Carbohydrate hydration: heavy water complexes of α and β anomers of glucose, galactose, fucose and xylose.
The singly and doubly hydrated complexes of the α and β anomers of a systematically varied set of monosaccharides, O-phenyl D-gluco-, D-galacto-, L-fuco- and D-xylopyranoside, have been generated in a cold molecular beam and probed through infrared-ultraviolet double resonance ion-dip (IRID) spectroscopy coupled with quantum mechanical calculations. A new 'twist' has been introduced by isotopic substitution, replacing H(2)O by D(2)O to separate the carbohydrate (OH) and hydrate (OD) vibrational signatures and also to relieve spectral congestion. The new spectroscopic and computational results have exposed subtle aspects of the intermolecular interactions which influence the finer details of their preferred structures, including the competing controls exerted by co-operative hydrogen bonding, bi-furcated and OH-π hydrogen bonding, stereoelectronic changes associated with the anomeric effect, and dispersion interactions. They also reassert the operation of general 'working rules' governing conformational change and regioselectivity in both singly and doubly hydrated monosaccharides.


Randomized trials with quality of life endpoints: are doctors' ratings of patients' physical symptoms interchangeable with patients' self-ratings?
The assessment of physical symptoms is a key component of quality of life studies in palliative care, but is often hampered by missing data from patient-completed questionnaires. In two large multicentre randomized trials of palliative treatment conducted by the Medical Research Council Lung Cancer Working Party, Involving over 700 patients, patients completed Rotterdam Symptom Checklists and doctors reported on eleven of the same physical symptoms at each assessment, using the same 4-point severity scale. Ratings by doctors and patients were compared with respect to compliance, severity, and outcomes for the respective trials. Doctors provided more data than patients: 66% vs. 52% in the first 6 months in one trial, 58% vs. 61% in the other. Comparisons of over 33,000 symptom assessments showed 78% complete agreement between doctor and patient, 18% disagreement by one, 4% two, and 1% three grades (complete disagreement). There was no change in levels of agreement over time, but increasing disagreement with increasing symptom severity, and a consistent bias towards doctors underestimating severity. Nevertheless, the two methods of data collection resulted in similar between-treatment conclusions. Therefore, in randomized trials the doctors' assessments of key physical symptoms may be sufficient for the between-treatment comparison. However, the fact that doctors underestimate symptom severity 15% of the time has important implications for palliative interventions.


Excretion of antibiotic resistance genes by dairy calves fed milk replacers with varying doses of antibiotics.
Elevated levels of antibiotic resistance genes (ARGs) in soil and water have been linked to livestock farms and in some cases feed antibiotics may select for antibiotic resistant gut microbiota. The purpose of this study was to examine the establishment of ARGs in the feces of calves receiving milk replacer containing no antibiotics versus subtherapeutic or therapeutic doses of tetracycline and neomycin. The effect of antibiotics on calf health was also of interest. Twenty-eight male and female dairy calves were assigned to one of the three antibiotic treatment groups at birth and fecal samples were collected at weeks 6, 7 (prior to weaning), and 12 (5 weeks after weaning). ARGs corresponding to the tetracycline (tetC, tetG, tetO, tetW, and tetX), macrolide (ermB, ermF), and sulfonamide (sul1, sul2) classes of antibiotics along with the class I integron gene, intI1, were monitored by quantitative polymerase chain reaction as potential indicators of direct selection, co-selection, or horizontal gene transfer of ARGs. Surprisingly, there was no significant effect of antibiotic treatment on the absolute abundance (gene copies per gram wet manure) of any of the ARGs except ermF, which was lower in the antibiotic-treated calf manure, presumably because a significant portion of host bacterial cells carrying ermF were not resistant to tetracycline or neomycin. However, relative abundance (gene copies normalized to 16S rRNA genes) of tetO was higher in calves fed the highest dose of antibiotic than in the other treatments. All genes, except tetC and intI1, were detectable in feces from 6 weeks onward, and tetW and tetG significantly increased (P < 0.10), even in control calves. Overall, the results provide new insight into the colonization of calf gut flora with ARGs in the early weeks. Although feed antibiotics exerted little effect on the ARGs monitored in this study, the fact that they also provided no health benefit suggests that the greater than conventional nutritional intake applied in this study overrides previously reported health benefits of antibiotics. The results suggest potential benefit of broader management strategies, and that cost and risk may be avoided by minimizing incorporation of antibiotics in milk replacer.


Relationship between gut microbiota and circulating metabolites in population-based cohorts.
Gut microbiota has been implicated in major diseases affecting the human population and has also been linked to triglycerides and high-density lipoprotein levels in the circulation. Recent development in metabolomics allows classifying the lipoprotein particles into more details. Here, we examine the impact of gut microbiota on circulating metabolites measured by Nuclear Magnetic Resonance technology in 2309 individuals from the Rotterdam Study and the LifeLines-DEEP cohort. We assess the relationship between gut microbiota and metabolites by linear regression analysis while adjusting for age, sex, body-mass index, technical covariates, medication use, and multiple testing. We report an association of 32 microbial families and genera with very-low-density and high-density subfractions, serum lipid measures, glycolysis-related metabolites, ketone bodies, amino acids, and acute-phase reaction markers. These observations provide insights into the role of microbiota in host metabolism and support the potential of gut microbiota as a target for therapeutic and preventive interventions.


Laparoscopic cholecystectomy in the third trimester of pregnancy: report of 3 cases.
Symptomatic cholelithiasis and acute appendicitis are the most common surgical conditions requiring nonobstetric abdominal surgery during pregnancy. Cholelithiasis is diagnosed in 0.07% of pregnancy and in about 40% of these patients surgery may be required. Pregnancy was once considered an absolute contraindication for laparoscopic surgery, but pregnant patients undergoing laparoscopic surgery have been reported increasingly in the past decade. However, most case reports and case series are confined to patients in the first and second trimester. We report here 3 patients who underwent laparoscopic cholecystectomy in the third trimester and review the relevant literature. Pregnant women in the third trimester who underwent laparoscopic cholecystectomy were reviewed between the years 2000 and 2004 at our hospital. Three pregnant patients in the third trimester at a gestational age of 28 weeks, and 2 at 26 weeks underwent laparoscopic cholecystectomy. Initial port was placed in all patients by Hasson open technique, few centimeters cephalad to fundal height. The insufflation pressure was maintained between 12 to 14 mm Hg. The duration of surgery ranged from 64 to 80 minutes (mean: 72 min). Obstetric assessment was carried out preoperatively and fetal well-being was monitored postoperatively. Tocolytic agents were used in 2 patients. There were no intraoperative or postoperative complications. All patients were discharged on the second postoperative day. All the 3 patients delivered healthy babies normally at full term (range: 39 to 40 wk). Laparoscopic cholecystectomy can be carried out safely in the third trimester of pregnancy with minimal risk to the fetus and the mother.


Predictors of unfavorable outcome in neurosyphilis: Multicenter ID-IRI Study.
Neurosyphilis (NS) has different clinical manifestations and can appear during any stage of syphilis. We aimed to identify the factors affecting poor outcome in NS patients. Patients with positive cerebrospinal fluid Venereal Disease Research Laboratory test, and positive serological serum treponemal or nontreponemal tests were classified as definite NS. The data of 141 patients with definite NS were submitted from 22 referral centers. Asymptomatic NS, syphilitic meningitis, meningovascular syphilis, tabes dorsalis, general paresis, and taboparesis were detected in 22 (15.6%), 67 (47.5%), 13 (9.2%), 10 (7%), 13 (9.2%), and 16 patients (11.3%), respectively. The number of HIV-positive patients was 43 (30.4%). The most common symptoms were headache (n = 55, 39%), fatigue (n = 52, 36.8%), and altered consciousness (50, 35.4%). Tabetic symptoms were detected in 28 (19.8%), paretic symptoms in 32 (22.6%), and vascular symptoms in 39 patients (27.6%). Eye involvement was detected in 19 of 80 patients (23.7%) who underwent eye examination and ear involvement was detected in eight of 25 patients (32%) who underwent ear examination. Crystallized penicillin was used in 109 (77.3%), procaine penicillin in seven (4.9%), ceftriaxone in 31 (21.9%), and doxycycline in five patients (3.5%). According to multivariate regression analysis, while headache was a protective factor in NS patients, double vision was significantly associated to poor outcome. We concluded that double vision indicated unfavorable outcome among NS patients. A high clinical suspicion is needed for the diagnosis NS. As determined in our study, the presence of headache in syphilitic patients can help in early diagnosis of central nervous system disease.


Diversification of Colonization Factors in a Multidrug-Resistant Escherichia coli Lineage Evolving under Negative Frequency-Dependent Selection.
Escherichia coli is a major cause of bloodstream and urinary tract infections globally. The wide dissemination of multidrug-resistant (MDR) strains of extraintestinal pathogenic E. coli (ExPEC) poses a rapidly increasing public health burden due to narrowed treatment options and increased risk of failure to clear an infection. Here, we present a detailed population genomic analysis of the ExPEC ST131 clone, in which we seek explanations for its success as an emerging pathogenic strain beyond the acquisition of antimicrobial resistance (AMR) genes. We show evidence for evolution toward separate ecological niches for the main clades of ST131 and differential evolution of anaerobic metabolism, key colonization, and virulence factors. We further demonstrate that negative frequency-dependent selection acting across accessory loci is a major mechanism that has shaped the population evolution of this pathogen.IMPORTANCE Infections with multidrug-resistant (MDR) strains of Escherichia coli are a significant global public health concern. To combat these pathogens, we need a deeper understanding of how they evolved from their background populations. By understanding the processes that underpin their emergence, we can design new strategies to limit evolution of new clones and combat existing clones. By combining population genomics with modelling approaches, we show that dominant MDR clones of E. coli are under the influence of negative frequency-dependent selection, preventing them from rising to fixation in a population. Furthermore, we show that this selection acts on genes involved in anaerobic metabolism, suggesting that this key trait, and the ability to colonize human intestinal tracts, is a key step in the evolution of MDR clones of E. coli.


