfer to adult court must be conducted before adjudication of the facts of the case. This requirement leads to problems for the juvenile court and for the psychiatric consultant in managing certain potentially incriminating information that the defendant may reveal in the evaluation process. Both explicity self-incriminating information, and also denial of involvement in the alleged offense, present problems in this regard. Explorations of procedural protections for dealing with explicity self-incriminating information, and of the clinical and forensic problems in interpreting defendants' denial of culpability in these circumstances, do not yield fully satisfying answers to the problems. The author suggests some procedural compromises, and discusses the dilemma at the boundary of juvenile court jurisdiction that underlies these problems.


Activation and detoxification metabolism of urban air pollutants 2-nitrobenzanthrone and carcinogenic 3-nitrobenzanthrone by rat and mouse hepatic microsomes.
2-Nitrobenzanthrone (2-NBA) has recently been detected in ambient air particulate matter. Its isomer 3-nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust. Understanding which enzymes are involved in metabolism of these toxicants is important in the assessment of individual susceptibility. Here, metabolism of 2-NBA and 3-NBA by rat and mouse hepatic microsomes containing cytochromes P450 (CYPs), their reductase (NADPH:CYP reductase), and NADH:cytochrome b5 reductase was investigated under anaerobic and aerobic conditions. In addition, using the same microsomal systems, 2-NBA and 3-NBA were evaluated to be enzymatically activated under anaerobic conditions to species generating 2-NBA- and 3-NBA-derived DNA adducts. High performance liquid chromatography (HPLC) with ultraviolet (UV) detection was employed for the separation and characterization of 2-NBA and 3-NBA metabolites formed by hepatic microsomes of rats and mice under the anaerobic and aerobic conditions. Microsomal systems isolated from the liver of the control (untreated) rats and rats pretreated with Sudan I, β-naphthoflavone (β-NF), phenobarbital (PB), ethanol and pregnenolon 16α-carbonitrile (PCN), the inducers of cytochromes P450 (CYP) 1A1, 1A1/2, 2B, 2E1 and 3A, respectively, were used in this study. Microsomes of mouse models, a control mouse line (wild-type, WT) and Hepatic Cytochrome P450 Reductase Null (HRN) mice with deleted gene of NADPH:CYP reductase in the liver, thus absenting this enzyme in their livers, were also employed. To detect and quantify the 2-NBA- and 3-NBA-derived DNA adducts, the 32P postlabeling technique was used. Both reductive metabolite of 3-NBA, 3-aminobenzanthrone (3-ABA), found to be formed predominantly under the anaerobic conditions, and two 3-NBA oxidative metabolites, whose structures have not yet been investigated, were formed by several microsomal systems used in the study. Whereas a 3-NBA reductive metabolite, 3-ABA, was found only in the microsomal systems of control rats, the rats treated with β-NF and PB, and microsomes of WT and HRN mice, all hepatic microsomes tested in the study were capable of activating this carcinogen under the reductive conditions to form DNA adducts. A stability of a reactive intermediate of 3-NBA, N-hydroxy-3-aminobenzanthrone that is formed during 3-NBA reduction to 3-ABA, to form nitrenium (and/or carbenium) ions binding to DNA in individual microsomes as well as binding of these ions to proteins of these microsomes, might be the reasons explaining this phenomenon. In contrast to 3-NBA, its isomer 2-NBA was not metabolized by any of the used enzymatic systems both under the anaerobic and aerobic conditions. Likewise, no DNA adducts were detectable after reaction of 2-NBA in these systems with DNA. The results found in this study, the first report on the metabolism of 2-NBA and 3-NBA by rat and mouse hepatic microsomes demonstrate that 3-NBA, in contrast to 2-NBA, is reductively activated to form 3-NBA-derived DNA adducts by these enzymatic systems. NADPH:CYP reductase can be responsible for formation of these DNA adducts in rat livers, while NADH:cytochrome b5 reductase can contribute to this process in livers of HRN mice.


Increasing access to quality health care for the poor: Community perceptions on quality care in Uganda.
This paper examines the community's perspectives and perceptions on quality of health care delivery in two Uganda districts. The paper addresses community concerns on service quality. It focuses on the poor because they are a vulnerable group and often bear a huge burden of disease. Community views were solicited and obtained using eight focus group discussions, six in-depth and 12 key informant interviews. User perceptions and definitions of the quality of health services depended on a number of variables related to technical competence, accessibility to services, interpersonal relations and presence of adequate drugs, supplies, staff, and facility amenities. Results indicate that service delivery to the poor in the general population is perceived to be of low quality. The factors that were mentioned as affecting the quality of services delivered were inadequate trained health workers, shortage of essential drugs, poor attitude of the health workers, and long distances to health facilities. This paper argues that there should be an improvement in the quality of health services with particular attention being paid to the poor. Despite wide focus on improvement of the existing infrastructure and donor funding, there is still low satisfaction with health services and poor perceived accessibility.


A gradient-directed Monte Carlo approach to molecular design.
The recently developed linear combination of atomic potentials (LCAP) approach [M. Wang et al., J. Am. Chem. Soc. 128, 3228 (2006)] allows continuous optimization in a discrete chemical space, and thus is useful in the design of molecules for targeted properties. To address further challenges arising from the rugged, continuous property surfaces in the LCAP approach, we develop a gradient-directed Monte Carlo (GDMC) strategy as an augmentation to the original LCAP optimization method. The GDMC method retains the power of exploring molecular space by utilizing local gradient information computed from the LCAP approach to jump between discrete molecular structures. It also allows random MC moves to overcome barriers between local optima on property surfaces. The combined GDMC-LCAP approach is demonstrated here for optimizing nonlinear optical properties in a class of donor-acceptor substituted benzene and porphyrin frameworks. Specifically, one molecule with four nitrogen atoms in the porphyrin ring was found to have a larger first hyperpolarizability than structures with the conventional porphyrin motif.


