Proanthocyanidins inhibit Ascaris suum glutathione-S-transferase activity and increase susceptibility of larvae to levamisole in vitro.
Proanthocyanidins (PAC) are a class of plant secondary metabolites commonly found in the diet that have shown potential to control gastrointestinal nematode infections. The anti-parasitic mechanism(s) of PAC remain obscure, however the protein-binding properties of PAC suggest that disturbance of key enzyme functions may be a potential mode of action. Glutathione-S-transferases (GSTs) are essential for parasite detoxification and have been investigated as drug and vaccine targets. Here, we show that purified PAC strongly inhibit the activity of both recombinant and native GSTs from the parasitic nematode Ascaris suum. As GSTs are involved in detoxifying xenobiotic substances within the parasite, we hypothesised that this inhibition may render parasites hyper-susceptible to anthelmintic drugs. Migration inhibition assays with A. suum larvae demonstrated that the potency of levamisole (LEV) and ivermectin (IVM) were significantly increased in the presence of PAC purified from pine bark (4.6-fold and 3.2-fold reduction in IC50 value for LEV and IVM, respectively). Synergy analysis revealed that the relationship between PAC and LEV appeared to be synergistic in nature, suggesting a specific enhancement of LEV activity, whilst the relationship between PAC and IVM was additive rather than synergistic, suggesting independent actions. Our results demonstrate that these common dietary compounds may increase the efficacy of synthetic anthelmintic drugs in vitro, and also suggest one possible mechanism for their well-known anti-parasitic activity.


Modelling biomacromolecular assemblies with continuum mechanics.
We have developed a continuum mechanical description of proteins using a finite element algorithm which has been generalized to include thermal fluctuations and which is therefore known as fluctuating finite element analysis (FFEA). Whereas conventional molecular dynamics (MD) simulations provide a trajectory in which each individual atomic position fluctuates, a FFEA trajectory shows how the overall shape of the protein changes due to thermal agitation. We describe the theoretical background to FFEA, its relationship to more established biomolecular modelling methods and provide examples of its application to the mesoscale biomolecular dynamics of the molecular motor dynein.


The worldwide epidemiology of prostate cancer: perspectives from autopsy studies.
Prostate cancer is the most frequently diagnosed non-skin cancer in the United States and the third leading cause of cancer deaths. International trends in the incidence, mortality and prevalence of prostate cancer are assessed. Databases from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute and the International Agency for Research on Cancer (IARC), and the literature on autopsy studies on prostate cancer were reviewed and summarized in the article. Prostate cancer remains an important public health concern in Western countries and an emerging malignancy in developing nations. Prostate cancer incidence is dependent on efforts to detect the disease. Autopsy studies provide accurate and useful information regarding comparative prevalence rates of the disease among regions of interest. Improved cancer registration is needed in developing nations. The prevalence of prostate cancer must be established to predict the expected incidence of the disease and in order to plan rational detection and treatment strategies. Clinically significant disease should be distinguished from insignificant disease which may pose little or no biological danger to the patient.


Monte Carlo calculated and experimentally determined output correction factors for small field detectors in Leksell Gamma Knife Perfexion beams.
The measurement of output factors (OF) for the small photon beams generated by Leksell Gamma Knife® (LGK) radiotherapy units is a challenge for the physicist due to the under or over estimation of these factors by a vast majority of the detectors commercially available. Output correction factors, introduced in the international formalism published by Alfonso (2008 Med. Phys. 35 5179-86), standardize the determination of OFs for small photon beams by correcting detector-reading ratios to yield OFs in terms of absorbed-dose ratios. In this work output correction factors for a number of detectors have been determined for LGK Perfexion™ (60)Co γ-ray beams by Monte Carlo (MC) calculations and measurements. The calculations were made with the MC system PENELOPE, scoring the energy deposited in the active volume of the detectors and in a small volume of water; the detectors simulated were two silicon diodes, one liquid ionization chamber (LIC), alanine and TLD. The calculated LIC output correction factors were within ± 0.4%, and this was selected as the reference detector for experimental determinations where output correction factors for twelve detectors were measured, normalizing their readings to those of the LIC. The MC-calculated and measured output correction factors for silicon diodes yielded corrections of up to 5% for the smallest LGK collimator size of 4 mm diameter. The air ionization chamber measurements led to extremely large output correction factors, caused by the well-known effect of partial volume averaging. The corrections were up to 7% for the natural diamond detector in the 4 mm collimator, also due to partial volume averaging, and decreased to within about ± 0.6% for the smaller synthetic diamond detector. The LIC, showing the smallest corrections, was used to investigate machine-to-machine output factor differences by performing measurements in four LGK units with different dose rates. These resulted in OFs within ± 0.6% and ± 0.2% for the 4 mm and 8 mm collimators, respectively, providing evidence for the use of generic OFs for these LGK beams. Using the experimentally derived output correction factors, OFs can be measured using a wide range of commercially available detectors.


Karrikin Improves Osmotic and Salt Stress Tolerance via the Regulation of the Redox Homeostasis in the Oil Plant Sapium sebiferum.
Karrikins are reported to stimulate seed germination, regulate seedling growth, and increase the seedling vigor in abiotic stress conditions in plants. Nevertheless, how karrikins alleviate abiotic stress remains largely elusive. In this study, we found that karrikin (KAR1) could significantly alleviate both drought and salt stress in the important oil plant Sapium sebiferum. KAR1 supplementation in growth medium at a nanomolar (nM) concentration was enough to recover seed germination under salt and osmotic stress conditions. One nanomolar of KAR1 improved seedling biomass, increased the taproot length, and increased the number of lateral roots under abiotic stresses, suggesting that KAR1 is a potent alleviator of abiotic stresses in plants. Under abiotic stresses, KAR1-treated seedlings had a higher activity of the key antioxidative enzymes, such as superoxide dismutase, peroxidase, catalase, and ascorbate peroxidase, in comparison with the control, which leads to a lower level of hydrogen peroxide, malondialdehyde, and electrolyte leakage. Moreover, the metabolome analysis showed that KAR1 treatment significantly increased the level of organic acids and amino acids, which played important roles in redox homeostasis under stresses, suggesting that karrikins might alleviate abiotic stresses via the regulation of redox homeostasis. Under abiotic stresses, applications of karrikins did not increase the endogenous abscisic acid level but altered the expression of several ABA signaling genes, such as SNF1-RELATED PROTEIN KINASE2.3, SNF1-RELATED PROTEIN KINASE2.6, ABI3, and ABI5, suggesting potential interactions between karrikins and ABA signaling in the stress responses. Conclusively, we not only provided the physiological and molecular evidence to clarify the mechanism of karrikins in the regulation of stress adaptation in S. sebiferum but also showed the potential value of karrikins in agricultural practices, which will lay a foundation for further studies about the role of karrikins in abiotic stress alleviation in plants.