Interleukin-19 in breast cancer.
Inflammatory cytokines within the tumor microenvironment are linked to progression in breast cancer. Interleukin- (IL-) 19, part of the IL-10 family, contributes to a range of diseases and disorders, such as asthma, endotoxic shock, uremia, psoriasis, and rheumatoid arthritis. IL-19 is expressed in several types of tumor cells, especially in squamous cell carcinoma of the skin, tongue, esophagus, and lung and invasive duct carcinoma of the breast. In breast cancer, IL-19 expression is correlated with increased mitotic figures, advanced tumor stage, higher metastasis, and poor survival. The mechanisms of IL-19 in breast cancer have recently been explored both in vitro and in vivo. IL-19 has an autocrine effect in breast cancer cells. It directly promotes proliferation and migration and indirectly provides a microenvironment for tumor progression, which suggests that IL-19 is a prognostic marker in breast cancer and that antagonizing IL-19 may have therapeutic potential.


Hepatic entrapment of esterified cholesterol drives continual expansion of whole body sterol pool in lysosomal acid lipase-deficient mice.
Cholesteryl ester storage disease (CESD) results from loss-of-function mutations in LIPA, the gene that encodes lysosomal acid lipase (LAL). Hepatomegaly and deposition of esterified cholesterol (EC) in multiple organs ensue. The present studies quantitated rates of synthesis, absorption, and disposition of cholesterol, and whole body cholesterol pool size in a mouse model of CESD. In 50-day-old lal(-/-) and matching lal(+/+) mice fed a low-cholesterol diet, whole animal cholesterol content equalled 210 and 50 mg, respectively, indicating that since birth the lal(-/-) mice sequestered cholesterol at an average rate of 3.2 mg·day(-1)·animal(-1). The proportion of the body sterol pool contained in the liver of the lal(-/-) mice was 64 vs. 6.3% in their lal(+/+) controls. EC concentrations in the liver, spleen, small intestine, and lungs of the lal(-/-) mice were elevated 100-, 35-, 15-, and 6-fold, respectively. In the lal(-/-) mice, whole liver cholesterol synthesis increased 10.2-fold, resulting in a 3.2-fold greater rate of whole animal sterol synthesis compared with their lal(+/+) controls. The rate of cholesterol synthesis in the lal(-/-) mice exceeded that in the lal(+/+) controls by 3.7 mg·day(-1)·animal(-1). Fractional cholesterol absorption and fecal bile acid excretion were unchanged in the lal(-/-) mice, but their rate of neutral sterol excretion was 59% higher than in their lal(+/+) controls. Thus, in this model, the continual expansion of the body sterol pool is driven by the synthesis of excess cholesterol, primarily in the liver. Despite the severity of their disease, the median life span of the lal(-/-) mice was 355 days.


Matter arising: off-targets and genome-scale RNAi screens in Drosophila.
Recently, the issue of off-target effects (OTEs) associated with long double stranded RNAs (dsRNAs) used in RNAi screens, such as those performed at the Drosophila RNAi Screening Center and other laboratories, has become a focus of great interest and some concern. Although OTEs have been recognized as an important source of false positives in mammalian studies (where short siRNAs are used as triggers), they were generally thought to be inconsequential in Drosophila RNAi experiments because of the use of long dsRNAs. Two recent papers have disputed this contention and show that significant off-target effects can take place with the use of some long dsRNAs in Drosophila cells. Together, these studies provide evidence that OTEs mediated by short homology stretches of 19nt or greater within long dsRNAs can contribute to false positives in Drosophila RNAi screens. Here, we address how widespread the occurrence of OTE is in Drosophila screens, focusing on the DRSC dsRNA collections, and we discuss the implication for the interpretation of results reported in RNAi screens to-date. Lastly, we summarize steps taken by the DRSC to redress that situation and include a set of recommendations to observe in future RNAi screens.


Insights on cross-species transmission of SARS-CoV-2 from structural modeling.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global pandemic that has infected more than 31 million people in more than 180 countries worldwide. Like other coronaviruses, SARS-CoV-2 is thought to have been transmitted to humans from wild animals. Given the scale and widespread geographical distribution of the current pandemic and confirmed cases of cross-species transmission, the question of the extent to which this transmission is possible emerges, as well as what molecular features distinguish susceptible from non-susceptible animal species. Here, we investigated the structural properties of several ACE2 orthologs bound to the SARS-CoV-2 spike protein. We found that species known not to be susceptible to SARS-CoV-2 infection have non-conservative mutations in several ACE2 amino acid residues that disrupt key polar and charged contacts with the viral spike protein. Our models also allow us to predict affinity-enhancing mutations that could be used to design ACE2 variants for therapeutic purposes. Finally, our study provides a blueprint for modeling viral-host protein interactions and highlights several important considerations when designing these computational studies and analyzing their results.


Preseason Training: The Effects of a 17-Day High-Intensity Shock Microcycle in Elite Tennis Players.
Preseasons in tennis are normally reduced to 5 to 7 weeks duration, and coaches should use an integrated approach to conditioning and skill-based work. The aim of the present study was to investigate the effects of adding a high-intensity training (HIT) shock microcycle to the normal training content in several physical performance indicators in the preseason training of high-level male tennis players. Over 17 days, 12 male tennis players performed 13 HIT sessions in addition to their usual training. Physical performance tests (30:15 intermittent fitness test [VIFT], 20 m sprint, countermovement jump [CMJ], repeated sprint ability [RSA]) were conducted before (pre-test) and 5 days after the intervention (post-test). After the shock microcycle, results showed a significant increase in the VIFT (p < 0.001; Large ES) and a significant decrease in the mean RSA time (RSAm) (p = 0.002; Small ES), while there were no significant changes in the other parameters analysed (e.g., 20 m, CMJ, best RSA time [RSAb]; percentage of decrement in the RSA [%Dec]). Moreover, the training load (TL) during tennis sessions was significantly higher (p < 0.01; Large ES) than the TL during the integrated sessions, except during the first training session. A 17-day shock microcycle (i.e., 13 HIT sessions) in addition to the regular tennis training significantly improved parameters that can impact physical performance in tennis. Moreover, additional sessions, including running exercises based on the 30:15ITF and on-court specific exercises, were characterised by significantly lower TL than tennis-training sessions. Key pointsHIT shock microcycle increases performance in professional tennis players in a short period of time.The inclusion of additional sessions, with running exercises based on the 30:15ITF and on-court specific exercises, was characterised by a significantly lower TL than tennis-training sessions alone.Coaches should be aware of TL (e.g., RPE) and fatigue-related parameters (e.g., muscle soreness) in order to avoid overreaching symptoms.


Quality-based procedures in Ontario: exploring health-care leaders' responses.
To examine health-care leaders' initial response to the implementation of orthopaedic quality based procedures (QBPs) in hospitals across Ontario, Canada. In 2012, Ontario, Canada shifted 91 hospitals to a patient-based funding (PBF) approach. This approach funds health-care organisations based on the number of patients treated with select procedures known as QBPs. An exploratory descriptive design was employed to better understand health-care leaders' early implementation experiences. Seventy organisational leaders from 20 hospitals participated in six focus groups and four interviews to discuss their initial responses to the implementation of two QBPs (primary unilateral hip replacement and primary unilateral knee replacement). Qualitative data underwent content analysis. Three key major themes emerged; (1) responding to change, (2) leading the change and (3) managing the change. Within each of these themes, barriers and benefits were identified. Leaders are accepting of PBF and QBPs. However, challenges exist that require further exploration including the need for a strong infrastructure, accurate and timely clinical and financial data, and policies to prevent unintended consequences. Implementing QBPs requires careful planning, adequate and appropriate resources, vertical and horizontal communication strategies, and policies to ensure that unintended consequences are avoided and positive outcomes achieved.


Pulmonary toxoplasmosis: a review.
Toxoplasma pneumonia is being recognized with increased frequency, especially in patients with AIDS. We reviewed the English-, French-, and Spanish-language literature from January 1966 through February 1991 to identify cases of postnatally acquired pneumonia associated with Toxoplasma gondii. We identified two distinct clinical syndromes, one in immunocompetent patients and one in patients with defects in cell-mediated immunity. Shortness of breath and cough were the most common symptoms and fever and rales the most common signs in both groups of patients. Lymphadenopathy and hepatosplenomegaly were reported more frequently for immunocompetent patients. Chest roentgenographs usually revealed bilateral interstitial infiltrates, but a variety of other roentgenographic findings were reported. Serological findings were suggestive of active toxoplasmosis in immunocompetent but not in immunosuppressed patients. In early reports, identification of T. gondii as the etiologic agent of pneumonia was based on serology or autopsy findings. In more recent reports, open lung biopsy and especially bronchoalveolar lavage were used for diagnosis. Mortality among patients with toxoplasma pneumonia was 55%. However, in cases of T. gondii pneumonia diagnosed during life, mortality was 0 for immunocompetent patients and 40% for immunosuppressed patients. In immunosuppressed patients, improvement was associated with specific antitoxoplasma drug therapy. Unfortunately, relapses were common. We also reviewed data on series of patients with disseminated toxoplasmosis manifested predominantly in extrapulmonary sites and found that 33% of these patients had evidence of subclinical pulmonary involvement even though pneumonia had not been diagnosed clinically.


Recruiting the social contacts of patients with STI for HIV screening in Lilongwe, Malawi: process evaluation and assessment of acceptability.
To explore acceptability of recruiting social contacts for HIV and sexually transmitted infection (STI) screening in Lilongwe, Malawi. In this observational study, three groups of 'seed' patients were enrolled: 45 HIV-infected patients with STI, 45 HIV-uninfected patients with STI and 45 community controls, who were also tested for HIV as part of the study. Each seed was given five coupons and asked to recruit up to five social contacts to the STI clinic. Seeds were told the programme for contacts would include HIV testing, STI screening and general health promotion. Seeds were asked to return after 1 month to report on the contact recruitment process. Seeds received $2 for each successfully recruited contact. Eighty-nine seeds (66%) returned for 1-month follow-up with no difference between the three seed groups (p=0.9). Returning seeds reported distributing most of their coupons (mean=4.1) and discussing each feature of the programme with most contacts-HIV testing (90%), STI screening (87%) and health promotion (91%). Seeds reported discussing their own HIV status with most contacts (52%), with a lower proportion of HIV-infected seeds discussing their HIV status (22%) than HIV-uninfected seeds (81%) or community seeds (64%) (p<0.001). Contact recruitment did not vary with socioeconomic status. Most seeds distributed all coupons and reported describing all aspects of the programme to most contacts. Patients with STI are able to act as health promoters within their social networks and may be a critical link to increasing STI and HIV status awareness among high-risk groups.


Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study.
Associations of hormone-receptor positive breast cancer with excess adiposity are reasonably well characterized; however, uncertainty remains regarding the association of body mass index (BMI) with hormone-receptor negative malignancies, and possible interactions by hormone replacement therapy (HRT) use. Within the European EPIC cohort, Cox proportional hazards models were used to describe the relationship of BMI, waist and hip circumferences with risk of estrogen-receptor (ER) negative and progesterone-receptor (PR) negative (n = 1,021) and ER+PR+ (n = 3,586) breast tumors within five-year age bands. Among postmenopausal women, the joint effects of BMI and HRT use were analyzed. For risk of ER-PR- tumors, there was no association of BMI across the age bands. However, when analyses were restricted to postmenopausal HRT never users, a positive risk association with BMI (third versus first tertile HR = 1.47 (1.01 to 2.15)) was observed. BMI was inversely associated with ER+PR+ tumors among women aged ≤49 years (per 5 kg/m2 increase, HR = 0.79 (95%CI 0.68 to 0.91)), and positively associated with risk among women ≥65 years (HR = 1.25 (1.16 to 1.34)). Adjusting for BMI, waist and hip circumferences showed no further associations with risks of breast cancer subtypes. Current use of HRT was significantly associated with an increased risk of receptor-negative (HRT current use compared to HRT never use HR: 1.30 (1.05 to 1.62)) and positive tumors (HR: 1.74 (1.56 to 1.95)), although this risk increase was weaker for ER-PR- disease (Phet = 0.035). The association of HRT was significantly stronger in the leaner women (BMI ≤22.5 kg/m2) than for more overweight women (BMI ≥25.9 kg/m2) for, both, ER-PR- (HR: 1.74 (1.15 to 2.63)) and ER+PR+ (HR: 2.33 (1.84 to 2.92)) breast cancer and was not restricted to any particular HRT regime. An elevated BMI may be positively associated with risk of ER-PR- tumors among postmenopausal women who never used HRT. Furthermore, postmenopausal HRT users were at an increased risk of ER-PR- as well as ER+PR+ tumors, especially among leaner women. For hormone-receptor positive tumors, but not for hormone-receptor negative tumors, our study confirms an inverse association of risk with BMI among young women of premenopausal age. Our data provide evidence for a possible role of sex hormones in the etiology of hormone-receptor negative tumors.


Fully automated, real-time, calibration-free, continuous noninvasive estimation of intracranial pressure in children.
In the search for a reliable, cooperation-independent, noninvasive alternative to invasive intracranial pressure (ICP) monitoring in children, various approaches have been proposed, but at the present time none are capable of providing fully automated, real-time, calibration-free, continuous and accurate ICP estimates. The authors investigated the feasibility and validity of simultaneously monitored arterial blood pressure (ABP) and middle cerebral artery (MCA) cerebral blood flow velocity (CBFV) waveforms to derive noninvasive ICP (nICP) estimates. Invasive ICP and ABP recordings were collected from 12 pediatric and young adult patients (aged 2-25 years) undergoing such monitoring as part of routine clinical care. Additionally, simultaneous transcranial Doppler (TCD) ultrasonography-based MCA CBFV waveform measurements were performed at the bedside in dedicated data collection sessions. The ABP and MCA CBFV waveforms were analyzed in the context of a mathematical model, linking them to the cerebral vasculature's biophysical properties and ICP. The authors developed and automated a waveform preprocessing, signal-quality evaluation, and waveform-synchronization "pipeline" in order to test and objectively validate the algorithm's performance. To generate one nICP estimate, 60 beats of ABP and MCA CBFV waveform data were analyzed. Moving the 60-beat data window forward by one beat at a time (overlapping data windows) resulted in 39,480 ICP-to-nICP comparisons across a total of 44 data-collection sessions (studies). Moving the 60-beat data window forward by 60 beats at a time (nonoverlapping data windows) resulted in 722 paired ICP-to-nICP comparisons. Greater than 80% of all nICP estimates fell within ± 7 mm Hg of the reference measurement. Overall performance in the nonoverlapping data window approach gave a mean error (bias) of 1.0 mm Hg, standard deviation of the error (precision) of 5.1 mm Hg, and root-mean-square error of 5.2 mm Hg. The associated mean and median absolute errors were 4.2 mm Hg and 3.3 mm Hg, respectively. These results were contingent on ensuring adequate ABP and CBFV signal quality and required accurate hydrostatic pressure correction of the measured ABP waveform in relation to the elevation of the external auditory meatus. Notably, the procedure had no failed attempts at data collection, and all patients had adequate TCD data from at least one hemisphere. Last, an analysis of using study-by-study averaged nICP estimates to detect a measured ICP > 15 mm Hg resulted in an area under the receiver operating characteristic curve of 0.83, with a sensitivity of 71% and specificity of 86% for a detection threshold of nICP = 15 mm Hg. This nICP estimation algorithm, based on ABP and bedside TCD CBFV waveform measurements, performs in a manner comparable to invasive ICP monitoring. These findings open the possibility for rational, point-of-care treatment decisions in pediatric patients with suspected raised ICP undergoing intensive care.


Rhodiola rosea Improves Lifespan, Locomotion, and Neurodegeneration in a Drosophila melanogaster Model of Huntington's Disease.
Huntington's disease (HD) is a dominant, late-onset disease characterized by choreiform movements, cognitive decline, and personality disturbance. It is caused by a polyglutamine repeat expansion in the Huntington's disease gene encoding for the Huntingtin protein (Htt) which functions as a scaffold for selective macroautophagy. Mutant Htt (mHtt) disrupts vesicle trafficking and prevents autophagosome fusion with lysosomes, thus deregulating autophagy in neuronal cells, leading to cell death. Autophagy has been described as a therapeutic target for HD, owing to the key role Htt plays in the cellular process. Rhodiola rosea, a plant extract used in traditional medicine in Europe and Asia, has been shown to attenuate aging in the fly and other model species. It has also been shown to inhibit the mTOR pathway and induce autophagy in bladder cancer cell lines. We hypothesized that R. rosea, by inducing autophagy, may improve the phenotype of a Huntington's disease model of the fly. Flies expressing HttQ93 which exhibit decreased lifespan, impaired locomotion, and increased neurodegeneration were supplemented with R. rosea extract, and assays testing lifespan, locomotion, and pseudopupil degeneration provided quantitative measures of improvement. Based on our observations, R. rosea may be further evaluated as a potential therapy for Huntington's disease.


Chloroplast biogenesis is regulated by direct action of the ubiquitin-proteasome system.
Development of chloroplasts and other plastids depends on the import of thousands of nucleus-encoded proteins from the cytosol. Import is initiated by TOC (translocon at the outer envelope of chloroplasts) complexes in the plastid outer membrane that incorporate multiple, client-specific receptors. Modulation of import is thought to control the plastid's proteome, developmental fate, and functions. Using forward genetics, we identified Arabidopsis SP1, which encodes a RING-type ubiquitin E3 ligase of the chloroplast outer membrane. The SP1 protein associated with TOC complexes and mediated ubiquitination of TOC components, promoting their degradation. Mutant sp1 plants performed developmental transitions that involve plastid proteome changes inefficiently, indicating a requirement for reorganization of the TOC machinery. Thus, the ubiquitin-proteasome system acts on plastids to control their development.


Modifying the ionosphere with intense radio waves.
The ionospheric modification experiments provide an opportunity to better understand the aeronomy of the natural ionosphere and also afford the control of a naturally occurring plasma, which will make possible further progress in plasma physics. The ionospheric modification by powerful radio waves is analogous to studies of laser and microwave heating of laboratory plasmas (20). " Anomalous" reflectivity effects similar to the observed ionospheric attenuation have already been noted in plasmas modulated by microwaves, and anomalous heating may have been observed in plasmas irradiated by lasers. Contacts have now been established between the workers in these diverse areas, which span a wide range of the electromagnetic spectrum. Perhaps ionospheric modification will also be a valuable technique in radio communications.


Ensemble cryo-EM elucidates the mechanism of translation fidelity.
Gene translation depends on accurate decoding of mRNA, the structural mechanism of which remains poorly understood. Ribosomes decode mRNA codons by selecting cognate aminoacyl-tRNAs delivered by elongation factor Tu (EF-Tu). Here we present high-resolution structural ensembles of ribosomes with cognate or near-cognate aminoacyl-tRNAs delivered by EF-Tu. Both cognate and near-cognate tRNA anticodons explore the aminoacyl-tRNA-binding site (A site) of an open 30S subunit, while inactive EF-Tu is separated from the 50S subunit. A transient conformation of decoding-centre nucleotide G530 stabilizes the cognate codon-anticodon helix, initiating step-wise 'latching' of the decoding centre. The resulting closure of the 30S subunit docks EF-Tu at the sarcin-ricin loop of the 50S subunit, activating EF-Tu for GTP hydrolysis and enabling accommodation of the aminoacyl-tRNA. By contrast, near-cognate complexes fail to induce the G530 latch, thus favouring open 30S pre-accommodation intermediates with inactive EF-Tu. This work reveals long-sought structural differences between the pre-accommodation of cognate and near-cognate tRNAs that elucidate the mechanism of accurate decoding.


Using a dynamic hydrology model to predict mosquito abundances in flood and swamp water.
We modeled surface wetness at high resolution, using a dynamic hydrology model, to predict flood and swamp water mosquito abundances. Historical meteorologic data, as well as topographic, soil, and vegetation data, were used to model surface wetness and identify potential fresh and swamp water breeding habitats in two northern New Jersey watersheds. Surface wetness was positively associated with the subsequent abundance of the dominant floodwater mosquito species, Aedes vexans, and the swamp water species, Anopheles walkeri. The subsequent abundance of Culex pipiens, a species that breeds in polluted, eutrophic waters, was negatively correlated with local modeled surface wetness. These associations permit real-time monitoring and forecasting of these floodwater and nonfloodwater species at high spatial and temporal resolution. These predictions will enable public health agencies to institute control measures before the mosquitoes emerge as adults, when their role as transmitters of disease comes into play.