Assessing the Mental Health of Fathers, Other Co-parents, and Partners in the Perinatal Period: Mixed Methods Evidence Synthesis.
Introduction: Five to 10 percentage of fathers experience perinatal depression and 5-15% experience perinatal anxiety, with rates increasing when mothers are also experiencing perinatal mental health disorders. Perinatal mental illness in either parent contributes to adverse child and family outcomes. While there are increasing calls to assess the mental health of both parents, universal services (e.g., maternity) and specialist perinatal mental health services usually focus on the mother (i.e., the gestational parent). The aim of this review was to identify and synthesize evidence on the performance of mental health screening tools and the acceptability of mental health assessment, specifically in relation to fathers, other co-parents and partners in the perinatal period. Methods: A systematic search was conducted using electronic databases (MEDLINE, PsycINFO, Maternity, and Infant Care Database and CINAHL). Articles were eligible if they included expectant or new partners, regardless of the partner's gender or relationship status. Accuracy was determined by comparison of screening tool with diagnostic interview. Acceptability was predominantly assessed through parents' and health professionals' perspectives. Narrative synthesis was applied to all elements of the review, with thematic analysis applied to the acceptability studies. Results: Seven accuracy studies and 20 acceptability studies were included. The review identified that existing evidence focuses on resident fathers and assessing depression in universal settings. All accuracy studies assessed the Edinburgh Postnatal Depression Scale but with highly varied results. Evidence on acceptability in practice is limited to postnatal settings. Amongst both fathers and health professionals, views on assessment are mixed. Identified challenges were categorized at the individual-, practitioner- and service-level. These include: gendered perspectives on mental health; the potential to compromise support offered to mothers; practitioners' knowledge, skills, and confidence; service culture and remit; time pressures; opportunity for contact; and the need for tools, training, supervision and onward referral routes. Conclusion: There is a paucity of published evidence on assessing the mental health of fathers, co-mothers, step-parents and other partners in the perinatal period. Whilst practitioners need to be responsive to mental health needs, further research is needed with stakeholders in a range of practice settings, with attention to ethical and practical considerations, to inform the implementation of evidence-based assessment.


Atrogin-1 inhibits Akt-dependent cardiac hypertrophy in mice via ubiquitin-dependent coactivation of Forkhead proteins.
Cardiac hypertrophy is a major cause of human morbidity and mortality. Although much is known about the pathways that promote hypertrophic responses, mechanisms that antagonize these pathways have not been as clearly defined. Atrogin-1, also known as muscle atrophy F-box, is an F-box protein that inhibits pathologic cardiac hypertrophy by participating in a ubiquitin ligase complex that triggers degradation of calcineurin, a factor involved in promotion of pathologic hypertrophy. Here we demonstrated that atrogin-1 also disrupted Akt-dependent pathways responsible for physiologic cardiac hypertrophy. Our results indicate that atrogin-1 does not affect the activity of Akt itself, but serves as a coactivator for members of the Forkhead family of transcription factors that function downstream of Akt. This coactivator function of atrogin-1 was dependent on its ubiquitin ligase activity and the deposition of polyubiquitin chains on lysine 63 of Foxo1 and Foxo3a. Transgenic mice expressing atrogin-1 in the heart displayed increased Foxo1 ubiquitylation and upregulation of known Forkhead target genes concomitant with suppression of cardiac hypertrophy, while mice lacking atrogin-1 displayed the opposite physiologic phenotype. These experiments define a role for lysine 63-linked ubiquitin chains in transcriptional coactivation and demonstrate that atrogin-1 uses this mechanism to disrupt physiologic cardiac hypertrophic signaling through its effects on Forkhead transcription factors.


Nutrigenetics and personalised nutrition: how far have we progressed and are we likely to get there?
Nutrigenetics and personalised nutrition are components of the concept that in the future genotyping will be used as a means of defining dietary recommendations to suit the individual. Over the last two decades there has been an explosion of research in this area, with often conflicting findings reported in the literature. Reviews of the literature in the area of apoE genotype and cardiovascular health, apoA5 genotype and postprandial lipaemia and perilipin and adiposity are used to demonstrate the complexities of genotype-phenotype associations and the aetiology of apparent between-study inconsistencies in the significance and size of effects. Furthermore, genetic research currently often takes a very reductionist approach, examining the interactions between individual genotypes and individual disease biomarkers and how they are modified by isolated dietary components or foods. Each individual possesses potentially hundreds of 'at-risk' gene variants and consumes a highly-complex diet. In order for nutrigenetics to become a useful public health tool, there is a great need to use mathematical and bioinformatic tools to develop strategies to examine the combined impact of multiple gene variants on a range of health outcomes and establish how these associations can be modified using combined dietary strategies.


Seagrasses as indicators for coastal trace metal pollution: a global meta-analysis serving as a benchmark, and a Caribbean case study.
Seagrass beds are highly productive coastal ecosystems providing a large array of ecosystem services including fisheries and carbon sequestration. As seagrasses are known to be highly sensitive to anthropogenic forcing, we evaluated the use of trace metal concentrations in seagrasses as bioindicators for trace metal pollution of coastal regions at both global and local scale. We carried out a meta-analysis based on literature data to provide a global benchmark list for trace metal accumulation in seagrasses, which was lacking in literature. We subsequently carried out a case study at the Caribbean islands of Curaçao and Bonaire to test for local-scale differences in trace metal concentrations in seagrasses, and internal metal allocation. The benchmark and local study show that trace metal concentrations in seagrass leaves, regardless of the species, can vary over a 100-1000-fold range, and are related to the level of anthropogenic pressure, making seagrasses highly valuable indicators.


Early hyperglycemia after allogenic kidney transplantation: does it induce infections.
Although impact of diabetes mellitus after solid organ transplantation is a broadly investigated issue, a potential impact of early hyperglycemia after renal transplantation has not received enough consideration. In this study, we aimed to evaluate the potential impact of early hyperglycemia on the hazards of infections development leading to re-hospitalization. We evaluated 1931 non diabetic renal allograft recipients, undergone renal transplantation at the Baqiyatallah Hospital, Tehran from 1984 to 2006. Level of hyperglycemia was defined at 126 mg/dL. Patients who had at least two glucose concentration results over the mentioned level in two different days during their early post transplantation period were determined as hyperglycemic. Overall, 7.6% of patients were determined as having early post transplant hyperglycemia. Multivariable hazard analysis using Cox regression model showed that early post transplantation hyperglycemia has an independent impact on rehospitalization of non-diabetic kidney allograft recipients for developing infectious diseases. Regarding findings of our study and previous studies we conclude that renal transplant recipients who develop hyperglycemia during their early post transplantation period should receive higher amount of attention over their follow up periods.


Perceptions of the impact of a large-scale collaborative improvement programme: experience in the UK Safer Patients Initiative.
In several countries, collaborative improvement programmes involving multiple health care organizations have been developed to address the issue of patient safety and reliability of care at an organization-wide level. In the UK, the Health Foundation's Safer Patients Initiative (SPI) was developed to achieve breakthrough improvement in the quality and safety of care in 24 acute hospital Trusts between 2004 and 2008. Research evidence for the effectiveness of programmes of this type and the mechanisms by which positive outcomes are achieved remains limited. We report a multi-method preliminary study based upon phase 1 of SPI to understand participant's perceptions of the local impact of the programme and to form the basis of future research in this area. Data were collected on the perceived local impact of SPI on a range of clinical, organizational and social dimensions relating to care quality and safety. Data were collected retrospectively from local SPI programme improvement teams using semi-structured interviews and surveys. Qualitative and quantitative analyses were performed, and the results synthesized under common themes and frameworks. Specific dimensions of care systems commonly considered to be affected by SPI, included culture, strategic priority, organizational capability and clinical care delivery. Survey data revealed the perceived importance for success of a range of programme components: quality improvement methodology, learning sessions and programme faculty support, along with predefined clinical practice changes. Safety climate and capability dimensions rated as most sensitive to the effects of the SPI programme related to multi-professional engagement and communication, the degree of routine monitoring of care processes and the capacity to evaluate the impact of changes to clinical work systems. Study findings support the view that programmes such as SPI have considerable impact upon the cultural, inter-professional, strategic and organizational aspects of care delivery, in addition to clinical working practices. The specific implications for understanding the effects of complex organization-level interventions and future research design are discussed.