Contrasting response of protein degradation to starvation and insulin as measured by release of N tau-methylhistidine or phenylalanine from the perfused rat heart.
An isotope-dilution method is described for the measurement of N tau-methylhistidine release from the perfused rat heart. We argue that release of N tau-methylhistidine is indicative of cardiac actin degradation. N tau-Methylhistidine release is compared with phenylalanine release in the presence of cycloheximide (phenylalanine release being a measure of degradation of mixed proteins). In hearts perfused with glucose plus acetate, the rate of actin degradation was increased by starvation and was not inhibited by insulin. In contrast, the rate of mixed-protein degradation was decreased by starvation and was inhibited by insulin. The fractional rate of degradation of mixed proteins in hearts from fed or starved rats was greater than that for actin. It is suggested that there are at least two pools of intracellular protein, the degradation rates of which differ in terms of their response to insulin and starvation.


Placental, Matrilineal, and Epigenetic Mechanisms Promoting Environmentally Adaptive Development of the Mammalian Brain.
The evolution of intrauterine development, vivipary, and placentation in eutherian mammals has introduced new possibilities and constraints in the regulation of neural plasticity and development which promote neural function that is adaptive to the environment that a developing brain is likely to encounter in the future. A range of evolutionary adaptations associated with placentation transfers disproportionate control of this process to the matriline, a period unique in mammalian development in that there are three matrilineal genomes interacting in the same organism at the same time (maternal, foetal, and postmeiotic oocytes). The interactions between the maternal and developing foetal hypothalamus and placenta can provide a template by which a mother can transmit potentially adaptive information concerning potential future environmental conditions to the developing brain. In conjunction with genomic imprinting, it also provides a template to integrate epigenetic information from both maternal and paternal lineages. Placentation also hands ultimate control of genomic imprinting and intergenerational epigenetic information transfer to the matriline as epigenetic markers undergo erasure and reprogramming in the developing oocyte. These developments, in conjunction with an expanded neocortex, provide a unique evolutionary template by which matrilineal transfer of maternal care, resources, and culture can be used to promote brain development and infant survival.


An immunoassay to evaluate human/environmental exposure to the antimicrobial triclocarban.
A sensitive, competitive indirect enzyme-linked immunosorbent assay (ELISA) for the detection of the antimicrobial triclocarban (TCC) was developed. The haptens were synthesized by derivatizing the para position of a phenyl moiety of TCC. The rabbit antisera were screened and the combination of antiserum 1648 and a heterologous competitive hapten containing a piperidine was further characterized. The IC(50) and detection range for TCC in buffer were 0.70 and 0.13-3.60 ng/mL, respectively. The assay was selective for TCC, providing only low cross-reactivity to TCC-related compounds and its major metabolites except for the closely related antimicrobial 3-trifluoromethyl-4,4'-dichlorocarbanilide. A liquid-liquid extraction for sample preparation of human body fluids resulted in an assay that measured low part per billion levels of TCC in small volumes of the samples. The limits of quantification of TCC were 5 ng/mL in blood/serum and 10 ng/mL in urine, respectively. TCC in human urine was largely the N- or N'-glucuronide. TCC concentrations of biosolids measured by the ELISA were similar to those determined by LC-MS/MS. This immunoassay can be used as a rapid, inexpensive, and convenient tool to aid researchers monitoring human/environmental exposure to TCC to better understand the health effects.


Berberine Attenuates Cerebral Ischemia-Reperfusion Injury Induced Neuronal Apoptosis by Down-Regulating the CNPY2 Signaling Pathway.
Berberine (BBR) has a neuroprotective effect against ischemic stroke, but its specific protective mechanism has not been clearly elaborated. This study explored the effect of BBR on the canopy FGF signaling regulator 2 (CNPY2) signaling pathway in the ischemic penumbra of rats. The model of cerebral ischemia-reperfusion injury (CIRI) was established by the thread embolization method, and BBR was gastrically perfused for 48 h or 24 h before operation and 6 h after operation. The rats were randomly divided into four groups: the Sham group, BBR group, CIRI group, and CIRI + BBR group. After 2 h of ischemia, followed by 24 h of reperfusion, we confirmed the neurologic dysfunction and apoptosis induced by CIRI in rats (p < 0.05). In the ischemic penumbra, the expression levels of CNPY2-regulated endoplasmic reticulum stress-induced apoptosis proteins (CNPY2, glucose-regulated protein 78 (GRP78), double-stranded RNA-activated protein kinase-like ER kinase (PERK), C/EBP homologous protein (CHOP), and Caspase-3) were significantly increased, but these levels were decreased after BBR treatment (p < 0.05). To further verify the inhibitory effect of BBR on CIRI-induced neuronal apoptosis, we added an endoplasmic reticulum-specific agonist and a PERK inhibitor to the treatment. BBR was shown to significantly inhibit the expression of apoptotic proteins induced by endoplasmic reticulum stress agonist, while the PERK inhibitor partially reversed the ability of BBR to inhibit apoptotic protein (p < 0.05). These results confirm that berberine may inhibit CIRI-induced neuronal apoptosis by downregulating the CNPY2 signaling pathway, thereby exerting a neuroprotective effect.


Association between prenatal psychological stress and oxidative stress during pregnancy.
Prenatal psychological stress during pregnancy has been associated with adverse reproductive outcomes. A growing animal literature supports an association between psychological stress and oxidative stress. We assessed this relationship in pregnant women, hypothesising that psychological stress is associated with higher concentrations of oxidative stress biomarkers during pregnancy. Psychosocial status and stressful life events (SLE) were self-reported. 8-iso-prostaglandin F2α (8-iso-PGF2α ) was measured as a biomarker of oxidative stress in urine samples at median 32 weeks' gestation. We examined SLEs individually (ever vs never) and in summary (any vs none) and psychosocial status as measured by individual subscales and in summary (poor vs good). Linear models estimated associations between these parameters and urinary 8-iso-PGF2α concentrations after adjusting for covariates. The geometric mean of 8-iso-PGF2α was significantly higher among pregnant women who were non-White, smokers, had less than a college education, higher pre-pregnancy BMI and were unmarried. Having ever had a death in the family (n = 39) during pregnancy was associated with a 22.9% increase in 8-iso-PGF2α in unadjusted models (95% confidence interval [CI] 1.50, 48.8). Poor psychosocial status was associated with a 13.1% (95% CI 2.43, 25.0) greater mean 8-iso-PGF2α in unadjusted analyses. Associations were attenuated, but remained suggestive, after covariate adjustment. These data suggest that 8-iso-PGF2α is elevated in pregnant women with who are at a sociodemographic disadvantage and who have higher psychological stress in pregnancy. Previous studies have observed that 8-iso-PGF2α levels are associated with adverse birth outcomes, oxidative stress could be a mediator in these relationships.