Antagonism of Salicylate by Pantoyltaurine.
Like pantothenic acid, pantolactone, and the pantoate ion, pantoyltaurine and other pantothenic acid analogues of this type antagonize the inhibitory effect of salicylate on E. coli. It is suggested that the active antagonist in a solution of such an analogue is pantolactone or pantoate. These (particularly the former) could conceivably be contaminants of the analogues. However, the liberation of pantoate by hydrolysis, appears to be a more likely explanation for the antisalicylate effect. The presence of pantolactone or pantoate in a solution of pantoyltaurine and similar analogues of pantothenic acid provides a possible explanation for the ineffectiveness of these drugs in inhibiting the growth of microorganisms which can utilize pantolactone or pantoate for the synthesis of pantothenic acid.


An integrative computational approach for prioritization of genomic variants.
An essential step in the discovery of molecular mechanisms contributing to disease phenotypes and efficient experimental planning is the development of weighted hypotheses that estimate the functional effects of sequence variants discovered by high-throughput genomics. With the increasing specialization of the bioinformatics resources, creating analytical workflows that seamlessly integrate data and bioinformatics tools developed by multiple groups becomes inevitable. Here we present a case study of a use of the distributed analytical environment integrating four complementary specialized resources, namely the Lynx platform, VISTA RViewer, the Developmental Brain Disorders Database (DBDB), and the RaptorX server, for the identification of high-confidence candidate genes contributing to pathogenesis of spina bifida. The analysis resulted in prediction and validation of deleterious mutations in the SLC19A placental transporter in mothers of the affected children that causes narrowing of the outlet channel and therefore leads to the reduced folate permeation rate. The described approach also enabled correct identification of several genes, previously shown to contribute to pathogenesis of spina bifida, and suggestion of additional genes for experimental validations. The study demonstrates that the seamless integration of bioinformatics resources enables fast and efficient prioritization and characterization of genomic factors and molecular networks contributing to the phenotypes of interest.


Molecular evidence for the expression of angiotensin converting enzyme in hemocytes of Locusta migratoria: stimulation by bacterial lipopolysaccharide challenge.
The presence of angiotensin converting enzyme (ACE) in insects has been reported many times, but numerous questions about the functional role of this enzyme in insects remain. Here we show by RT-PCR experiments that ACE has a wide tissue distribution in Locusta migratoria, suggesting diverse roles for this enzyme in the locust. Immune challenge through injection of bacterial lipopolysaccharides resulted in a tenfold increase of ACE gene transcripts in the hemocytes and is suggestive for a role of ACE in the cellular defense of the locust. However, phenotypic knockout experiments with the ACE inhibitor captopril showed that ACE is not essential for the efficient clearance of injected E. coli bacteria.


Raman spectroscopic signature of semen and its potential application to forensic body fluid identification.
A great potential of Raman spectroscopy for non-destructive, confirmatory identification of body fluids at the crime scene has been reported recently (Virkler and Lednev, Forensic Sci. Int. 2008). However, that analysis was carried out on only one sample of each body fluid and did not take into account any variations that might occur between different donors of the same fluid. This paper reports on the role of heterogeneity within a sample as well as among multiple donors for human semen. Near-infrared (NIR) Raman spectroscopy was used to measure spectra of pure dried human semen samples from multiple donors in a controlled laboratory environment. The major chemical components that contributed to the Raman spectrum of semen were determined and used to tentatively identify the principal spectral components. The issue of potential spectral variations that could arise between different donors of semen was also addressed. Advanced statistical analysis of spectra obtained from multiple spots on dry samples showed that dry semen is heterogeneous and its Raman spectra could be presented as a linear combination of a fluorescent background and three spectral components. The relative contribution of each of the three components varies with donor, so no single spectrum could effectively represent an experimental Raman spectrum of dry semen in a quantitative way. The combination of the three spectral components could be considered to be a spectroscopic signature for semen. This proof-of-concept approach shows the potential for Raman spectroscopy to identify an unknown substance to be semen during forensic analysis.


Person-centred care in practice: perspectives from a short course regimen for multi-drug resistant tuberculosis in Karakalpakstan, Uzbekistan.
Person-centred care, an internationally recognised priority, describes the involvement of people in their care and treatment decisions, and the consideration of their needs and priorities within service delivery. Clarity is required regarding how it may be implemented in practice within different contexts. The standard multi-drug resistant tuberculosis (MDR-TB) treatment regimen is lengthy, toxic and insufficiently effective. 2019 World Health Organisation guidelines include a shorter (9-11-month) regimen and recommend that people with MDR-TB be involved in the choice of treatment option. We examine the perspectives and experiences of people with MDR-TB and health-care workers (HCW) regarding person-centred care in an MDR-TB programme in Karakalpakstan, Uzbekistan, run by Médecins Sans Frontières and the Ministry of Health. A qualitative study comprising 48 interviews with 24 people with MDR-TB and 20 HCW was conducted in June-July 2019. Participants were recruited purposively to include a range of treatment-taking experiences and professional positions. Interview data were analysed thematically using coding to identify emerging patterns, concepts, and categories relating to person-centred care, with Nvivo12. People with MDR-TB were unfamiliar with shared decision-making and felt uncomfortable taking responsibility for their treatment choice. HCW were viewed as having greater knowledge and expertise, and patients trusted HCW to act in their best interests, deferring the choice of appropriate treatment course to them. HCW had concerns about involving people in treatment choices, preferring that doctors made decisions. People with MDR-TB wanted to be involved in discussions about their treatment, and have their preference sought, and were comfortable choosing whether treatment was ambulatory or hospital-based. Participants felt it important that people with MDR-TB had knowledge and understanding about their treatment and disease, to foster their sense of preparedness and ownership for treatment. Involving people in their care was said to motivate sustained treatment-taking, and it appeared important to have evidence of treatment need and effect. There is a preference for doctors choosing the treatment regimen, linked to shared decision-making unfamiliarity and practitioner-patient knowledge imbalance. Involving people in their care, through discussions, information, and preference-seeking could foster ownership and self-responsibility, supporting sustained engagement with treatment.


The urgent need to change the current medical approach on tobacco cessation in Latin America.
Despite of the accumulation of scientific evidence confirming the health consequences of smoking and the new paradigm of smoking as a disease where nicotine is the drug that modifies the functional and morphological characteristics of the brain in dependent smokers, tobacco smoking continues as an important public health problem in many Latin American countries. In contrast with big advances in the tobacco control area, as an example the Framework Convention on Tobacco Control signed by 168 countries, the role of health professional in the fight against tobacco is still less than ideal. In many Latin American schools of medicine, deficiencies in medical education has led to insecure physicians when they have to motivate their patients to stop smoking or to prevent young people to begin tobacco consumption. If each general practitioner or specialist during their daily medical assistance could talk to their smoker patients about the big benefits of stop smoking and support them to get free of tobacco, we would be winning a battle against smoking. Also if we could achieve generations of young non smoking doctors, who could be a real example for patients, this could also impact the prevalence of smokers. In this article we analyze the neurobiological bases of nicotine addiction, which we think are missing in the medical curriculum and could help doctors to understand tobacco smoking as a disease rather than a risk factor, and discuss the main reasons supporting an urgent change in the medical approach of tobacco cessation in Latin America as well as the need to actualize the medical curriculum in order to give physicians the skills needed to intervene successfully with their smoker patients and to be themselves non smokers.


Variation in the lipoprotein lipase gene influences exercise-induced left ventricular growth.
The adult heart relies predominantly on fatty acids (FA) for energy generation, and defects in FA catabolism cause dramatic left ventricular (LV) growth in early age. Since lipoprotein lipase (LPL) is the key enzyme in plasma triglyceride catabolism and is highly expressed in the myocardium, we investigated an association between the functional LPL gene serine 447 stop (S447X) variant and exercise-induced LV growth. The S447X variant was genotyped in 146 British Army recruits undergoing a 10-week exercise programme. Over the training period, X447 allele carriers showed less LV growth than S447 homozygotes (SS, 5.8+/-0.7%; SX, 2.2+/-1.5%; P=0.03) and a decrease in systolic blood pressure (DeltaSBP: SS, 1.9+/-1.3 mmHg; SX, -5.7+/-2.2 mmHg; P=0.015). Although LPL genotype did not significantly predict LV growth with DeltaSBP in statistical modelling (LPL, P=0.14; DeltaSBP, P=0.06), regression analysis indicated that LPL S447X genotype effect on DeltaSBP accounted for only 20% of the effect on LV growth. In multivariate analysis, LPL, peroxisome-proliferator-activated receptor alpha and angiotensin-converting enzyme genotypes were independent predictors of cardiac growth. Thus, LPL S447X genotype influenced exercise-induced changes in LV mass and SBP. Change in blood pressure accounted for a proportion of LV growth. These data suggest that increased myocardial FA availability may reduce exercise-induced LV growth.


Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment.
Cytokine disturbances have been suggested to be associated with the Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) for decades. Fifty female CFS patients were included in a study on the effect of the interleukin-1-receptor antagonist anakinra or placebo during 4 weeks. EDTA plasma was collected from patients before and directly after treatment. At baseline, plasma samples were collected at the same time from 48 healthy, age-matched female neighborhood controls. A panel of 92 inflammatory markers was determined in parallel in 1 μL samples using a 'proximity extension assay' (PEA) based immunoassay. Since Transforming growth factor beta (TGF-β) and interleukin-1 receptor antagonist (IL-1Ra) were not included in this platform, these cytokines were measured with ELISA. In CFS/ME patients, the 'normalized protein expression' value of IL-12p40 and CSF-1 was significantly higher (p value 0.0042 and 0.049, respectively). Furthermore, using LASSO regression, a combination of 47 markers yielded a prediction model with a corrected AUC of 0.73. After correction for multiple testing, anakinra had no effect on circulating cytokines. TGF-β did not differ between patients and controls. In conclusion, this study demonstrated increased IL-12p40 and CSF-1 concentrations in CFS/ME patients in addition to a set of predictive biomarkers. There was no effect of anakinra on circulating cytokines other than IL-1Ra. ClinicalTrials.gov Identifier: NCT02108210 , Registered April 2014.