Holins in bacteria, eukaryotes, and archaea: multifunctional xenologues with potential biotechnological and biomedical applications.
Holins form pores in the cytoplasmic membranes of bacteria for the primary purpose of releasing endolysins that hydrolyze the cell wall and induce cell death. Holins are encoded within bacteriophage genomes, where they promote cell lysis for virion release, and within bacterial genomes, where they serve a diversity of potential or established functions. These include (i) release of gene transfer agents, (ii) facilitation of programs of differentiation such as those that allow sporulation and spore germination, (iii) contribution to biofilm formation, (iv) promotion of responses to stress conditions, and (v) release of toxins and other proteins. There are currently 58 recognized families of holins and putative holins with members exhibiting between 1 and 4 transmembrane α-helical spanners, but many more families have yet to be discovered. Programmed cell death in animals involves holin-like proteins such as Bax and Bak that may have evolved from bacterial holins. Holin homologues have also been identified in archaea, suggesting that these proteins are ubiquitous throughout the three domains of life. Phage-mediated cell lysis of dual-membrane Gram-negative bacteria also depends on outer membrane-disrupting "spanins" that function independently of, but in conjunction with, holins and endolysins. In this minireview, we provide an overview of their modes of action and the first comprehensive summary of the many currently recognized and postulated functions and uses of these cell lysis systems. It is anticipated that future studies will result in the elucidation of many more such functions and the development of additional applications.


The acceptability of screening for Carbapenemase Producing Enterobacteriaceae (CPE): cross-sectional survey of nursing staff and the general publics' perceptions.
Carbapenemase Producing Enterobacteriaceae (CPE) has spread rapidly and presents a growing challenge in antimicrobial resistance (AMR) management internationally. Screening for CPE may involve a rectal swab, there are limited treatment options for affected patients, and colonised patients are cared for in isolation to protect others. These measures are sound infection prevention precautions; however, the acceptability of CPE screening and its consequences are currently unknown.The aim of this study was 'To determine factors influencing acceptability of CPE screening from the perspectives of nursing staff and the general public.' National cross-sectional surveys of nursing staff (n = 450) and the general public (n = 261). The Theoretical Domains Framework (TDF) guided data collection and analysis. Regression modelling was used to identify factors that predicted acceptability of CPE screening. For nursing staff, the following predictor variables were significant: intention to conduct CPE screening (OR 14.19, CI 5.14-39.22); belief in the severity of the consequences of CPE (OR 7.13, CI 3.26-15.60); knowledge of hospital policy for screening (OR 3.04, CI 1.45-6.34); preference to ask patients to take their own rectal swab (OR 2.89, CI 1.39-6.0); awareness that CPE is an organism of growing concern (OR 2.44, CI 1.22-4.88). The following predictor variables were significant for the general public: lack of knowledge of AMR (β - .11, p = .01); social influences (β .14,p = .032); social norms (β .21p = .00); acceptability of being isolated if colonised (β .22, p = .000), beliefs about the acceptability of rectal swabbing (β .15, p = .00), beliefs about the impact of careful explanation about CPE screening from a health professional (β .32, p = .00).Integrating results from staff and public perspectives points to the importance of knowledge of AMR, environmental resources, and social influences in shaping acceptability. This is the first study to systematically examine the acceptability of CPE screening across nursing staff and the public. The use of TDF enabled identification of the mechanisms of action, or theoretical constructs, likely to be important in understanding and changing CPE related behaviour amongst professionals and public alike.


Long-Term Land Use Affects Phosphorus Speciation and the Composition of Phosphorus Cycling Genes in Agricultural Soils.
Agriculturally-driven land transformation is increasing globally. Improving phosphorus (P) use efficiency to sustain optimum productivity in diverse ecosystems, based on knowledge of soil P dynamics, is also globally important in light of potential shortages of rock phosphate to manufacture P fertilizer. We investigated P chemical speciation and P cycling with solution 31P nuclear magnetic resonance, P K-edge X-ray absorption near-edge structure spectroscopy, phosphatase activity assays, and shotgun metagenomics in soil samples from long-term agricultural fields containing four different land-use types (native and tame grasslands, annual croplands, and roadside ditches). Across these land use types, native and tame grasslands showed high accumulation of organic P, principally orthophosphate monoesters, and high acid phosphomonoesterase activity but the lowest abundance of P cycling genes. The proportion of inositol hexaphosphates (IHP), especially the neo-IHP stereoisomer that likely originates from microbes rather than plants, was significantly increased in native grasslands than croplands. Annual croplands had the largest variances of soil P composition, and the highest potential capacity for P cycling processes based on the abundance of genes coding for P cycling processes. In contrast, roadside soils had the highest soil Olsen-P concentrations, lowest organic P, and highest tricalcium phosphate concentrations, which were likely facilitated by the neutral pH and high exchangeable Ca of these soils. Redundancy analysis demonstrated that IHP by NMR, potential phosphatase activity, Olsen-P, and pH were important P chemistry predictors of the P cycling bacterial community and functional gene composition. Combining chemical and metagenomics results provides important insights into soil P processes and dynamics in different land-use ecosystems.


Heart murmur and anaemia in the pediatric population.
Innocent heart murmurs are hearth murmurs that occur in patients with a normal heart structure. They do not represent a disease of the heart and vascular system, and should not be treated as such. Iron-deficiency anaemia often causes, along with other symptoms, systolic heart murmurs and tachycardia. It appears in children of all ages representing a most common haematological paediatric disease. To establish the influence of iron-deficiency anaemia on genesis of innocent murmurs and to compare auscultatory and phono-electrocardiographic findings in patients with anaemia and heart murmurs before and after iron therapy. The study includes 120 patients with innocent heart murmurs that have been auscultated at cardio-rheumatic outpatient department of Pediatric Clinic of the Clinical Center of the University of Sarajevo, during the period from 01/01/2004 to 31/12/2004. Further diagnostic procedure, i.e. laboratory tests, diagnosed iron-deficiency anaemia in 30/120 patients. These patients have been followed in this study. 22/30 patients had systolic murmur I/II intensity of Levin scale; 8/30 patients had II/VI systolic murmurs of intensity by Levin. The highest number of examinees had 0-1 years of age, and in this group the number of boys was higher than the number of girls (M: F = 12:4). During the auscultatory and phono-ECG examinations of murmurs, 6 patients had haemoglobin values less than 95 g/l, which corresponds to an average and severe type of anaemia. 24 patients had haemoglobin values between 95 and 110 g/l, which corresponds to benign type of anaemia. The most numerous were patients aged between 0 - 1 year (3 patients with hemoglobin value Hb < 95 g/l, 13 patients with hemoglobin value Hb 95-110 g/l). All patients were treated with iron medicaments. After three months, clinical and laboratory re-evaluation was performed and it has demonstrated that after iron therapy 24 patients had level of a haemoglobin Hb >110 g/l and 6 patients had haemoglobin levels between 95 and 110 g/l. By auscultatory and phono-ECG examinations, murmurs of a level of intensity I/II was registered in only one child, while in the other 29 patients there were not any registered heart murmurs. Diagnosis of anaemia in the paediatric population group delays definitive diagnosis of heart murmurs. Innocent murmurs in children with sideropenic anaemia occur as its consequence. After adequately conducted iron therapy, i.e. cured anaemia, heart murmurs were not auscultated.