Refeeding and weight restoration outcomes in anorexia nervosa: Challenging current guidelines.
Cohort study from February 2003 through May 2011 to determine weight restoration and refeeding complication outcomes for patients with anorexia nervosa (AN) treated in an integrated inpatient-partial hospital eating disorder program designed to produce rapid weight gain and weight restoration in the majority. Consecutive admissions (females and males, adolescents and adults; N = 361 patients, 461 admissions) at least 1.8 kg below target weight with AN or subthreshold variants were included. Main outcome measures were rates of hypophosphatemia, transfer to medicine, or death; rates of weight gain and percent achieving weight restoration. Hypophosphatemia was present in 7.9% of cases at admission and in 18.5% at some point during treatment. Hypophosphatemia was mild to moderate. Lower admission body mass index (BMI), but not rate of weight gain, predicted hypophosphatemia [OR = 0.65; p < .00001 (95% CI 0.57-0.76)]. Five patients (1.1%) were transferred to medicine or surgery, none because of refeeding. There were no deaths. Mean inpatient weight gain was 1.98 kg/week; mean partial hospital weight gain was 1.36 kg/week. By program discharge, 71.8% of adults reached a BMI of 19, 58.5% a BMI of 20. For adolescents, 80.4% came within 2 kg of their target weight; 76.1% came within 1 kg. Refeeding patients with AN using a hospital-based, behavioral protocol may be accomplished safely and more rapidly than generally recognized, weight restoring most patients by discharge. Helpful elements may include the program's integrated, step-down structure; multidisciplinary team approach emphasizing group therapy to effect behavior change; and close medical monitoring for those with BMI < 15.


Human papillomavirus (HPV) 6, 11, 16, and 18 seroprevalence is associated with sexual practice and age: results from the multinational HPV Infection in Men Study (HIM Study).
Few human papillomavirus (HPV) serology studies have evaluated type-specific seroprevalence of vaccine HPV types in men. This study investigates seroprevalence of HPV 6, 11, 16, and 18, and associated risk factors in men residing in three countries (United States, Mexico, and Brazil). Data from 1,477 men aged 18 to 70 enrolled in the HPV Infection in Men Study (HIM Study) were analyzed. Serum antibody testing was performed with virus-like particle-based ELISA. Potential risk factors were assessed for individual HPV types by the use of logistic regression. Overall, HPV-6, 11, 16, and 18 seroprevalence was 14.8%, 17.3%, 11.2%, and 5.8%, respectively. Thirty-four percent of men were seropositive to one or more HPV types. When examined by sexual practice, 31.2% of men who had sex with women, 65.6% of men who had sex with men (MSM), and 59.4% of men who had sex with both men and women (MSMW) were seropositive to one or more HPV types. Seroprevalence increased with age among young-to-middle-aged men with significant upward age trends observed for HPV 11, 16, and 18. Men with multiple lifetime male anal sex partners were 2 to 4 times more likely to be HPV 6 or 11 seropositive and 3 to 11 times more likely to be HPV 16 or 18 seropositive. Our data indicate that exposures to vaccine HPV types were common in men and highly prevalent among MSM and MSMW. Our study provides strong evidence that the practice of same-sex anal intercourse is an independent risk factor for seroprevalence of individual vaccine HPV types. Examination of antibody responses to HPV infections at various anatomic sites in future studies is needed to elaborate on the mechanism.


The Brassica napus receptor-like protein RLM2 is encoded by a second allele of the LepR3/Rlm2 blackleg resistance locus.
Leucine-rich repeat receptor-like proteins (LRR-RLPs) are highly adaptable parts of the signalling apparatus for extracellular detection of plant pathogens. Resistance to blackleg disease of Brassica spp. caused by Leptosphaeria maculans is largely governed by host race-specific R-genes, including the LRR-RLP gene LepR3. The blackleg resistance gene Rlm2 was previously mapped to the same genetic interval as LepR3. In this study, the LepR3 locus of the Rlm2 Brassica napus line 'Glacier DH24287' was cloned, and B. napus transformants were analysed for recovery of the Rlm2 phenotype. Multiple B. napus, B. rapa and B. juncea lines were assessed for sequence variation at the locus. Rlm2 was found to be an allelic variant of the LepR3 LRR-RLP locus, conveying race-specific resistance to L. maculans isolates harbouring AvrLm2. Several defence-related LRR-RLPs have previously been shown to associate with the RLK SOBIR1 to facilitate defence signalling. Bimolecular fluorescence complementation (BiFC) and co-immunoprecipitation of RLM2-SOBIR1 studies revealed that RLM2 interacts with SOBIR1 of Arabidopsis thaliana when co-expressed in Nicotiana benthamiana. The interaction of RLM2 with AtSOBIR1 is suggestive of a conserved defence signalling pathway between B. napus and its close relative A. thaliana.


Assessment of Clinical, Histopathological, and Bacteriological Findings in Treated Leprosy Patients with Persistent Skin Lesions: A Retrospective Cohort Study.
Since the introduction of multidrug therapy (MDT), various disabilities/morbidities due to leprosy have been prevented. However, there is a subset of patients in whom the skin lesions do not resolve completely or remain unchanged despite a full course of MDT, which is a great source of anxiety to the patient and their family members. Hence, we tried to ascertain the putative causes and risk factors of persistent skin lesions (PSLs) by analyzing the clinical, histopathological, bacteriological, and drug resistance patterns. This is a retrospective, cohort study wherein 35 patients who had PSLs after completion of MDT were included. The majority of the patients were 18 to 30 years of age, with males predominating. Borderline tuberculoid leprosy was the most common clinical spectrum observed (71.4%). The majority had PSLs distributed predominantly over photo-exposed sites (upper limbs > trunk > face). Eight patients (22.8%) had a history of contact with leprosy patients in their family, and six patients (17.1%) had associated comorbidities. Improvement in histopathological parameters such as a decrease in granuloma fraction was observed in 22 patients (62.8%) with PSLs after release from treatment in comparison with baseline. Four patients (11.4%) were noted to have drug resistance (three to rifampicin and one to dapsone). Thus, our study emphasizes that leprosy patients with PSLs after completion of MDT should undergo histopathological evaluation and drug resistance studies.


Replication of LC-MS untargeted lipidomics results in patients with calcific coronary disease: An interlaboratory reproducibility study.
Recently a lipidomics approach was able to identify perturbed fatty acyl chain (FAC) and sphingolipid moieties that could stratify patients according to the severity of coronary calcification, a form of subclinical atherosclerosis. Nevertheless, these findings have not yet been reproduced before generalising their application. The aim of this study was to evaluate the reproducibility of lipidomics approaches by replicating previous lipidomic findings in groups of patients with calcific coronary artery disease (CCAD). Patients were separated into the following groups based on their calcium score (CS); no calcification (CS: 0; n=26), mild calcification (CS: 1-250; n=27) and severe calcification (CS: >250; n=17). Two serum samples were collected from each patient and used for comparative analyses by 2 different laboratories, in different countries and time points using liquid chromatography coupled to mass spectrometry untargeted lipidomics methods. Six identical metabolites differentiated patients with severe coronary artery calcification from those with no calcification were found by both laboratories independently. Additionally, relative intensities from the two analyses demonstrated high correlation coefficients. Phosphatidylcholine moieties with 18-carbon FAC were identified in lower intensities and 20:4 FAC in higher intensities in the serum of diseased group. Moreover, 3 common sphingomyelins were detected. This is the first interlaboratory reproducibility study utilising lipidomics applications in general and specifically in patients with CCAD. Lipid profiling applications in patients with CCAD are very reproducible in highly specialised and experienced laboratories and could be applied in clinical practice in order to spare patients diagnostic radiation.