MicroRNAs: Meta-controllers of gene expression in synaptic activity emerge as genetic and diagnostic markers of human disease.
MicroRNAs are members of the non-protein-coding family of RNAs. They serve as regulators of gene expression by modulating the translation and/or stability of messenger RNA targets. The discovery of microRNAs has revolutionized the field of cell biology, and has permanently altered the prevailing view of a linear relationship between gene and protein expression. The increased complexity of gene regulation is both exciting and daunting, as emerging evidence supports a pervasive role for microRNAs in virtually every cellular process. This review briefly describes microRNA processing and formation of RNA-induced silencing complexes, with a focus on the role of RNA binding proteins in this process. We also discuss mechanisms for microRNA-mediated regulation of translation, particularly in dendritic spine formation and function, and the role of microRNAs in synaptic plasticity. We then discuss the evidence for altered microRNA function in cognitive brain disorders, and the effect of gene mutations revealed by single nucleotide polymorphism analysis on altered microRNA function and human disease. Further, we present evidence that altered microRNA expression in circulating fluids such as plasma/serum can correlate with, and serve as, novel diagnostic biomarkers of human disease.


The increasing unemployment gap between the low and high educated in West Germany. Structural or cyclical crowding-out?
This paper addresses trends in education-specific unemployment risks at labor market entry in West Germany from the mid-1970s to the present. In line with previous research it shows that vocationally qualified school-leavers have relatively lower unemployment risks than school-leavers with general education. Over time, the gap in unemployment risks between the low-educated and medium- and highly educated labor market entrants substantially widened for both sexes. The literature identifies two different mechanisms for this trend: structural or cyclical crowding out. While in the former scenario low-educated become increasingly unemployed due to an oversupply of tertiary graduates and displacement from above, in the latter their relative unemployment risk varies with the business cycle. The results provide evidence for cyclical rather than structural crowding-out in West Germany. Since macroeconomic conditions became generally worse over time, this strongly explains the widening unemployment gap between the low-educated and all other education groups.


Proteomics and lipidomics analyses reveal modulation of lipid metabolism by perfluoroalkyl substances in liver of Atlantic cod (Gadus morhua).
The aim of the present study was to investigate effects of defined mixtures of polycyclic aromatic hydrocarbons (PAHs) and perfluoroalkyl substances (PFASs), at low, environmentally relevant (1× = L), or high (20× = H) doses, on biological responses in Atlantic cod (Gadus morhua). To this end, farmed juvenile cod were exposed at day 0 and day 7 via intraperitoneal (i.p.) injections, in a two-week in vivo experiment. In total, there were 10 groups of fish (n = 21-22): two control groups, four separate exposure groups of PAH and PFAS mixtures (L, H), and four groups combining PAH and PFAS mixtures (L/L, H/L, L/H, H/H). Body burden analyses confirmed a dose-dependent accumulation of PFASs in cod liver and PAH metabolites in bile. The hepatosomatic index (HSI) was significantly reduced for three of the combined PAH/PFAS exposure groups (L-PAH/H-PFAS, H-PAH/L-PFAS, H-PAH/H-PFAS). Analysis of the hepatic proteome identified that pathways related to lipid degradation were significantly affected by PFAS exposure, including upregulation of enzymes in fatty acid degradation pathways, such as fatty acid β-oxidation. The increased abundances of enzymes in lipid catabolic pathways paralleled with decreasing levels of triacylglycerols (TGs) in the H-PFAS exposure group, suggest that PFAS increase lipid catabolism in Atlantic cod. Markers of oxidative stress, including catalase and glutathione S-transferase activities were also induced by PFAS exposure. Only minor and non-significant differences between exposure groups and control were found for cyp1a and acox1 gene expressions, vitellogenin concentrations in plasma, Cyp1a protein synthesis and DNA fragmentation. In summary, our combined proteomics and lipidomics analyses indicate that PFAS may disrupt lipid homeostasis in Atlantic cod.


Improvement of Spatial and Non-verbal General Reasoning Abilities in Female Veterinary Medical Students Over the First 64 Weeks of an Integrated Curriculum.
Spatial visualization ability is defined as the ability to mentally rotate two- and three-dimensional figures. Visual reasoning is the ability to manipulate mental images of an object to reach a certain conclusion and has been linked to spatial ability. There is currently limited information about how entry-level spatial and visual reasoning abilities may be enhanced with progression through the rigorous veterinary medical curriculum. The present study made use of two tests that measure spatial ability and one test that measures non-verbal general reasoning ability in female veterinary students: Guay's Visualization of Views Test, Adapted Version (VVT), Mental Rotations Test (MRT), and Raven's Advanced Progressive Matrices Test, short form (APMT). Tests were given immediately before commencing the integrated veterinary medical curriculum (T0), at week 32 (T1), and at week 64 (T2) into the program. Results showed improved spatial visualization ability as measured by VVT and MRT and improved non-verbal general reasoning ability as measured by APMT at both 32 and 64 weeks. The spatial ability scores measured by VVT and MRT showed a positive correlation with non-verbal general reasoning ability scores (APMT), supporting the idea that these abilities are linked.


A critical appraisal of the reporting of the National Acute Spinal Cord Injury Studies (II and III) of methylprednisolone in acute spinal cord injury.
From the beginning, the reporting of the results of National Acute Spinal Cord Injury Studies (NASCIS) II and III has been incomplete, leaving clinicians in the spinal cord injury (SCI) community to use or avoid using methylprednisolone in acute SCI on the basis of faith rather than a publicly developed scientific consensus. NASCIS II was initially reported by National Institutes of Health announcements, National Institutes of Health facsimiles to emergency room physicians, and the news media. The subsequent report in the New England Journal of Medicine implied that there was a positive result in the primary efficacy analysis for the entire 487 patient sample. However, this analysis was in fact negative, and the positive result was found only in a secondary analysis of the subgroup of patients who received treatment within 8 hours. In addition, that subgroup apparently had only 62 patients taking methylprednisolone and 67 receiving placebo. The NASCIS II and III reports embody specific choices of statistical methods that have strongly shaped the reporting of results but have not been adequately challenged or or even explained. These studies show statistical artifacts that call their results into question. In NASCIS II, the placebo group treated before 8 hours did poorly, not only when compared with the methylprednisolone group treated before 8 hours but even when compared with the placebo group treated after 8 hours. Thus, the positive result may have been caused by a weakness in the control group rather than any strength of methylprednisolone. In NASCIS III, a randomization imbalance occurred that allocated a disproportionate number of patients with no motor deficit (and therefore no chance for recovery) to the lower dose control group. When this imbalance is controlled for, much of the superiority of the higher dose group seems to disappear. The NASCIS group's decision to admit persons with minor SCIs with minimal or no motor deficit not only enables statistical artifacts it complicates the interpretation of results from the population actually sampled. Perhaps one half of the NASCIS III sample may have had at most a minor deficit. Thus, we do not know whether the results of these studies reflect the severely injured population to which they have been applied. The numbers, tables, and figures in the published reports are scant and are inconsistently defined, making it impossible even for professional statisticians to duplicate the analyses, to guess the effect of changes in assumptions, or to supply the missing parts of the picture. Nonetheless, even 9 years after NASCIS II, the primary data have not been made public. The reporting of the NASCIS studies has fallen far short of the guidelines of the ICH/FDA and of the Evidence-based Medicine Group. Despite the lucrative "off label" markets for methylprednisolone in SCI, no Food and Drug Association indication has been obtained. There has been no public process of validation. These shortcomings have denied physicians the chance to use confidently a drug that many were enthusiastic about and has left them in an intolerably ambiguous position in their therapeutic choices, in their legal exposure, and in their ability to perform further research to help their patients.


Effect of early exposure on the integration of dental implants in the baboon: Part 1--Clinical findings at uncovering.
There has been increased discussion on the advantages of a one- versus a two-stage surgical approach in the placement of dental endosseous implants. This study evaluated the influence of early implant exposure on crestal bone height adjacent to the implant surface and Periotest values at uncovering in the baboon. Forty-eight implants (24 commercially pure titanium, 24 titanium alloy) were placed in maxillary and mandibular posterior sites in 6 baboons. Implant exposure was evaluated weekly for 3 weeks after implant placement. The level of bone adjacent to the dental implants was measured at placement from the top of the implant collar to the crest of the bone at the mesial, distal, buccal, and lingual surfaces. The maxillary sites were measured again at a 6-month uncovering, while the mandibular sites were measured at a 3-month uncovering. Periotest readings were also recorded at uncovering. Early implant exposure was more common in the mandible, with the majority occurring by the second week postplacement. There were no significant differences in the crestal bone height changes at uncovering between the pure titanium and alloy implants in either arch. In the maxilla, the changes in crestal bone height were not statistically different between exposed and nonexposed implants at any aspect. In the mandible, the difference in 3-month changes between exposed and nonexposed implants was significant for the distal, buccal, and lingual aspects. The overall percentage of implants with a Periotest reading in the "good" category was greater for the nonexposed sites as compared to exposed sites. The results of this study suggest that the two-stage surgical approach results in a better clinical outcome as compared to the one-stage approach in the baboon model.