What is the best or most relevant global minimum for nanoclusters? Predicting, comparing and recycling cluster structures with WASP@N.
To address the question posed in the title, we have created, and now report details of, an open-access database of cluster structures with a web-assisted interface and toolkit as part of the WASP@N project. The database establishes a map of connectivities within each structure, the information about which is coded and kept as individual labels, called hashkeys, for the nanoclusters. These hashkeys are the basis for structure comparison within the database, and for establishing a map of connectivities between similar structures (topologies). The database is successfully used as a key element in a data-mining study of (MX)12 clusters of three binary compounds (LiI, SrO and GaAs) of which the database has no prior knowledge. The structures are assessed on the energy landscapes determined by the corresponding bulk interatomic potentials. Global optimisation, using a Lamarckian genetic algorithm, is used to search for low lying minima on the same energy landscape to confirm that the data-mined structures form a representative sample of the landscapes, with only very few structures missing from the close energy neighbourhood of the respective global minima.


Perennation of Uncinula necator in Vineyards of Eastern Washington.
Studies on the mode of perennation of Uncinula necator in Eastern Washington were conducted over a 4-year period. Evidence of perennation of U. necator in infected dormant buds was not evident during vineyard surveys conducted over the period. Cleistothecia retrieved from bark fissures and senesced leaves contained viable ascospores at bud burst and later. The proportion of cleistothecia retrieved from bark that contained viable ascospores at bud burst ranged from 0.19 to 0.48, 0.09 to 0.72, 0.18 to 0.22, and 0.48 to 0.67 in 1998, 1999, 2000, and 2001, respectively. Viability of cleistothecia retrieved from senesced leaves in two vineyards at bud burst was 0.41 and 0.40 in 1998 and was 0.5 and 0.4 in 1999. Ascospore release in lab studies occurred from the late-dormant stage through the prebloom and (in some cases) the bloom stages. The initial ascosporic infection of Chardonnay leaves began at the late-dormant stage; colony numbers then declined through the prebloom and bloom stages. In vineyard studies, ascospores were trapped as late as 70 days after bud burst during rain events of 3.9 to 9.6 mm. Detection of ascospores in vineyard air preceded the initial occurrence of powdery mildew symptoms and signs and the occurrence of conidia in volumetric spore traps by several days. Cleistothecia are the only known source of primary inoculum in the grape-production regions of Eastern Washington.


Child development assessment tools in low-income and middle-income countries: how can we use them more appropriately?
Global emphasis has shifted beyond reducing child survival rates to improving health and developmental trajectories in childhood. Optimum early childhood experience is believed to allow children to benefit fully from educational opportunities resulting in improved human capital. Investment in early childhood initiatives in low-income and middle-income countries (LMICs) is increasing. These initiatives use early childhood developmental assessment tools (CDATs) as outcome measures. CDATs are also key measures in the evaluation of programmatic health initiatives in LMICs, influencing public health policy. Interpretation of CDAT outcomes requires understanding of their structure and psychometric properties. This article reviews the structure and main methods of CDAT development with specific considerations when applied in LMICs.


Protective effects of diets supplemented with omega-3 polyunsaturated fatty acids and calcium against colorectal tumor formation.
This study is to evaluate the effect of dietary omega-3 polyunsaturated fatty acid (omega-3 PUFA) and/or calcium supplementation on colon tissue of the carcinogenic N-methyl-N-nitrosurea (NMU)-injected rats and to investigate this effect by the assessment of the oxidative stress. The rats were divided into four groups: those fed with a standard diet, with a diet supplemented by omega-3 PUFA, those fed with a diet with calcium, and those fed with a standard diet with the combination of omega-3 PUFA and calcium. Rats were injected with an intrarectal NMU. After 32 weeks, colon tissue specimens and plasma were taken to histopathologically investigate and analyze tissue superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activities and erythrocyte MDA levels. The tumor incidences in supplemented-diet groups II and IV were found to be significantly lower when compared with those of the controls (P < 0.05). Superoxide dismutase and glutathione peroxidase antioxidative enzyme activities in colorectal tissue were increased in the study groups when compared with control rats (P < 0.001) and MDA levels were significantly lower than in the controls (P < 0.001) while the levels in group IV were rather decreased than those in group III (P = 0.011). These results suggest that the dietary supplementation of PUFA and/or calcium may be useful in the prevention of colorectal tumor formation.


An fMRI investigation of expectation violation in magic tricks.
Magic tricks violate the expected causal relationships that form an implicit belief system about what is possible in the world around us. Observing a magic effect seemingly invalidates our implicit assumptions about what action causes which outcome. We aimed at identifying the neural correlates of such expectation violations by contrasting 24 video clips of magic tricks with 24 control clips in which the expected action-outcome relationship is upheld. Using fMRI, we measured the brain activity of 25 normal volunteers while they watched the clips in the scanner. Additionally, we measured the professional magician who had performed the magic tricks under the assumption that, in contrast to naïve observers, the magician himself would not perceive his own magic tricks as an expectation violation. As the main effect of magic - control clips in the normal sample, we found higher activity for magic in the head of the caudate nucleus (CN) bilaterally, the left inferior frontal gyrus and the left anterior insula. As expected, the magician's brain activity substantially differed from these results, with mainly parietal areas (supramarginal gyrus bilaterally) activated, supporting our hypothesis that he did not experience any expectation violation. These findings are in accordance with previous research that has implicated the head of the CN in processing changes in the contingency between action and outcome, even in the absence of reward or feedback.