Alzheimer's disease: is a vaccine possible?
The cause of Alzheimer's disease is still unknown, but the disease is distinctively characterized by the accumulation of β-amyloid plaques and neurofibrillary tangles in the brain. These features have become the primary focus of much of the research looking for new treatments for the disease, including immunotherapy and vaccines targeting β-amyloid in the brain. Adverse effects observed in a clinical trial based on the β-amyloid protein were attributed to the presence of the target antigen and emphasized the relevance of finding safer antigen candidates for active immunization. For this kind of approach, different vaccine formulations using DNA, peptide, and heterologous prime-boost immunization regimens have been proposed. Promising results are expected from different vaccine candidates encompassing B-cell epitopes of the β-amyloid protein. In addition, recent results indicate that targeting another protein involved in the etiology of the disease has opened new perspectives for the effective prevention of the illness. Collectively, the evidence indicates that the idea of finding an effective vaccine for the control of Alzheimer's disease, although not without challenges, is a possibility.


Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death.
The profound neuroprotection observed in poly(ADP-ribose) polymerase-1 (PARP-1) null mice to ischemic and excitotoxic injury positions PARP-1 as a major mediator of neuronal cell death. We report here that apoptosis-inducing factor (AIF) mediates PARP-1-dependent glutamate excitotoxicity in a caspase-independent manner after translocation from the mitochondria to the nucleus. In primary murine cortical cultures, neurotoxic NMDA exposure triggers AIF translocation, mitochondrial membrane depolarization, and phosphatidyl serine exposure on the cell surface, which precedes cytochrome c release and caspase activation. NMDA neurotoxicity is not affected by broad-spectrum caspase inhibitors, but it is prevented by Bcl-2 overexpression and a neutralizing antibody to AIF. These results link PARP-1 activation with AIF translocation in NMDA-triggered excitotoxic neuronal death and provide a paradigm in which AIF can substitute for caspase executioners.


The Arizona Cognitive Test Battery for Down Syndrome: Test-Retest Reliability and Practice Effects.
A multisite study investigated the test-retest reliability and practice effects of a battery of assessments to measure neurocognitive function in individuals with Down syndrome (DS). The study aimed to establish the appropriateness of these measures as potential endpoints for clinical trials. Neurocognitive tasks and parent report measures comprising the Arizona Cognitive Test Battery (ACTB) were administered to 54 young participants with DS (7-20 years of age) with mild to moderate levels of intellectual disability in an initial baseline evaluation and a follow-up assessment 3 months later. Although revisions to ACTB measures are indicated, results demonstrate adequate levels of reliability and resistance to practice effects for some measures. The ACTB offers viable options for repeated testing of memory, motor planning, behavioral regulation, and attention. Alternative measures of executive functioning are required.


Prevalence and spectrum of p53 mutations associated with smoking in breast cancer.
To explore the role of smoking in breast cancer, we undertook a population-based study to evaluate the prevalence and spectrum of p53 mutations in the breast tumors of smokers and nonsmokers. We evaluated 456 archival invasive breast tumors for mutations in exons 4-8 of the p53 gene, using single-strand conformational polymorphism analysis and manual sequencing. Statistical analyses were performed to determine the association of p53 mutations with clinical and smoking characteristics. Of 108 mutations identified, 77 (71%) were point mutations and 31 (29%) were deletions or insertions. A higher prevalence of p53 mutations was found in the breast tumors of current smokers (36.5%; P = 0.02) compared with never smokers (23.6%), whereas fewer mutations were found in former smokers (16.2%; P = 0.09). After adjustment for age, race, menopausal status, clinical stage, tumor size, and family history of breast cancer, current smokers were significantly more likely to harbor any p53 mutation [odds ratio (OR), 2.11; 95% confidence interval (CI), 1.17-3.78], p53 transversions (OR, 3.37; 95% CI, 1.03-11.06), and G:C-->T:A transversions (OR, 10.53; 95% CI, 1.77-62.55) compared with never smokers. Stage at diagnosis did not account for the increase in p53 mutation-positive breast cancer among current smokers. Former smokers were also more likely than never smokers to harbor G:C-->T:A transversions (OR, 2.43; 95% CI, 0.37-15.73), although this association was not statistically significant. Among former smokers, the prevalence of p53 mutations varied with time since quitting: former smokers who quit smoking for longer than 1 year had a lower prevalence of p53 mutations (10.5% for 1-5 years and 12.9% for >5 years) than those who had stopped smoking within the year of their cancer diagnosis (26.3%). Our results indicate that cigarette smoking appears to modify the prevalence and spectrum of p53 mutations in breast tumors. Moreover, the difference in mutational spectra observed between smokers and nonsmokers is suggestive of the genotoxic effects of smoking in breast tissue.


Effect of N supply on the carbon economy of barley when accounting for plant size.
Nitrogen availability and ontogeny both affect the relative growth rate (RGR) of plants. In this study of barley (Hordeum vulgare L.) we determined which growth parameters are affected by nitrate (N) availability, and whether these were confounded by differences in plant size, reflecting differences in growth. Plants were hydroponically grown on six different nitrate (N) concentrations for 28 days, and nine harvests were performed to assess the effect of N on growth parameters. Most growth parameters showed similar patterns of responses to N supply whether compared at common time points or common plant sizes. N had a significant effect on the biomass allocation: increasing N increased leaf mass ratio (LMR) and decreased root mass ratio (RMR). Specific leaf area (SLA) was not significantly affected by N. RGR increased with increasing N supply up to 1 mM, associated with increases in both LMR and net assimilation rate (NAR). Increases in N supply above 1 mM did not increase RGR as increases in LMR were offset by decreases in NAR. The high RGR at suboptimal N supply suggest a higher nitrogen use efficiency (biomass/N supply). The reasons for the homeostasis of growth under suboptimal N levels are discussed.


Time series analysis and its relationship with longitudinal analysis.
This paper discusses the relationship between longitudinal analysis of inter-individual (co-)variation and time series analysis of intra-individual (co-)variation. To set the stage for this discussion, first a tutorial overview of modern techniques of multivariate time series analysis is given which highlights the central role of rate-space modeling. Some increasingly general instances of the state-spuce model are presented, followed by a concise description of two recent applications involving nonlinear state-space modeling of oscillatory finger motion and nonlinear growth, respectively. We then consider the question under which conditions longitudinal factor analysis of inter-individual covariation will yield the same results as dynamic factor analysis of single-subject time series data. The conditions concerned can be derived from ergodicity theory and turn out to be very restrictive. This implies that the results obtained in analyses of inter-individual variation (like the construction and validation of measurement scales) cannot be generalized to the assessment and prediction of individual developmental processes (e.g., in single-subject counseling). A simple illustration with simulated data is given, to the best of our knowledge for the first time, in which a factor analysis of inter-individual covariation yields a satisfactorily fitting solution that has no relationship whatsoever to the factor structures characterizing the intra-individual covariation of each subject in the sample.