Protective effect of vanadyl sulfate on skin injury in streptozotocin-induced diabetic rats.
The aim of the present study was to investigate the effect of vanadyl sulfate supplementation on the skin tissues of diabetic and control rats. In this study, 6-6.5 months old male Swiss albino rats were used. The animals were randomly divided into the following four groups: group I, control (nondiabetic intact animals); group II, vanadyl sulfate control; group III, streptozotocin (STZ)-diabetic animals and group IV, STZ-diabetic animals given vanadyl sulfate. The animals were made diabetic by intraperitoneal injection of a single dose of 65 mg/kg STZ in 0.01 M citrate buffer (pH = 4.5). From day 1 to day 60, 100 mg/kg vanadyl sulfate was given daily by gavage technique to one of the control and diabetic groups. Body weights and blood glucose levels were estimated on experimental days 0, 1 and 60. On the 60th day, skin tissue samples were taken, glutathione (GSH), lipid peroxidation (LPO), nonenzymatic glycosylation (NEG) and protein levels, catalase (CAT), superoxide dismutase (SOD) and glutathione-S-transferase (GST) activities were determined. Blood glucose, skin LPO and NEG levels increased, but skin GSH levels and CAT, SOD and GST activities decreased in the STZ group. Treatment with vanadyl sulfate reversed these effects. The present study showed that vanadyl sulfate exerted antioxidant properties and may prevent skin damage caused by diabetes.


Repeated Cold Stress Enhances the Acute Restraint Stress-Induced Hyperthermia in Mice.
The rodents exposed to repeated cold stress according to a specific schedule, known as specific alternation of rhythm in temperature (SART), exhibit autonomic imbalance, and is now used as an experimental model of fibromyalgia. To explore the susceptibility of SART-stressed animals to novel acute stress, we tested whether exposure of mice to SART stress for 1 week alters the extent of acute restraint stress-induced hyperthermia. Mice were subjected to 7-d SART stress sessions; i.e., the mice were alternately exposed to 24 and 4°C at 1-h intervals during the daytime (09:00-16:00) and kept at 4°C overnight (16:00-09:00). SART-stressed and unstressed mice were exposed to acute restraint stress for 20-60 min, during which rectal temperature was monitored. Serum corticosterone levels were measured before and after 60-min exposure to restraint stress. SART stress itself did not alter the body temperature or serum corticosterone levels in mice. Acute restraint stress increased the body temperature and serum corticosterone levels, both responses being greater in SART-stressed mice than unstressed mice. The enhanced hyperthermic responses to acute restraint stress in SART-stressed mice were significantly attenuated by SR59230A, a β3 adrenoceptor antagonist, but unaffected by diazepam, an anxiolytic, mifepristone, a glucocorticoid receptor antagonist, or indomethacin, a cyclooxygenase inhibitor. These results suggest that SART stress enhances the susceptibility of mice to acute restraint stress, characterized by increased hyperthermia and corticosterone secretion, and that the increased hyperthermic responses to acute stress might involve accelerated activation of sympathetic β3 adrenoceptors, known to regulate non-shivering thermogenesis in the brown adipose tissue.


ENvironmental Dynamics Underlying Responsive Extreme Survivors (ENDURES) of Glioblastoma: A Multidisciplinary Team-based, Multifactorial Analytical Approach.
Although glioblastoma (GBM) is a fatal primary brain cancer with short median survival of 15 months, a small number of patients survive >5 years after diagnosis; they are known as extreme survivors (ES). Because of their rarity, very little is known about what differentiates these outliers from other patients with GBM. For the purpose of identifying unknown drivers of extreme survivorship in GBM, the ENDURES consortium (ENvironmental Dynamics Underlying Responsive Extreme Survivors of GBM) was developed. This consortium is a multicenter collaborative network of investigators focused on the integration of multiple types of clinical data and the creation of patient-specific models of tumor growth informed by radiographic and histologic parameters. Leveraging our combined resources, the goals of the ENDURES consortium are 2-fold: (1) to build a curated, searchable, multilayered repository housing clinical and outcome data on a large cohort of ES patients with GBM; and (2) to leverage the ENDURES repository for new insights into tumor behavior and novel targets for prolonging survival for all patients with GBM. In this article, the authors review the available literature and discuss what is already known about ES. The authors then describe the creation of their consortium and some preliminary results.


Parafoveal color discrimination: a chromaticity locus of enhanced discrimination.
Are boundaries between color categories associated with enhanced discrimination? In the present experiments, chromatic thresholds were obtained for discriminations along lines orthogonal to the yellow-blue axis of color space. The targets were parafoveal and thresholds were measured with a spatial two-alternative forced choice. In interleaved experimental runs, we also obtained empirical estimates of the subjective yellow-blue line by asking observers to categorize colors as reddish or greenish. Both types of measurement were made in the presence of a steady background that was metameric to equal-energy white. In a limited region from desaturated yellow to desaturated blue, an enhanced discrimination is found near the subjective transition between reddish and greenish hues. This line of optimal discrimination is not aligned with either of the cardinal axes of color space: In a MacLeod-Boynton chromaticity diagram, it runs obliquely with negative slope.


Proteomics indicators of the rapidly shifting physiology from whole mountain pine beetle, Dendroctonus ponderosae (Coleoptera: Curculionidae), adults during early host colonization.
We developed proteome profiles for host colonizing mountain pine beetle adults, Dendroctonus ponderosae Hopkins (Coleoptera: Curculionidae). Adult insects were fed in pairs on fresh host lodgepole pine, Pinus contorta Dougl. ex Loud, phloem tissue. The proteomes of fed individuals were monitored using iTRAQ and compared to those of starved beetles, revealing 757 and 739 expressed proteins in females and males, respectively, for which quantitative information was obtained. Overall functional category distributions were similar for males and females, with the majority of proteins falling under carbohydrate metabolism (glycolysis, gluconeogenesis, citric acid cycle), structure (cuticle, muscle, cytoskeleton), and protein and amino acid metabolism. Females had 23 proteins with levels that changed significantly with feeding (p<0.05, FDR<0.20), including chaperones and enzymes required for vitellogenesis. In males, levels of 29 proteins changed significantly with feeding (p<0.05, FDR<0.20), including chaperones as well as motor proteins. Only two proteins, both chaperones, exhibited a significant change in both females and males with feeding. Proteins with differential accumulation patterns in females exhibited higher fold changes with feeding than did those in males. This difference may be due to major and rapid physiological changes occurring in females upon finding a host tree during the physiological shift from dispersal to reproduction. The significant accumulation of chaperone proteins, a cytochrome P450, and a glutathione S-transferase, indicate secondary metabolite-induced stress physiology related to chemical detoxification during early host colonization. The females' activation of vitellogenin only after encountering a host indicates deliberate partitioning of resources and a balancing of the needs of dispersal and reproduction.


FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma.
Oncogenic transcription factors drive many human cancers, yet identifying and therapeutically targeting the resulting deregulated pathways has proven difficult. Squamous cell carcinoma (SCC) is a common and lethal human cancer, and relatively little progress has been made in improving outcomes for SCC due to a poor understanding of its underlying molecular pathogenesis. While SCCs typically lack somatic oncogene-activating mutations, they exhibit frequent overexpression of the p53-related transcription factor p63. We developed an in vivo murine tumor model to investigate the function and key transcriptional programs of p63 in SCC. Here, we show that established SCCs are exquisitely dependent on p63, as acute genetic ablation of p63 in advanced, invasive SCC induced rapid and dramatic apoptosis and tumor regression. In vivo genome-wide gene expression analysis identified a tumor-survival program involving p63-regulated FGFR2 signaling that was activated by ligand emanating from abundant tumor-associated stroma. Correspondingly, we demonstrate the therapeutic efficacy of extinguishing this signaling axis in endogenous SCCs using the clinical FGFR2 inhibitor AZD4547. Collectively, these results reveal an unanticipated role for p63-driven paracrine FGFR2 signaling as an addicting pathway in human cancer and suggest a new approach for the treatment of SCC.


Estimating Marginal Healthcare Costs Using Genetic Variants as Instrumental Variables: Mendelian Randomization in Economic Evaluation.
Accurate measurement of the marginal healthcare costs associated with different diseases and health conditions is important, especially for increasingly prevalent conditions such as obesity. However, existing observational study designs cannot identify the causal impact of disease on healthcare costs. This paper explores the possibilities for causal inference offered by Mendelian randomization, a form of instrumental variable analysis that uses genetic variation as a proxy for modifiable risk exposures, to estimate the effect of health conditions on cost. Well-conducted genome-wide association studies provide robust evidence of the associations of genetic variants with health conditions or disease risk factors. The subsequent causal effects of these health conditions on cost can be estimated using genetic variants as instruments for the health conditions. This is because the approximately random allocation of genotypes at conception means that many genetic variants are orthogonal to observable and unobservable confounders. Datasets with linked genotypic and resource use information obtained from electronic medical records or from routinely collected administrative data are now becoming available and will facilitate this form of analysis. We describe some of the methodological issues that arise in this type of analysis, which we illustrate by considering how Mendelian randomization could be used to estimate the causal impact of obesity, a complex trait, on healthcare costs. We describe some of the data sources that could be used for this type of analysis. We conclude by considering the challenges and opportunities offered by Mendelian randomization for economic evaluation.


Response of driven sessile drops with contact-line dissipation.
A partially-wetting sessile drop is driven by a sinusoidal pressure field that produces capillary waves on the liquid/gas interface. Response diagrams and phase shifts for the droplet, whose contact-line moves with contact-angle that is a smooth function of the contact line speed, are reported. Contact-line dissipation originating from the contact-line speed condition leads to damping for drops with finite contact-line mobility, even for inviscid fluids. The critical mobility and associated driving frequency to generate the largest contact-line dissipation is computed. Viscous dissipation is approximated using the irrotational flow and the critical Ohnesorge number bounding regions beyond which a given mode becomes over-damped is computed. Regions of modal coexistence where two modes can be simultaneously excited by a single forcing frequency are identified. Predictions compare favorably to related experiments on vibrated drops.