NH2-terminally modified gastric inhibitory polypeptide exhibits amino-peptidase resistance and enhanced antihyperglycemic activity.
Gastric inhibitory polypeptide (GIP) is an important insulin-releasing hormone of the enteroinsular axis that, like glucagon-like peptide 1(7-36) amide (tGLP-1), has a functional profile of possible therapeutic value for type 2 diabetes. Both incretin hormones are rapidly inactivated in plasma by the exopeptidase dipeptidyl peptidase (DPP) IV. The present study examined the ability of NH2-terminal modification of human GIP to protect from plasma degradation and enhance insulin-releasing and antihyperglycemic activity. Degradation of GIP by incubation at 37 degrees C with purified DPP IV was clearly evident after 4 h (54% intact). After 12 h, >60% of GIP was converted to GIP(3-42), whereas >99% of NH2-terminally modified Tyr1-glucitol GIP remained intact. Tyr1-glucitol GIP was similarly resistant to serum degradation. The formation of GIP(3-42) was almost completely abolished by inhibition of plasma DPP IV with diprotin A. Effects of GIP and Tyr1-glucitol GIP were examined in Wistar rats after intraperitoneal injection of either peptide (10 nmol/kg) together with glucose (18 mmol/kg). Plasma glucose concentrations were significantly lower and insulin concentrations higher after both peptides compared with glucose alone. More importantly, individual glucose values at 15 and 30 min together with the areas under the curve (AUCs) for glucose were significantly lower after administration of Tyr1-glucitol GIP compared with GIP (AUC 255 +/- 33 vs. 368 +/- 8 mmol x l(-1) x min(-1), respectively; P < 0.01). This was associated with a significantly greater and more protracted insulin response after Tyr1-glucitol GIP than GIP (AUC 773 +/- 41 vs. 639 +/- 39 ng x ml(-1) x min(-1); P < 0.05). These data demonstrate that Tyr1-glucitol GIP displays resistance to plasma DPP IV degradation and exhibits enhanced antihyperglycemic activity and insulin-releasing action in vivo.


Application of localized ³¹P MRS saturation transfer at 7 T for measurement of ATP metabolism in the liver: reproducibility and initial clinical application in patients with non-alcoholic fatty liver disease.
Saturation transfer (ST) phosphorus MR spectroscopy ((31)P MRS) enables in vivo insight into energy metabolism and thus could identify liver conditions currently diagnosed only by biopsy. This study assesses the reproducibility of the localized (31)P MRS ST in liver at 7 T and tests its potential for noninvasive differentiation of non-alcoholic fatty liver (NAFL) and steatohepatitis (NASH). After the ethics committee approval, reproducibility of the localized (31)P MRS ST at 7 T and the biological variation of acquired hepato-metabolic parameters were assessed in healthy volunteers. Subsequently, 16 suspected NAFL/NASH patients underwent MRS measurements and diagnostic liver biopsy. The Pi-to-ATP exchange parameters were compared between the groups by a Mann-Whitney U test and related to the liver fat content estimated by a single-voxel proton ((1)H) MRS, measured at 3 T. The mean exchange rate constant (k) in healthy volunteers was 0.31 ± 0.03 s(-1) with a coefficient of variation of 9.0 %. Significantly lower exchange rates (p < 0.01) were found in NASH patients (k = 0.17 ± 0.04 s(-1)) when compared to healthy volunteers, and NAFL patients (k = 0.30 ± 0.05 s(-1)). Significant correlation was found between the k value and the liver fat content (r = 0.824, p < 0.01). Our data suggest that the (31)P MRS ST technique provides a tool for gaining insight into hepatic ATP metabolism and could contribute to the differentiation of NAFL and NASH. • 1D localized (31) P MRS saturation transfer in the liver is reproducible at 7 T • NASH patients have decreased hepatic Pi-to-ATP exchange rate • In this study, hepatic metabolic activity correlates with liver fat content.


Characterization of the functional properties of env genes from long-term survivors of human immunodeficiency virus type 1 infection.
A small number of persons infected with human immunodeficiency virus type 1 (HIV-1) remain clinically and immunologically healthy for more than a decade after infection. Recent reports suggest that these individuals may be infected with an attenuated strain of HIV-1; however, a common genetic basis for viral attenuation has not been found in all cases. In the present study, we examined the functional properties of the HIV-1 env genes from six long-term survivors. env clones were generated by PCR amplification of proviral env sequences, followed by cloning of the amplified regions into expression vectors. Eight to ten clones from each subject were screened by transient transfection for expression of the envelope precursor glycoprotein, gp160. Those clones expressing gp160 were then cotransfected with an HIV-1 luciferase reporter vector, pNL4-3Env(-)LUC(+) and evaluated for their ability to mediate infection of phytohemagglutinin-activated peripheral blood mononuclear cells in single-cycle infectivity assays. Clones expressing gp160 were identified for all six long-term survivors, indicating the presence of proviral env genes with intact open reading frames. For two subjects, D and DH, the encoded envelope glycoproteins yielded high levels of luciferase activity when pseudotyped onto HIV-1 virions and tested in single-cycle infectivity assays. In contrast, envelope glycoproteins cloned from four other long-term survivors were poorly processed and failed to mediate infection. Sequencing of the gp120/41 cleavage site and conserved gp41 cysteine residues of these clones did not reveal any obvious mutations to explain the functional defects. The functional activity of env clones from long-term survivors D and DH was comparable to that seen with several primary HIV-1 env genes cloned from individuals with disease progression and AIDS. These results suggest that the long-term survival of subjects D and DH is not associated with overt functional defects in env; however, functional abnormalities in env may contribute to maintaining a long-term asymptomatic state in the other four cases we studied.


Regionally distinct processing of rewards and punishments by the primate ventromedial prefrontal cortex.
The ventromedial prefrontal cortex (vmPFC) is thought to be related to emotional experience and to the processing of stimulus and action values. However, little is known about how single vmPFC neurons process the prediction and reception of rewards and punishments. We recorded from monkey vmPFC neurons in an experimental situation with alternating blocks, one in which rewards were delivered and one in which punishments were delivered. Many vmPFC neurons changed their activity between blocks. Importantly, neurons in ventral vmPFC were persistently more active in the appetitive "reward" block, whereas neurons in dorsal vmPFC were persistently more active in the aversive "punishment" block. Furthermore, within ventral vmPFC, posterior neurons phasically encoded probability of reward, whereas anterior neurons tonically encoded possibility of reward. We found multiple distinct nonlinear valuation mechanisms within the primate prefrontal cortex. Our findings suggest that different subregions of vmPFC contribute differentially to the processing of valence. By conveying such multidimensional and nonlinear signals, the vmPFC may enable flexible control of decisions and emotions to adapt to complex environments.