Low-Energy Hot Plasma and Particles in Saturn's Magnetosphere.
The low-energy charged particle instrument on Voyager 2 measured low-energy electrons and ions (energies greater, similar 22 and greater, similar 28 kiloelectron volts, respectively) in Saturn's magnetosphere. The magnetosphere structure and particle population were modified from those observed during the Voyager 1 encounter in November 1980 but in a manner consistent with the same global morphology. Major results include the following. (i) A region containing an extremely hot ( approximately 30 to 50 kiloelectron volts) plasma was identified and extends from the orbit of Tethys outward past the orbit of Rhea. (ii) The low-energy ion mantle found by Voyager 1 to extend approximately 7 Saturn radii inside the dayside magnetosphere was again observed on Voyager 2, but it was considerably hotter ( approximately 30 kiloelectron volts), and there was an indication of a cooler ( < 20 kiloelectron volts) ion mantle on the nightside. (iii) At energies greater, similar 200 kiloelectron volts per nucleon, H(1), H(2), and H(3) (molecular hydrogen), helium, carbon, and oxygen are important constituents in the Saturnian magnetosphere. The presence of both H(2) and H(3) suggests that the Saturnian ionosphere feeds plasma into the magnetosphere, but relative abundances of the energetic helium, carbon, and oxygen ions are consistent with a solar wind origin. (iv) Low-energy ( approximately 22 to approximately 60 kiloelectron volts) electron flux enhancements observed between the L shells of Rhea and Tethys by Voyager 2 on the dayside were absent during the Voyager 1 encounter. (v) Persistent asymmetric pitch-angle distributions of electrons of 60 to 200 kiloelectron volts occur in the outer magnetosphere in conjunction with the hot ion plasma torus. (vi) The spacecraft passed within approximately 1.1 degrees in longitude of the Tethys flux tube outbound and observed it to be empty of energetic ions and electrons; the microsignature of Enceladus inbound was also observed. (vii) There are large fluxes of electrons of approximately 1.5 million electron volts and smaller fluxes of electrons of approximately 10 million electron volts and of protons greater, similar 54 million electron volts inside the orbits of Enceladus and Mimas; all were sharply peaked perpendicular to the local magnetic field. (viii) In general, observed satellite absorption signatures were not located at positions predicted on the basis of dipole magnetic field models.


Community approach for reducing small field measurement errors: Experience over 24 centres.
The complexity of the modern Stereotactic Body Radiation Therapy (SBRT) techniques requires comprehensive quality assurance programs, to ensure the right treatment to the patient. Dosimetry of small radiation fields is a challenge especially for radiotherapy centres starting to work on this issue. The matter to be discussed here concerns the need of detailed measurement procedures and cross checks to be paired to the usual recommendations on detectors and correction factors. The presented work involved 24 Italian radiotherapy centres, with the specific purpose to minimize systematic errors in output factor measurements over different radiotherapy centres. Using the unshielded silicon diode IBA Razor, reference curves for the relative signal ratio (RSR) as a function of beam size were created for each Linac family. With this study we have demonstrated consistency of small field dosimetry on all the centres involved, moreover all radiotherapy centres using Razor are allowed to compare measurements amongst each other and centres with values deviating more than 5% from the reference curve are advised to repeat their measurements. With this procedure, some critical issues were detected from two centres in RSR measurements, that, if implemented into the own treatment planning system, would induce an unwanted overdosage larger than 5%. The proposed approach could allow one to envision high-skilled therapy centres providing support to those featuring minor experience and could represent an important strategy for the clinical implementation of emerging technologies at high quality levels. The methodology adopted exploits crowd knowledge methods which could be applied in others areas of radiation dosimetry.


A sensitivity analysis of the Children's Treatment Network trial: a randomized controlled trial of integrated services versus usual care for children with special health care needs.
The value of integrated care through comprehensive, coordinated, and family-centered services has been increasingly recognized for improving health outcomes of children with special health care needs (CSHCN). In a randomized controlled trial (RCT), the integrated care provided through the Children's Treatment Network (CTN) was compared with usual care in improving the psychosocial health of target CSHCN. In this paper, we aimed to estimate the effect of CTN care by conducting multiple analyses to handle noncompliance in the trial. The trial recruited target children in Simcoe County and York Region, ON, Canada. Children were randomized to receive CTN or usual care and were followed for 2 years. The CTN group received integrated services through multiple providers to address their specific needs while the usual care group continued to receive care directed by their parents. The outcome was change in psychosocial quality of life at 2 years. We conducted intention-to-treat, as-treated, per-protocol, and instrumental variable analyses to analyze the outcome. The trial randomized 445 children, with 229 in the intervention group and 216 in the control group. During follow-up, 52% of children in the intervention group did not receive complete CTN care for various reasons. At 2 years, we did not find a significant improvement in psychosocial quality of life among the children receiving CTN care compared with usual care (intention-to-treat mean difference 1.50, 95% confidence interval -1.49 to 4.50; P = 0.32). Other methods of analysis yielded similar results. Although the effect of CTN care was not significant, there was evidence showing benefits of integrated care for CSHCN. More RCTs are needed to demonstrate the magnitude of such an effect. The CTN study highlights the key challenges in RCTs when assessing interventions involving integrated care, and informs further RCTs including similar evaluations.


The impact on malaria of biannual treatment with azithromycin in children age less than 5 years: a prospective study.
The MORDOR study, a cluster randomized clinical trial, showed that single-dose azithromycin (20 mg/kg) administered biannually for 2 years to preschool children reduced mortality; a study was conducted to determine its effect on clinical symptomatic episodes of malaria as a potential mechanism for mortality benefit. A randomized control trial (RCT) was conducted, whereby 30 randomly selected communities in Kilosa District, Tanzania were randomized to receive 6-monthly treatment of children ages 1-59 months with single-dose azithromycin (20 mg/kg) vs. placebo. A prospective cohort study was nested within the RCT: children, aged 1 to 35 months at baseline, were randomly selected in each community and evaluated at 6-monthly intervals for 2 years. At each visit, the children were assessed for recent or ongoing fever and anti-malarial treatment; a rapid diagnostic test (RDT) for malaria was performed. The two major outcomes of interest were prevalence of RDT positivity and clinical malaria. The latter was defined as RDT-positivity with fever at time of evaluation and/or reported fever in the 3 days prior to evaluation. Methods that account for correlations at community level and within individuals over time were used to evaluate associations. At baseline, the prevalence rates in the children in the azithromycin and placebo arms were 17.6% vs. 15.5% for RDT positivity (p = 0.76) and 6.1% vs. 4.3% (p = 0.56) for clinical malaria. There was a decline in both RDT-positivity and clinical malaria over time in both arms. The difference by treatment assignment was not significant for clinical malaria; it was significant for RDT-positivity with greater odds of decline in the placebo arm (p = 0.01). Lack of evidence for a significant difference in the prevalence of clinical malaria in children at any visit following treatment suggests that the effect of single-dose azithromycin on malaria is at best transient and limited in scope. Chance overrepresentation of non-seasonal transmission in the communities in the azithromycin arm may account for higher rates of RDT-positivity and less decline over time. Trial registration Clinicaltrials.gov NCT02047981.