Contrast sensitivity comparison between AcrySof ReSTOR and Acri.LISA aspheric intraocular lenses.
To evaluate distance contrast sensitivity under photopic, mesopic, and mesopic with glare conditions after implantation of the AcrySof ReSTOR (Alcon Laboratories Inc) and Acri.LISA (Carl Zeiss Meditec) intraocular lenses (IOLs). Binocular contrast sensitivity function was measured with the Optec 6500 FACT contrast sensitivity chart at distance and at three lighting conditions (85 cd/m2 and 3 cd/m2 with and without glare) in 36 eyes of 18 patients implanted with the AcrySof ReSTOR aspheric SN6AD3 IOL and 40 eyes of 20 patients implanted with the Acri.LISA 366D IOL. Results after implantation were compared between lenses at 1 and 6 months. Our results revealed that both IOLs provided good best spectacle-corrected visual acuities at distance and near vision (approximately 20/20), and no statistically significant differences were noted between models at different time points after surgery. Both IOLs provided contrast sensitivity within the normal range in photopic conditions. Under low lighting conditions, a reduction in contrast sensitivity for both lenses, particularly at higher spatial frequencies, was noted. No significant differences were observed between both IOLs at any lighting condition. The AcrySof ReSTOR SN6AD3 and Acri.LISA aspheric IOLs provided contrast sensitivity within normal range under photopic conditions and a reduction in contrast sensitivity under mesopic conditions, with no significant differences between the two brands.


What makes public health studies ethical? Dissolving the boundary between research and practice.
The generation of evidence is integral to the work of public health and health service providers. Traditionally, ethics has been addressed differently in research projects, compared with other forms of evidence generation, such as quality improvement, program evaluation, and surveillance, with review of non-research activities falling outside the purview of the research ethics board. However, the boundaries between research and these other evaluative activities are not distinct. Efforts to delineate a boundary - whether on grounds of primary purpose, temporality, underlying legal authority, departure from usual practice, or direct benefits to participants - have been unsatisfactory.Public Health Ontario has eschewed this distinction between research and other evaluative activities, choosing to adopt a common framework and process to guide ethical reflection on all public health evaluative projects throughout their lifecycle - from initial planning through to knowledge exchange. The Public Health Ontario framework was developed by a working group of public health and ethics professionals and scholars, in consultation with individuals representing a wide range of public health roles. The first part of the framework interprets the existing Canadian research ethics policy statement (commonly known as the TCPS 2) through a public health lens. The second part consists of ten questions that guide the investigator in the application of the core ethical principles to public health initiatives.The framework is intended for use by those designing and executing public health evaluations, as well as those charged with ethics review of projects. The goal is to move toward a culture of ethical integrity among investigators, reviewers and decision-makers, rather than mere compliance with rules. The framework is consonant with the perspective of the learning organization and is generalizable to other public health organizations, to health services organizations, and beyond. Public Health Ontario has developed an ethics framework that is applicable to any evidence-generating activity, regardless of whether it is labelled research. While developed in a public health context, it is readily adaptable to other health services organizations and beyond.


Depletion of the yeast nuclear exosome subunit Rrp6 results in accumulation of polyadenylated RNAs in a discrete domain within the nucleolus.
Recent data reveal that a substantial fraction of transcripts generated by RNA polymerases I, II, and III are rapidly degraded in the nucleus by the combined action of the exosome and a noncanonical poly(A) polymerase activity. This work identifies a domain within the yeast nucleolus that is enriched in polyadenylated RNAs in the absence of the nuclear exosome RNase Rrp6 or the exosome cofactor Mtr4. In normal yeast cells, poly(A)(+) RNA was undetectable in the nucleolus but the depletion of either Rrp6 or Mtr4 led to the accumulation of polyadenylated RNAs in a discrete subnucleolar region. This nucleolar poly(A) domain is enriched for the U14 snoRNA and the snoRNP protein Nop1 but is distinct from the nucleolar body that functions in snoRNA maturation. In strains lacking both Rrp6 and the poly(A) polymerase Trf4, the accumulation of poly(A)(+) RNA was suppressed, suggesting the involvement of the Trf4-Air1/2-Mtr4 polyadenylation (TRAMP) complex. The accumulation of polyadenylated snoRNAs in a discrete nucleolar domain may promote their recognition as substrates for the exosome.


Vitamin D intake and breast cancer risk: a case-control study in Italy.
Vitamin D has been suggested to play a protective role against several cancers, including breast cancer. We used data from a case-control study conducted in Italy from 1991 to 1994 to study the relation between dietary intake of vitamin D and breast cancer risk. Subjects were 2569 women with incident, histologically confirmed breast cancer and 2588 hospital controls. Odds ratios (ORs) and 95% confidence intervals (CIs) according to deciles of vitamin D intake were estimated by multiple logistic regression models. After allowance for major risk factors for breast cancer and dietary covariates including calcium and energy intake, there was no association with vitamin D up to the seventh decile. Thereafter, the OR declined, so that the overall trend was statistically significantly inverse. The OR for subjects in the three highest deciles of consumption compared with those in the lowest ones combined was 0.79 (95% CI 0.70-0.90). Intake of vitamin D >3.57 microg or 143 IU appeared to have a protective effect against breast cancer. The inverse association was consistent across strata of menopausal status. This study adds to the existing evidence that vitamin D intake in inversely associated with breast cancer risk.


Effectiveness of forward collision warning and autonomous emergency braking systems in reducing front-to-rear crash rates.
The objective of this study was to evaluate the effectiveness of forward collision warning (FCW) alone, a low-speed autonomous emergency braking (AEB) system operational at speeds up to 19mph that does not warn the driver prior to braking, and FCW with AEB that operates at higher speeds in reducing front-to-rear crashes and injuries. Poisson regression was used to compare rates of police-reported crash involvements per insured vehicle year in 22 U.S. states during 2010-2014 between passenger vehicle models with FCW alone or with AEB and the same models where the optional systems were not purchased, controlling for other factors affecting crash risk. Similar analyses compared rates between Volvo 2011-2012 model S60 and 2010-2012 model XC60 vehicles with a standard low-speed AEB system to those of other luxury midsize cars and SUVs, respectively, without the system. FCW alone, low-speed AEB, and FCW with AEB reduced rear-end striking crash involvement rates by 27%, 43%, and 50%, respectively. Rates of rear-end striking crash involvements with injuries were reduced by 20%, 45%, and 56%, respectively, by FCW alone, low-speed AEB, and FCW with AEB, and rates of rear-end striking crash involvements with third-party injuries were reduced by 18%, 44%, and 59%, respectively. Reductions in rear-end striking crashes with third-party injuries were marginally significant for FCW alone, and all other reductions were statistically significant. FCW alone and low-speed AEB reduced rates of being rear struck in rear-end crashes by 13% and 12%, respectively, but FCW with AEB increased rates of rear-end struck crash involvements by 20%. Almost 1 million U.S. police-reported rear-end crashes in 2014 and more than 400,000 injuries in such crashes could have been prevented if all vehicles were equipped with FCW and AEB that perform similarly as systems did for study vehicles.


Ecological impacts of invasive alien species along temperature gradients: testing the role of environmental matching.
Invasive alien species (IAS) can cause substantive ecological impacts, and the role of temperature in mediating these impacts may become increasingly significant in a changing climate. Habitat conditions and physiological optima offer predictive information for IAS impacts in novel environments. Here, using meta-analysis and laboratory experiments, we tested the hypothesis that the impacts of IAS in the field are inversely correlated with the difference in their ambient and optimal temperatures. A meta-analysis of 29 studies of consumptive impacts of IAS in inland waters revealed that the impacts of fishes and crustaceans are higher at temperatures that more closely match their thermal growth optima. In particular, the maximum impact potential was constrained by increased differences between ambient and optimal temperatures, as indicated by the steeper slope of a quantile regression on the upper 25th percentile of impact data compared to that of a weighted linear regression on all data with measured variances. We complemented this study with an experimental analysis of the functional response (the relationship between predation rate and prey supply) of two invasive predators (freshwater mysid shrimp, Hemimysis anomala and Mysis diluviana) across. relevant temperature gradients; both of these species have previously been found to exert strong community-level impacts that are corroborated by their functional responses to different prey items. The functional response experiments showed that maximum feeding rates of H. anomala and M. diluviana have distinct peaks near their respective thermal optima. Although variation in impacts may be caused by numerous abiotic or biotic habitat characteristics, both our analyses point to temperature as a key mediator of IAS impact levels in inland waters and suggest that IAS management should prioritize habitats in the invaded range that more closely match the thermal optima of targeted invaders.


Wireless fabric patch sensors for wearable healthcare.
Two novel wireless fabric patch sensors are introduced for low energy wearable healthcare. The first is a wirelessly powered patch sensor that can be attached to a patient to capture electrocardiogram (ECG) while consuming only 12 microW. By using fabric circuit board technology, the band-aid like sensor is implemented. The second wearable cardiac heathcare sensor, fabricated in the form of 4-layer compact smart poultice type including flexible battery, can extend to monitor bio-impedance together with ECG signals at 16 different sites of the heart with 25 reconfigurable electrodes. It also provides cm-range inductive coupled remote system start-up and duty-cycled data transmission using body as communication channel for a low energy wireless interconnectivity. Both sensors exploit dry fabric electrodes to minimize skin irritation during clinical long term operation.


Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats.
The possibility of decreasing the gastrointestinal (GI) toxic effects of 5-fluorouracil (5-FU) on the digestive tract such as its injury of cells and induction of diarrhea, without reducing its antitumor activity, was investigated in rats. Oxonic acid was found to inhibit the phosphorylation of 5-FU to 5-fluorouridine-5'-monophosphate catalyzed by pyrimidine phosphoribosyl-transferase in a different manner from allopurinol in cell-free extracts and intact cells in vitro. On p.o. administration of 5-FU (2 mg/kg) and a potent inhibitor of 5-FU degradation to Yoshida sarcoma-bearing rats, oxonic acid (10 mg/kg) was found to inhibit the formation of 5-fluorouridine-5'-monophosphate from 5-FU and its subsequent incorporation into the RNA fractions of small and large intestine but not of tumor and bone marrow tissues. This selective inhibition of 5-FU phosphorylation in the GI tract was due to the much higher concentrations of oxonic acid in GI tissues than in other tissues and the blood. On p.o. administration with the 5-FU derivative, UFT, which is a combined form of 1 M tegafur and 4 M uracil and usually administered p.o. to cancer patients in Japan, oxonic acid (10-50 mg/kg) markedly reduced injury of GI tissues and/or severe diarrhea without influencing the antitumor effect of UFT. These findings suggest that coadministration of oxonic acid suppresses the GI toxicity of 5-FU and its derivatives without affecting their antitumor activity and thus prolongs the life span of cancer-bearing rats.