Rapid Real-time Tracking of Nonpharmaceutical Interventions and Their Association With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Positivity: The Coronavirus Disease 2019 (COVID-19) Pandemic Pulse Study.
Current mitigation strategies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rely on the population-wide adoption of nonpharmaceutical interventions (NPIs). Monitoring the adoption of NPIs and their associations with SARS-CoV-2 infection history can provide key information for public health. We sampled 1030 individuals in Maryland from 17-28 June 2020 to capture sociodemographically and geographically resolved information about NPI adoption and access to SARS-CoV-2 testing, and examine associations with self-reported SARS-CoV-2 positivity. Overall, 92% reported traveling for essential services and 66% visited friends/family. Use of public transport was reported by 18%. In total, 68% reported strict social distancing indoors and 53% reported strict masking indoors; indoor social distancing was significantly associated with age, and race/ethnicity and income were associated with masking. Overall, 55 participants (5.3%) self-reported ever testing positive for SARS-CoV-2, with strong dose-response relationships between several forms of movement frequency and SARS-CoV-2 positivity. In a multivariable analysis, a history of SARS-CoV-2 infection was negatively associated with strict social distancing (adjusted odds ratio [aOR] for outdoor social distancing, 0.10; 95% confidence interval, .03-.33). Only public transport use (aOR for >7 times vs never, 4.3) and visiting a place of worship (aOR for ≥3 times vs never, 16.0) remained significantly associated with SARS-CoV-2 infection after adjusting for strict social distancing and demographics. These results support public health messaging that strict social distancing during most activities can reduce SARS-CoV-2 transmission. Additional considerations are needed for indoor activities with large numbers of persons (places of worship and public transportation), where even NPIs may not be possible or sufficient.


Innovation and problem solving: a review of common mechanisms.
Behavioural innovations have become central to our thinking about how animals adjust to changing environments. It is now well established that animals vary in their ability to innovate, but understanding why remains a challenge. This is because innovations are rare, so studying innovation requires alternative experimental assays that create opportunities for animals to express their ability to invent new behaviours, or use pre-existing ones in new contexts. Problem solving of extractive foraging tasks has been put forward as a suitable experimental assay. We review the rapidly expanding literature on problem solving of extractive foraging tasks in order to better understand to what extent the processes underpinning problem solving, and the factors influencing problem solving, are in line with those predicted, and found, to underpin and influence innovation in the wild. Our aim is to determine whether problem solving can be used as an experimental proxy of innovation. We find that in most respects, problem solving is determined by the same underpinning mechanisms, and is influenced by the same factors, as those predicted to underpin, and to influence, innovation. We conclude that problem solving is a valid experimental assay for studying innovation, propose a conceptual model of problem solving in which motor diversity plays a more central role than has been considered to date, and provide recommendations for future research using problem solving to investigate innovation. This article is part of a Special Issue entitled: Cognition in the wild.


Descriptive epidemiology of birth defects thought to arise by new mutation.
The current study is the first to examine the association of a broad range of sociodemographic factors with conditions thought to arise most of the time by de novo mutation. Data were taken from 1999 to 2009 from the Texas Birth Defects Registry (TBDR), a statewide active surveillance program. We used Poisson regression to generate crude and adjusted measures of association; the latter included models with all variables and with a parsimonious subset of variables. There were 1694 cases with any of the phenotypes in the panel, 1100 cases in a subpanel with ≥90% of cases thought to arise de novo, 523 with chromosomal deletion disorders, and 243 with imprinting disorders. In the most parsimonious models, there was an increasing time trend in all groups except imprinting (p ≤ 0.01). Plurality (twins, triplets, etc.) was associated with greater risk of all groups except chromosomal deletions (p ≤ 0.01). Parental age showed strong trends with all groups; paternal age was most important for the total and imprinting groups (p ≤ 0.0001), and maternal age for the others (p ≤ 0.04). De novo mutation phenotypes were more prevalent among offspring of fathers who are non-Hispanic White compared with some other race/ethnic groups. This study suggests that birth defects arising by new mutation may be more prevalent among offspring of older parents and in plural births. The increasing time pattern and race/ethnic pattern may be related to greater use of or access to genetic tests. This approach to mutation epidemiology seems feasible for birth defects registries to consider.


Fanconi anemia and DNA replication repair.
There has been a recent profusion of reviews on Fanconi anemia (FA), which will give readers a comprehensive outline of the field R.D. Kennedy, A.D. D'Andrea, The Fanconi anemia/BRCA pathway: new faces in the crowd, Genes Dev. 19 (2005) 2925-2940; L.J. Niedernhofer, A.S. Lalai, J.H. Hoeijmakers, Fanconi anemia (cross)linked to DNA repair, Cell 123 (2005) 1191-1198; H. Joenje, K.J. Patel, The emerging genetic and molecular basis of Fanconi anaemia, Nat. Rev. Genet. 2 (2001) 446-457. Here, we will focus on key areas that place the FA proteins in the context of DNA repair during replication. In addition, where possible we will put forward propositions that in our opinion need addressing, and where possible provide models that can be tested.


Genetic quality assurance and genetic monitoring of laboratory mice and rats: FELASA Working Group Report.
Genetic quality assurance (QA), including genetic monitoring (GeMo) of inbred strains and background characterization (BC) of genetically altered (GA) animal models, should be an essential component of any QA programme in laboratory animal facilities. Genetic quality control is as important for ensuring the validity of the animal model as health and microbiology monitoring are. It should be required that studies using laboratory rodents, mainly mice and rats, utilize genetically defined animals. This paper, presented by the FELASA Working Group on Genetic Quality Assurance and Genetic Monitoring of Laboratory Murines, describes the objectives of and available methods for genetic QA programmes in rodent facilities. The main goals of any genetic QA programme are: (a) to verify the authenticity and uniformity of inbred stains and substrains, thus ensuring a genetically reliable colony maintenance; (b) to detect possible genetic contamination; and (c) to precisely describe the genetic composition of GA lines. While this publication focuses mainly on mouse and rat genetic QA, the principles will apply to other rodent species some of which are briefly mentioned within the context of inbred and outbred stocks.


Research Funding: the Case for a Modified Lottery.
The time-honored mechanism of allocating funds based on ranking of proposals by scientific peer review is no longer effective, because review panels cannot accurately stratify proposals to identify the most meritorious ones. Bias has a major influence on funding decisions, and the impact of reviewer bias is magnified by low funding paylines. Despite more than a decade of funding crisis, there has been no fundamental reform in the mechanism for funding research. This essay explores the idea of awarding research funds on the basis of a modified lottery in which peer review is used to identify the most meritorious proposals, from which funded applications are selected by lottery. We suggest that a modified lottery for research fund allocation would have many advantages over the current system, including reducing bias and improving grantee diversity with regard to seniority, race, and gender.