Factors affecting the restaging accuracy of magnetic resonance imaging after preoperative chemoradiation in patients with rectal cancer.
We evaluated patient or tumor factors associated with the preoperative restaging accuracy of magnetic resonance imaging (MRI) for determining T and N stages as well as circumferential resection margin (CRM) involvement after chemoradiation (CRT) in patients with locally advanced rectal cancer. Seventy-seven patients with rectal cancer that were treated with preoperative CRT (50.4 Gy) followed by radical resection were included. Post-CRT MRI was performed approximately 4 weeks after preoperative CRT. The median tumor distance from the anal verge was 6 cm, 48 (62%) of which were anterior and 29 (38%) posterior. The median tumor diameter was 3 cm. A stage-by-stage comparison showed that correct staging occurred in 62%, 43%, and 86% of patients for T staging, N staging, and CRM prediction, respectively. Shorter distance to the anal verge (<5 cm), smaller tumor diameter (<1 cm), and anterior tumor location were associated with incorrect T staging. There were no significant variables in terms of N staging accuracy. Shorter tumor distance and anterior tumor location were associated with incorrect CRM prediction. Our findings suggest that specific tumor factors such as small, distal, or anterior rectal tumors are closely associated with the accuracy of MRI after preoperative CRT.


eHealth literacy and preferences for eHealth resources in parents of children with complex CHD.
Introduction This study aimed to (a) examine eHealth literacy, beliefs, and behaviours in parents of children with complex CHD, and (b) identify parents' preferences for the content, format, features, and functions of eHealth resources for CHD. Materials and methods Families (n=198) of children born between 2008 and 2011 and diagnosed with CHD requiring surgery were mailed a survey assessing a range of variables including eHealth literacy, beliefs, and behaviours as well as preferences for the format, functions, features, and content of eHealth resources for CHD. A total of 132 parents (83 mothers, 49 fathers) completed the survey (response rate: 50%). Mothers (96%) were more likely to access eHealth resources than fathers (83%, χ2=6.74, p=0.009). Despite high eHealth resource use, eHealth literacy was relatively low, with results demonstrating considerable and widespread gaps in awareness of, access to, and communication about eHealth resources. Over 50% of parents reported that decisions regarding their child's healthcare were influenced, to some extent, by web-based resources. Barriers to doctor-patient communication about eHealth included limited consultation time and concern about doctors' disapproval. Participants demonstrated a strong desire for "eHealth prescriptions" from their child's healthcare team, and perceived a wide range of eHealth topics as highly important, including treatment-related complications as well as physical, cognitive, and emotional development in children with CHD. Discussion Results suggest a need for stronger, more proactive partnerships between clinicians, researchers, educators, technologists, and patients and families to bring about meaningful innovations in the development and implementation of eHealth interventions in paediatric cardiology.


N-WASP, WAVE and Mena play different roles in the organization of actin cytoskeleton in lamellipodia.
WASP- and Ena/VASP-family proteins have been reported to regulate the cortical actin cytoskeleton as downstream effectors of the Rho-family small G-proteins Rac and Cdc42, but their functions are little understood. We observed the localization of the WASP family proteins, N-WASP and WAVE, and the Ena/VASP family protein, Mena, in protruding lamellipodia. Rat fibroblast cell line 3Y1 protruded lamellipodia on poly-L-lysine-coated substrate without any trophic factor. N-WASP and Cdc42 were concentrated along the actin filament bundles of microspikes but not at the tips. By immunofluorescence and immunoelectron microscopy, both WAVE and Mena were observed to localize at the lamellipodium edge. Interestingly, Mena tended to concentrate at the microspike tips but WAVE did not. At the edge of the lamellipodium, the correlation between the fluorescence from Mena and actin filaments stained with the specific antibody and rhodamine-phalloidin, respectively, was much higher than that between WAVE and actin filament. The Ena/VASP homology 2 (EVH2) domain of avian Ena, an avian homolog of Mena, was localized to the lamellipodium edge and concentrated at the tip of microspikes. The SCAR homology domain (SHD) of human WAVE was distributed along the lamellipodium edge. These results indicate that N-WASP, WAVE and Mena have different roles in the regulation of the cortical actin cytoskeleton in the protruding lamellipodium. WAVE and Mena should be recruited to the lamellipodium edge through SHD and the EVH2 domain, respectively, to regulate the actin polymerization near the cell membrane. N-WASP should regulate the formation of the actin filament bundle in addition to activating Arp2/3 complex in lamellipodium under the control of Cdc42.


Analysis of IFITM-IFITM Interactions by a Flow Cytometry-Based FRET Assay.
The interferon-induced transmembrane proteins 1-3 (IFITM1-3) inhibit host cell entry of several viruses. However, it is incompletely understood how IFITM1-3 exert antiviral activity. Two phenylalanine residues, F75 and F78, within the intramembrane domain 1 (IM1) were previously shown to be required for IFITM3/IFITM3 interactions and for inhibition of viral entry, suggesting that IFITM/IFITM interactions might be pivotal to antiviral activity. Here, we employed a fluorescence resonance energy transfer (FRET) assay to analyze IFITM/IFITM interactions. For assay calibration, we equipped two cytosolic, non-interacting proteins, super yellow fluorescent protein (SYFP) and super cyan fluorescent protein (SCFP), with signals that target proteins to membrane rafts and also analyzed a SCFP-SYFP fusion protein. This strategy allowed us to discriminate background signals resulting from colocalization of proteins at membrane subdomains from signals elicited by protein-protein interactions. Coexpression of IFITM1-3 and IFITM5 fused to fluorescent proteins elicited strong FRET signals, and mutation of F75 and F78 in IFITM3 (mutant IFITM3-FF) abrogated antiviral activity, as expected, but did not alter cellular localization and FRET signals. Moreover, IFITM3-FF co-immunoprecipitated efficiently with wild type (wt) IFITM3, lending further support to the finding that lack of antiviral activity of IFITM3-FF was not due to altered membrane targeting or abrogated IFITM3-IFITM3 interactions. Collectively, we report an assay that allows quantifying IFITM/IFITM interactions. Moreover, we confirm residues F75 and F78 as critical for antiviral activity but also show that these residues are dispensable for IFITM3 membrane localization and IFITM3/IFITM3 interactions.


Unprecedented Fluorophore Photostability Enabled by Low-Loss Organic Hyperbolic Materials.
The dynamics of photons in fluorescent molecules plays a key role in fluorescence imaging, optical sensing, organic photovoltaics, and displays. Photobleaching is an irreversible photodegradation process of fluorophores, representing a fundamental limitation in relevant optical applications. Chemical reagents are used to suppress the photobleaching rate but with exceptionally high specificity for each type of fluorophore. Here, using organic hyperbolic materials (OHMs), an optical platform to achieve unprecedented fluorophore photostability without any chemical specificity is demonstrated. A more than 500-fold lengthening of the photobleaching lifetime and a 230-fold increase in the total emitted photon counts are observed simultaneously. These exceptional improvements solely come from the low-loss hyperbolic dispersion of OHM films and the large resultant Purcell effect in the visible spectral range. The demonstrated OHM platform may open up a new paradigm in nanophotonics and organic plasmonics for super-resolution imaging and the engineering of light-matter interactions at the nanoscale.


[The use of ultraviolet irradiation of the blood in treating keratitis].
The paper analyses results after treatment of inflammatory diseases of the cornea by means of a quantum ultraviolet hemotherapy using the apparatus "Izol'da" MD-73M. The original method for treatment of keratitis represents a combination of ultraviolet radiation of blood and subconjunctival injections of heparinized autologous blood preliminary radiated by ultraviolet rays. High clinical effectiveness of the method (rise of visometric values, shortening of the bed-days, etc.) is shown and it is recommended to be widely used for treatment of quickly progressing, severe lesions of the cornea.