Birth weight, working memory and epigenetic signatures in IGF2 and related genes: a MZ twin study.
Neurodevelopmental disruptions caused by obstetric complications play a role in the etiology of several phenotypes associated with neuropsychiatric diseases and cognitive dysfunctions. Importantly, it has been noticed that epigenetic processes occurring early in life may mediate these associations. Here, DNA methylation signatures at IGF2 (insulin-like growth factor 2) and IGF2BP1-3 (IGF2-binding proteins 1-3) were examined in a sample consisting of 34 adult monozygotic (MZ) twins informative for obstetric complications and cognitive performance. Multivariate linear regression analysis of twin data was implemented to test for associations between methylation levels and both birth weight (BW) and adult working memory (WM) performance. Familial and unique environmental factors underlying these potential relationships were evaluated. A link was detected between DNA methylation levels of two CpG sites in the IGF2BP1 gene and both BW and adult WM performance. The BW-IGF2BP1 methylation association seemed due to non-shared environmental factors influencing BW, whereas the WM-IGF2BP1 methylation relationship seemed mediated by both genes and environment. Our data is in agreement with previous evidence indicating that DNA methylation status may be related to prenatal stress and later neurocognitive phenotypes. While former reports independently detected associations between DNA methylation and either BW or WM, current results suggest that these relationships are not confounded by each other.


The Effect of Reading Interventions among Poor Readers at a Forensic Psychiatric Clinic.
The aim of the present study was to investigate the effect of a short period, 15 sessions, of reading interventions in a sample of adult forensic psychiatric patients: 61 patients with decoding difficulties - 44 in the experimental group and 17 in the comparison group - with an average age of 31.6 participated. Of these, 36% were female, and 29% had an immigrant background. The participants carried out a battery of reading tests. The results in the experimental group showed a medium effect size (d = .36 to .76) on all reading tests between pre- and post-test. The comparison group, however, showed no gain at all between the test occasions. The results indicate that a proportionally low reading intervention effort produces improvement in reading. This study discusses the importance of including reading assessment and offering remediation in order to reach optimal future social adjustment for patients in forensic clinics.


A fast but accurate excitonic simulation of the electronic circular dichroism of nucleic acids: how can it be achieved?
We present and discuss a simple and fast computational approach to the calculation of electronic circular dichroism spectra of nucleic acids. It is based on a exciton model in which the couplings are obtained in terms of the full transition-charge distributions, as resulting from TDDFT methods applied on the individual nucleobases. We validated the method on two systems, a DNA G-quadruplex and a RNA β-hairpin whose solution structures have been accurately determined by means of NMR. We have shown that the different characteristics of composition and structure of the two systems can lead to quite important differences in the dependence of the accuracy of the simulation on the excitonic parameters. The accurate reproduction of the CD spectra together with their interpretation in terms of the excitonic composition suggest that this method may lend itself as a general computational tool to both predict the spectra of hypothetic structures and define clear relationships between structural and ECD properties.


Dynamic Amygdala Influences on the Fronto-Striatal Brain Mechanisms Involved in Self-Control of Impulsive Desires.
Human decisions are guided by a variety of motivational factors, such as immediate rewards, long-term goals, and emotions. We used functional magnetic resonance imaging to investigate the dynamic functional interactions between the amygdala, the nucleus accumbens, and the prefrontal cortex that underlie the influences of emotions, desires, and rationality on human decisions. We found that increased functional connectivity between the amygdala and the nucleus accumbens facilitated the approach of an immediate reward in the presence of emotional information. Further, increased functional interactions of the anteroventral prefrontal cortex with the amygdala and the nucleus accumbens were associated with rational decisions in dilemma situations. These findings support previous animal studies by demonstrating that emotional signals from the amygdala and goal-oriented information from prefrontal cortices interface in the nucleus accumbens to guide human decisions and reward-directed actions.


Neuropsychological functioning and health-related quality of life: pediatric acute liver failure study group results.
Pediatric acute liver failure (PALF) is a rare but serious event, with poorly understood functional outcomes. The goal was to determine the prevalence of reduced neuropsychological functioning and health-related quality of life (HRQOL) following PALF. This multicenter study examined neuropsychological functioning and HRQOL 1 to 6 (median 3.8) years after PALF. Participants ages 6 to 16 (median 9.9) years were recruited from the PALF registry and administered measures of intelligence, visual spatial/visual motor coordination, attention, executive function, depression, and adaptive skills. HRQOL and fatigue were assessed using the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0) and PedsQL Multidimensional Fatigue Scale. A total of 36 patients participated; 50% were boys and 67% were white. Median age at PALF was 5.6 years. A history of grade 3 or 4 hepatic encephalopathy was reported in 5/36 (14%) participants and 23/36 (64%) received a liver transplant. Visual spatial ability was significantly better than norms (P = 0.009), but motor coordination was worse (P = 0.04). Teachers (P = 0.04 to P < 0.0001) and parents (P = 0.005) reported more executive deficits versus norms, and participants had worse attention (P = 0.02). Participants did not differ significantly from norms on IQ, depression, or adaptive functioning. All of the child self-report PedsQL Generic Core and fatigue scales were significantly lower than a matched healthy sample (P = 0.001 to P < 0.0001) and parent proxy report was lower on the fatigue scales (P = 0.001 to P < 0.0001). Long-term PALF survivors demonstrate average IQ and visual spatial ability, but greater than expected impairments in motor skills, attention, executive function, HRQOL, and fatigue.


Structural fold, conservation and Fe(II) binding of the intracellular domain of prokaryote FeoB.
FeoB is a G-protein coupled membrane protein essential for Fe(II) uptake in prokaryotes. Here, we report the crystal structures of the intracellular domain of FeoB (NFeoB) from Klebsiella pneumoniae (KpNFeoB) and Pyrococcus furiosus (PfNFeoB) with and without bound ligands. In the structures, a canonical G-protein domain (G domain) is followed by a helical bundle domain (S-domain), which despite its lack of sequence similarity between species is structurally conserved. In the nucleotide-free state, the G-domain's two switch regions point away from the binding site. This gives rise to an open binding pocket whose shallowness is likely to be responsible for the low nucleotide-binding affinity. Nucleotide binding induced significant conformational changes in the G5 motif which in the case of GMPPNP binding was accompanied by destabilization of the switch I region. In addition to the structural data, we demonstrate that Fe(II)-induced foot printing cleaves the protein close to a putative Fe(II)-binding site at the tip of switch I, and we identify functionally important regions within the S-domain. Moreover, we show that NFeoB exists as a monomer in solution, and that its two constituent domains can undergo large conformational changes. The data show that the S-domain plays important roles in FeoB function.


Conscience and consciousness: a definition.
While consciousness has been examined extensively in its different aspects, like in philosophy, psychiatry, neurophysiology, neuroplasticity, etc., conscience though it is an equal important aspect of the human existence, which remains an unknown to a great degree as an almost transcendental aspect of the human mind. It has not been examined as thoroughly as consciousness and largely remains a "terra incognita" for its neurophysiology, brain topography, etc. Conscience and consciousness are part of a system of information that governs our experience and decision making process. The intent of this paper is to define these terms, to discuss about consciousness from both neurological and quantum physics point of view, the relationship between the dynamics of consciousness and neuroplasticity and to highlight the relationship between conscience, stress and health.


Selective and superselective angiography of pediatric moyamoya disease angioarchitecture: the anterior circulation.
The angioarchitecture of the so-called moyamoya vessels in children has not been explicitly analyzed. We aimed to investigate the precise anatomy of the vascular anastomotic networks in patients with childhood moyamoya disease. Six children diagnosed with moyamoya disease for the first time underwent an angiographic investigation with selective and superselective injections. We recorded the arterial branches feeding the moyamoya anastomotic networks, their connections and the recipient vessels. Depending on the level of the steno-occlusive lesion, the feeding vessels included the medial striate arteries, the perforators of the choroidal segment of the carotid, the uncal artery, the medial and lateral branches of the intraventricular segment of the anterior choroidal artery, perforators of the communicating segment, the superior hypophyseal arteries, the prechiasmal branches of the ophthalmic artery, the ethmoidal arteries and the dural branches of the cavernous carotid. Through connections, which are described, the recipient vessels were the lateral striate arteries and the middle cerebral, the medial striate arteries and the anterior cerebral, medullary arteries around the ventricular system, anterior temporal branches of the middle cerebral, orbitofrontal and frontopolar branches of the anterior cerebral, as well as other cortical branches of the anterior and middle cerebral territories. The use of high quality selective and superselective angiography enabled us to clearly demonstrate for the first time aspects of the microangiographic anatomy of the moyamoya anastomotic network previously only vaguely or incompletely described.


Vertebroplasty, first 1000 levels of a single center: evaluation of the outcomes and complications.
Percutaneous polymethylmethacrylate (PMMA) vertebroplasty has become a common procedure for treatment of pain and disability associated with vertebral compression fractures. We reviewed the experience with our first 1000 consecutively treated vertebral compression fractures in an attempt to demonstrate both the short- and long-term safety and efficacy of percutaneous vertebroplasty. The first 1000 compression fractures treated by vertebroplasty at our institution were identified from a comprehensive prospectively acquired vertebroplasty data base. All patients treated with vertebroplasty were included, regardless of the underlying pathologic cause. Chart reviews of the procedure notes, imaging studies, clinical visits, and follow-up telephone interviews were performed for each patient. Evaluation at each follow-up time point included pain response (subjective and visual analog pain score), change in mobility, change in pain medication usage, and modified Roland-Morris Disability Questionnaire. Statistical analysis was performed on the pain response and change in the Roland-Morris score at each follow-up time point. Significant procedure-related complications that occurred from the time of the procedure were also specifically extracted from the patients' charts. There was a dramatic improvement in all the evaluated parameters following percutaneous vertebroplasty. The improvement in pain, mobility, medication usage, and Roland-Morris score was noticed immediately after the procedure and persisted through the 2-year follow-up. There was a low rate of complications from the procedure, the most common being rib fractures. According to our results, practitioners can quote a high success rate and low complication rate for vertebroplasty when making treatment recommendations for painful spinal compression fractures.