Admission to hospital in the UK at a weekend does not influence the prognosis of adults with community-acquired pneumonia.
Outcomes for adults with community-acquired pneumonia (CAP) admitted to hospital at the weekend were compared with those admitted during weekdays using data from the British Thoracic Society national CAP audits. Of 31 400 cases, 40.7% were weekend admissions; these patients were older (mean age 72 vs 71.3 years, p=0.001) and more likely to have high severity CAP (28.9% vs 27.1%, p trend 0.003) but had slightly lower adjusted 30-day inpatient mortality (aOR 0.94 95% CI 0.88 to 1.01) compared with those admitted during weekdays. More patients in the weekend group received antibiotics within 4 hours of admission (70.3% vs 68.7%, aOR 1.07 95% CI 1.01 to 1.12). We did not observe increased mortality for adults admitted at the weekend with CAP.


Heterogeneity and relaxation dynamics of the photoexcited retinal Schiff base cation in solution.
We present steady-state and broadband femtosecond fluorescence spectra of the protonated Schiff base of retinal in various protic and aprotic solvents, as a function of the excitation wavelength. A detailed spectral decomposition of the time-resolved fluorescence spectra allows us to isolate three spectral components: (i) the vibrationally relaxed S(1) fluorescence, (ii) a vibrationally hot S(1) fluorescence, and (iii) a higher-lying emission that undergoes spectral evolution on a time scale of 300-400 fs, which we assign to S(2) fluorescence. The vibrationally "cold" S(1) fluorescence exhibits three decay components upon 400 nm excitation (except in acetonitrile, which has two), but only two of them upon 570 nm excitation. These components clearly demonstrate the heterogeneity of the S(1) state in the sense that emission stems from several shallow potential surface minima. We discuss a connection between these decay channels and reactive and nonreactive excited-state paths on the basis of their solvent-dependent population and of previous high-performance liquid chromatography studies. There is no clear trend of the fluorescence decay times with solvent properties. Rather, a solvent effect manifests itself in acetonitrile, in that the number of fluorescence decay channels is smaller and that the quenching of the hot fluorescence seems more efficient. This effect has to do with the population pathways leading to the fluorescent states. These observations stress the heterogeneity of excited retinal Schiff base, influencing the decay but also the population channels. They also reinforce the claim that steric effects play an important role in the dynamics of the protein.


Acute and repeated administration of MDPV increases aggressive behavior in mice: forensic implications.
MDPV is a synthetic cathinone illegally marketed and consumed for its psychostimulant effects, which are similar to those produced by cocaine, amphetamines, and MDMA. Clinical reports indicate that MDPV produces euphoria, increases alertness, and at high doses causes agitation, psychosis, tachycardia and hypertension, hallucinations, delirium, hyperthermia, rhabdomyolysis, and even death. In rodents, MDPV reproduces the typical physiological effects of psychostimulant drugs, demonstrating greater potency than cocaine. Nevertheless, its role in aggressive behavior has been reported but not yet experimentally confirmed. Therefore, the aim of this study was to evaluate the effects of acute and repeated MDPV (0.01-10 mg/kg i.p.) administration on aggressive behavior in mice and to compare them with those of cocaine (0.01-10 mg/kg i.p.) administration. To this purpose, the resident-intruder test in isolated mice and the spontaneous and stimulated aggressiveness tests for group-housed mice were employed. The present study shows for the first time that MDPV enhances aggressive behavior and locomotion in mice with greater potency and efficacy than cocaine treatment. Moreover, the aggressive and locomotor responses are enhanced after repeated administration, indicating that a sensitization mechanism comes into play. These results, although from preclinical investigation, are suggestive that human MDPV intake could be a problem for public health and the criminal justice system. Thus, investigation by police officers and medical staff is needed to prevent interpersonal violence induced by the consumption of synthetic cathinones.


Daily stressor reactivity during adolescence: The buffering role of parental warmth.
This study examined youth stressor reactivity in the form of links between daily stressors and adolescents' negative affect, physical health symptoms, and cortisol patterns. We also tested whether youth gender and parental warmth moderated these linkages. Participants were the children of employees in the information technology division of a large company (N = 132, mean age = 13.39 years, 55% female). Youth completed daily diary telephone interviews on 8 consecutive evenings and provided saliva samples at 4 time points over 4 days to assess daily stressors and youth physiological and affective functioning. Parental warmth was assessed during in-home interviews. Multilevel modeling was used to account for interdependencies in the data. Youth who experienced more daily stressors, on average, reported more negative affect and physical health symptoms, on average. Furthermore, on days youth reported more stressors than usual (compared to their own across-day average), they also exhibited more physical health symptoms, reduced evening cortisol decline (e.g., flatter slopes), higher bedtime cortisol, and more negative affect. Girls had stronger within-person linkages between daily stressors and daily negative affect than boys. Parental warmth moderated these within-person linkages: Youth who experienced more parental warmth had lower negative affect and steeper cortisol decline than usual on less stressful days. However, youth who experienced less parental warmth had higher negative affect and their cortisol levels declined less, even on days with lower-than-usual stress. Daily stressors are associated with youth's affective and physiological functioning, but parental warmth can support youth's stress recovery. (PsycINFO Database Record


Carbon dioxide elimination during high-frequency jet ventilation for rigid bronchoscopy.
Oxygen saturation and carbon dioxide values should be monitored during high-frequency jet ventilation (HFJV). Modern transcutaneous PCO2 (PtcCO2) measurement allows the estimation of ventilation efficiency. We studied how tests of lung function could predict carbon dioxide elimination during HFJV. Lung function tests from 180 adult patients undergoing rigid bronchoscopy were analysed as factors affecting carbon dioxide elimination. The lung function test results showed a significant relationship with the efficiency of carbon dioxide elimination; the greatest impairment of carbon dioxide elimination was found in patients with combined abnormalities of lung function. Further factors associated with difficult carbon dioxide elimination were male gender and elevated body weight. Of the patients investigated, 72% had normal carbon dioxide elimination, whereas in 23% hypercapnia could be avoided only by increasing the driving pressure. The prevalence of abnormal preoperative lung function test results predicts (sensitivity 76%, positive predictive value 27%) impaired carbon dioxide elimination during jet ventilation and rigid bronchoscopy.


Assisted reproductive technologies and the risk of birth defects--a systematic review.
The risk of birth defects in infants born following assisted reproductive technology (ART) treatment is a controversial question. Most publications examining the prevalence of birth defects in ICSI and IVF infants compared to spontaneously conceived infants have serious methodological limitations; despite this, most researchers have concluded that there is no increased risk. We carried out a systematic review to identify all papers published by March 2003 with data relating to the prevalence of birth defects in infants conceived following IVF and/or ICSI compared with spontaneously conceived infants. Independent expert reviewers used criteria defined a priori to determine whether studies were suitable for inclusion in a meta-analysis. Fixed effects meta-analysis was performed for all studies and reviewer-selected studies. Twenty-five studies were identified for review. Two-thirds of these showed a 25% or greater increased risk of birth defects in ART infants. The results of meta-analyses of the seven reviewer-selected studies and of all 25 studies suggest a statistically significant 30-40% increased risk of birth defects associated with ART. Pooled results from all suitable published studies suggest that children born following ART are at increased risk of birth defects compared with spontaneous conceptions. This information should be made available to couples seeking ART treatment.