Tear fluid extracellular DNA: diagnostic and therapeutic implications in dry eye disease.
To determine the abundance of extracellular DNA (eDNA) in tear fluid of patients with dry eye disease (DED) and to report clinical outcomes after DNase I eyedrops use to reduce excessive tear fluid eDNA. Tear fluid was collected from healthy control subjects and patients with DED. The eDNA abundance was determined with the PicoGreen dye assay. The DED symptoms and clinical signs were recorded and correlated with eDNA abundance. Two patients with DED having excessive eDNA in tear fluid were treated with DNase I eyedrops. The PicoGreen dye assay measures tear fluid eDNA abundance after a 2-minute incubation time. With longer incubations, admixed cells also contribute to eDNA measurements. The mean (SE) eDNA abundance in healthy control subjects' tear fluid was 1.4 (0.2) μg/mL. The mean (SE) eDNA abundance in tear fluid of patients with nonautoimmune DED, autoimmune DED, and graft versus host disease was significantly higher: the values were 2.9 (0.6), 5.2 (1.2), and 9.1 (2.3) μg/mL, respectively (P < 0.05). In most of these patients, the PicoGreen dye kinetic assay of tear fluid showed an increase in fluorescence signal due to the presence of viable cells in tear fluid. Tear fluid eDNA had the best correlation with corneal Rose Bengal staining (r = 0.55). Treatment of patients having DED with DNase I eyedrops reduced eDNA abundance, abrogated signal increase, and improved comfort. Excessive eDNA is present in tear fluid of patients with dry eyes. A novel therapeutic approach for managing DED may be to measure eDNA abundance in tear fluid with the PicoGreen dye assay and reduce excessive amounts with DNase I eyedrops.


Lack of Lrp5 Signaling in Osteoblasts Sensitizes Male Mice to Diet-Induced Disturbances in Glucose Metabolism.
Wnt signaling through the low-density lipoprotein-related receptor 5 (Lrp5) coreceptor regulates osteoblast maturation, matrix mineralization, and intermediary metabolism. In the mature osteoblast, signals downstream of Lrp5 are required for normal long-chain fatty acid β-oxidation. Mice rendered deficient for this coreceptor in osteoblasts and osteocytes accumulate body fat with elevated serum lipid levels but retain normal insulin sensitivity. In the present study, we challenged Lrp5-mutant mice with a high-fat diet (HFD) to determine whether they were more susceptible to diet-induced disturbances in glucose homeostasis. The HFD-fed Lrp5 mutant mice maintained a low bone mass phenotype with an increase in adipose tissue mass and hypertriglyceridemia and hypercholesterolemia. Examination of glucose metabolism revealed that Lrp5 deficiency in the osteoblast also resulted in hyperglycemia and hyperinsulinemia, with reductions in glucose tolerance, insulin sensitivity, and serum undercarboxylated osteocalcin. The results from in vivo genetic epistasis and in vitro studies suggest that this phenotype proceeds via the accumulation of diacylglycerol species and impaired insulin signaling in Lrp5-deficient osteoblasts. In turn, glucose uptake and osteocalcin production are diminished in mutant osteoblasts. Taken together, these data identify a link between Wnt-Lrp5 signaling and insulin signaling in the osteoblast that has the potential to influence energy balance and compound the detrimental effects of a HFD on whole-body metabolism.


Unanimous versus partial rejection: How the number of excluders influences the impact of ostracism in children.
Previous research has shown that ostracism-the experience of being ignored and excluded-has negative effects on all of us, young and old. Using a Cyberball paradigm, the present research replicates the effects of ostracism on the moods (anger, anxiety, happiness, and anger) and fundamental needs (belongingness, control, meaningful existence, and self-esteem) of children (Study 1) and then extends the literature by examining the role of the number of ostracizers and inclusive members in this process by randomly assigning children to conditions varying in degree of ostracism (Study 2). Results of both studies showed that experiencing ostracism strongly and negatively affected all moods and fundamental needs-with the exception of anxiety. Study 2 in addition showed that the ratio of excluders to inclusive group members had different effects across outcomes. In all cases, complete ostracism produced the worst outcomes, suggesting that the presence of even a single ally reduces children's distress. For sadness, unanimous ostracism seemed particularly toxic. In some cases, facing two ostracizers produced significantly worse outcomes than only one, suggesting that consensual rejection might drive the negative effects on happiness, and sense of belonging, control, and meaningful existence. For self-esteem, only one ostracizer (in the presence of two inclusive members) was sufficient to induce a negative effect. Aggr. Behav. 43:190-203, 2017. © 2016 Wiley Periodicals, Inc.


"It is the fear of exercise that stops me" - attitudes and dimensions influencing physical activity in pulmonary hypertension patients.
Pulmonary hypertension is a progressive cardiorespiratory disease that is characterized by considerable morbidity and mortality. While physical activity can improve symptoms and quality of life, engagement in this population is suboptimal. The aim of this study was to explore attitudes towards exercise and the dimensions that influence physical activity participation in individuals with pulmonary hypertension. Virtual, semi-structured interviews were conducted with individuals, with a formal diagnosis of pulmonary hypertension. Participants were recruited through the Pulmonary Hypertension Association of Ireland. Interviews were transcribed and analysed using thematic analysis. Nineteen patients were interviewed (n = 19). There was a female preponderance (n = 13) and the mean age was 50 ± 12 years. Three themes were identified and included fear, perceived value of exercise and environmental factors. Fear was the primary theme and included three sub-themes of fear of (i) over-exertion, (ii) physical damage and (iii) breathlessness. The perceived value of exercise encompassed two distinct sub-themes of perceived (i) exercise importance and (ii) benefits of exercise. Environmental factors included the terrain, weather conditions and location. Fear of overexertion, harm and dyspnoea strongly influenced attitudes to and engagement in physical activity. This study revealed heterogenous patient perspectives regarding the importance of physical activity and exercise. Future interventions that mitigate fear and promote the value of physical activity for individuals with pulmonary hypertension may have considerable benefits in promoting physical activity engagement. Such interventions require multidisciplinary involvement, including specialised pulmonary hypertension clinicians and exercise and behaviour change specialists.


Evidence of congenital heart disease in the offspring of parents with atrioventricular defects.
Fifty-two of the 56 offspring from 90 patients with proven atrioventricular defects were examined. There were five with congenital heart disease. The defects were concordant in three and discordant in two. The mother was the affected propositus in all cases. In this relatively small sample the incidence of congenital heart disease in the offspring of parents with atrioventricular defects was 9.6%, or 14.3% if only the female propositi were considered. This is a much higher figure than that reported for the simple forms of isolated congenital heart disease.