Comparison of Effects of Different Dexmedetomidine and Chloral Hydrate Doses Used in Sedation on Electroencephalography in Pediatric Patients.
The aim of this study was to compare the efficacy and safety of different oral chloral hydrate and dexmedetomidine doses used for sedation during electroencephalography (EEG) in children. One hundred sixty children aged 1 to 9 years with American Society of Anesthesiologists physical status I-II who were uncooperative during EEG recording or who were referred to our electrodiagnostic unit for sleep EEG were included to the study. The patients were randomly assigned into 4 groups. In groups D1 and D2, patients received oral dexmedetomidine doses of 2 and 3 µg/kg, respectively. In group C1 and C2, patients received oral chloral hydrate doses of 50 and 100 mg/kg, respectively. The induction time was significantly shorter in group C2 compared with other groups (P = .000). The rate of adverse effects was significantly higher in group C2 compared with the dexmedetomidine groups (D1 and D2; P = .004). In conclusion, dexmedetomidine can be used safely for sedation during EEG in children.


Exploring novel targets for antimalarial drug discovery: plasmodial protein kinases.
Protein kinases are pursued drug targets in numerous diseases including parasitic infections such as malaria. Plasmodium falciparum, the deadliest malarial parasite, relies on numerous protein kinases to regulate growth and differentiation through a complex life cycle that alternates between an invertebrate and vertebrate host. Many of the protein kinases are uncharacterized, however genetic and biochemical approaches have identified homologues of known eukaryotic kinases families as well as unique families of plasmodial kinases. Several classes of protein kinases have been studied, revealing that not only are these kinases essential for parasite viability, but that structure-based drug design strategies can be applicable to identify protein kinase inhibitors as antimalarial agents. In this review, we profile plasmodial protein kinases that have been characterized. Such a profile allows comparison across the plasmodial kinome and aids in placing these kinases within signaling networks responsible for biological activity but also provides a rationale to develop inhibitors that target multiple plasmodial kinases. With wide spread malaria drug resistance, coupled by a parasite that can develop resistance quickly to new drugs, the development of multi-kinase inhibitors may be extremely efficacious and reduce the likelihood for resistance.


Conservative management of invasive cervical resorption: a case report.
Invasive cervical resorption is a condition that affects the root surface area below the epithelial attachment. Multiple treatment modalities are advocated, involving exposure of the invasive defect, removal of the granulation tissue and sealing with various restorative materials. This report demonstrates conservative treatment of a patient presenting with peri-apical periodontitis in upper right central and lateral incisors, along with Class II invasive resorption defect cervically on the mesial aspect of the central incisor, as a result of trauma. As the patient was not willing for any surgical intervention, only ortho-grade root canal treatment was carried out in both teeth, with Calcium hydroxide as intra-canal medicament. At three year follow-up, the patient remains asymptomatic demonstrating radiographic evidence of infilling of defect with bone-like tissue. Within the limitations of this report, it was seen that this conservative method for halting the progression of invasive cervical resorption could be under taken in patients who are un-willing for surgical intervention or in whom surgery is contra-indicated.


Rabies Risk: Difficulties Encountered during Management of Grouped Cases of Bat Bites in 2 Isolated Villages in French Guiana.
In French Guiana, from 1984 to 2011, 14 animal rabies cases and 1 human rabies case (2008) were diagnosed. In January 2011, vampire-bat attacks occurred in 2 isolated villages. In mid-January, a medical team from the Cayenne Centre for Anti-Rabies Treatment visited the sites to manage individuals potentially exposed to rabies and, in April, an anti-rabies vaccination campaign for dogs was conducted. Twenty individuals were bitten by bats in 1 month, most frequently on the feet. The median time to start management was 15 days. The complete Zagreb vaccination protocol (2 doses on day 0 and 1 dose on days 7 and 21) was administered to 16 patients, 12 also received specific immunoglobulins. The antibody titration was obtained for 12 patients (different from those who received immunoglobulins). The antibody titers were ≥0.5 EU/mL for all of them. The serology has not been implemented for the 12 patients who received immunoglobulins. Accidental destruction of a vampire-bat colony could be responsible for the attacks. The isolation and absence of sensitization of the populations were the main explanations for the management difficulties encountered. Sensitization programs should be conducted regularly.


Control of t-lymphocyte and B-lymphocyte activation by two complementing Ir-GLphi immune response genes.
The possibility that the two complementing alpha- and beta-Ir-GLphi genes are independently responsible for controlling events in T lymphocytes and B lymphocytes, respectively, has been tested in double adoptive transfer experiments utilizing cells from appropriate inbred strains of mice. The results of these studies show that the functions of T lymphocytes and B lymphocytes and the cooperative interactions between T and B cells require the presence of both alpha- and beta-genes in each respective cell type. Moreover, evidence has been obtained in these studies that indicates a preference for the alpha- and beta-Ir-GLphi genes in the cis position to obtain the most effective T-B-cell interactions. The possible implications of these findings are discussed.


Haplotype synthesis analysis reveals functional variants underlying known genome-wide associated susceptibility loci.
The functional mechanisms underlying disease association remain unknown for Genome-wide Association Studies (GWAS) susceptibility variants located outside coding regions. Synthesis of effects from multiple surrounding functional variants has been suggested as an explanation of hard-to-interpret findings. We define filter criteria based on linkage disequilibrium measures and allele frequencies which reflect expected properties of synthesizing variant sets. For eligible candidate sets, we search for haplotype markers that are highly correlated with associated variants. Via simulations we assess the performance of our approach and suggest parameter settings which guarantee 95% sensitivity at 20-fold reduced computational cost. We apply our method to 1000 Genomes data and confirmed Crohn's Disease (CD) and Type 2 Diabetes (T2D) variants. A proportion of 36.9% allowed explanation by three-variant-haplotypes carrying at least two functional variants, as compared to 16.4% for random variants ([Formula: see text]). Association could be explained by missense variants for MUC19, PER3 (CD) and HMG20A (T2D). In a CD GWAS-imputed using haplotype reference consortium data (64 976 haplotypes)-we could confirm the syntheses of MUC19 and PER3 and identified synthesis by missense variants for 6 further genes (ZGPAZ, GPR65, CLN3/NPIPB8, LOC102723878, rs2872507, GCKR). In all instances, the odds ratios of the synthesizing haplotypes were virtually identical to that of the index SNP. In summary, we demonstrate the potential of synthesis analysis to guide functional follow-up of GWAS findings. All methods are implemented in the C/C ++ toolkit GetSynth, available at http://sourceforge.net/projects/getsynth/ firstname.lastname@example.com Supplementary data are available at Bioinformatics online.