Diagnostic accuracy of computed tomographic colonography for the detection of advanced neoplasia in individuals at increased risk of colorectal cancer.
Computed tomographic (CT) colonography has been recognized as an alternative for colorectal cancer (CRC) screening in average-risk individuals, but less information is available on its performance in individuals at increased risk of CRC. To assess the accuracy of CT colonography in detecting advanced colorectal neoplasia in asymptomatic individuals at increased risk of CRC using unblinded colonoscopy as the reference standard. This was a multicenter, cross-sectional study. Individuals at increased risk of CRC due to either family history of advanced neoplasia in first-degree relatives, personal history of colorectal adenomas, or positive results from fecal occult blood tests (FOBTs) were recruited in 11 Italian centers and 1 Belgian center between December 2004 and May 2007. Each participant underwent CT colonography followed by colonoscopy on the same day. Sensitivity and specificity of CT colonography in detecting individuals with advanced neoplasia (ie, advanced adenoma or CRC) 6 mm or larger. Of 1103 participants, 937 were included in the final analysis: 373 cases in the family-history group, 343 in the group with personal history of adenomas, and 221 in the FOBT-positive group. Overall, CT colonography identified 151 of 177 participants with advanced neoplasia 6 mm or larger (sensitivity, 85.3%; 95% confidence interval [CI], 79.0%-90.0%) and correctly classified results as negative for 667 of 760 participants without such lesions (specificity, 87.8%; 95% CI, 85.2%-90.0%). The positive and negative predictive values were 61.9% (95% CI, 55.4%-68.0%) and 96.3% (95% CI, 94.6%-97.5%), respectively; after group stratification, a significantly lower negative predictive value was found for the FOBT-positive group (84.9%; 95% CI, 76.2%-91.3%; P < .001). In a group of persons at increased risk for CRC, CT colonography compared with colonoscopy resulted in a negative predictive value of 96.3% overall. When limited to FOBT-positive persons, the negative predictive value was 84.9%.


Vaccines for preventing typhoid fever.
Typhoid fever and paratyphoid fever continue to be important causes of illness and death, particularly among children and adolescents in south-central and southeast Asia. Two typhoid vaccines are widely available, Ty21a (oral) and Vi polysaccharide (parenteral). Newer typhoid conjugate vaccines are at varying stages of development and use. The World Health Organization has recently recommended a Vi tetanus toxoid (Vi-TT) conjugate vaccine, Typbar-TCV, as the preferred vaccine for all ages. To assess the effects of vaccines for preventing typhoid fever. In February 2018, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, and mRCT. We also searched the reference lists of all included trials. Randomized and quasi-randomized controlled trials (RCTs) comparing typhoid fever vaccines with other typhoid fever vaccines or with an inactive agent (placebo or vaccine for a different disease) in adults and children. Human challenge studies were not eligible. Two review authors independently applied inclusion criteria and extracted data, and assessed the certainty of the evidence using the GRADE approach. We computed vaccine efficacy per year of follow-up and cumulative three-year efficacy, stratifying for vaccine type and dose. The outcome addressed was typhoid fever, defined as isolation of Salmonella enterica serovar Typhi in blood. We calculated risk ratios (RRs) and efficacy (1 - RR as a percentage) with 95% confidence intervals (CIs). In total, 18 RCTs contributed to the quantitative analysis in this review: 13 evaluated efficacy (Ty21a: 5 trials; Vi polysaccharide: 6 trials; Vi-rEPA: 1 trial; Vi-TT: 1 trial), and 9 reported on adverse events. All trials but one took place in typhoid-endemic countries. There was no information on vaccination in adults aged over 55 years of age, pregnant women, or travellers. Only one trial included data on children under two years of age.Ty21a vaccine (oral vaccine, three doses)A three-dose schedule of Ty21a vaccine probably prevents around half of typhoid cases during the first three years after vaccination (cumulative efficacy 2.5 to 3 years: 50%, 95% CI 35% to 61%, 4 trials, 235,239 participants, moderate-certainty evidence). These data include patients aged 3 to 44 years.Compared with placebo, this vaccine probably does not cause more vomiting, diarrhoea, nausea or abdominal pain (2 trials, 2066 participants; moderate-certainty evidence), headache, or rash (1 trial, 1190 participants; moderate-certainty evidence); however, fever (2 trials, 2066 participants; moderate-certainty evidence) is probably more common following vaccination.Vi polysaccharide vaccine (injection, one dose)A single dose of Vi polysaccharide vaccine prevents around two-thirds of typhoid cases in the first year after vaccination (year 1: 69%, 95% CI 63% to 74%; 3 trials, 99,979 participants; high-certainty evidence). In year 2, trial results were more variable, with the vaccine probably preventing between 45% and 69% of typhoid cases (year 2: 59%, 95% CI 45% to 69%; 4 trials, 194,969 participants; moderate-certainty evidence). These data included participants aged 2 to 55 years of age.The three-year cumulative efficacy of the vaccine may be around 55% (95% CI 30% to 70%; 11,384 participants, 1 trial; low-certainty evidence). These data came from a single trial conducted in South Africa in the 1980s in participants aged 5 to 15 years.Compared with placebo, this vaccine probably did not increase the incidence of fever (3 trials, 132,261 participants; moderate-certainty evidence) or erythema (3 trials, 132,261 participants; low-certainty evidence); however, swelling (3 trials, 1767 participants; moderate-certainty evidence) and pain at the injection site (1 trial, 667 participants; moderate-certainty evidence) were more common in the vaccine group.Vi-rEPA vaccine (two doses)Administration of two doses of the Vi-rEPA vaccine probably prevents between 50% and 96% of typhoid cases during the first two years after vaccination (year 1: 94%, 95% CI 75% to 99%; year 2: 87%, 95% CI 56% to 96%, 1 trial, 12,008 participants; moderate-certainty evidence). These data came from a single trial with children two to five years of age conducted in Vietnam.Compared with placebo, both the first and the second dose of this vaccine increased the risk of fever (1 trial, 12,008 and 11,091 participants, low-certainty evidence) and the second dose increase the incidence of swelling at the injection site (one trial, 11,091 participants, moderate-certainty evidence).Vi-TT vaccine (two doses)We are uncertain of the efficacy of administration of two doses of Vi-TT (PedaTyph) in typhoid cases in children during the first year after vaccination (year 1: 94%, 95% CI -1% to 100%, 1 trial, 1625 participants; very low-certainty evidence). These data come from a single cluster-randomized trial in children aged six months to 12 years and conducted in India. For single dose Vi-TT (Typbar-TCV), we found no efficacy trials evaluating the vaccine with natural exposure.There were no reported serious adverse effects in RCTs of any of the vaccines studied. The licensed Ty21a and Vi polysaccharide vaccines are efficacious in adults and children older than two years in endemic countries. The Vi-rEPA vaccine is just as efficacious, although data is only available for children. The new Vi-TT vaccine (PedaTyph) requires further evaluation to determine if it provides protection against typhoid fever. At the time of writing, there were only efficacy data from a human challenge setting in adults on the Vi-TT vaccine (Tybar), which clearly justify the ongoing field trials to evaluate vaccine efficacy.


The role of balancing selection in maintaining human RhD blood group polymorphism: A preregistered cross-sectional study.
Maintenance of genetic polymorphism remains one of the big questions of evolutionary biology, which for a long time tended to be explained by balancing selection. This explanation was later criticized, but now is again accepted as an important mechanism in evolution. Human blood group systems seem affected by balancing selection especially strongly. In this preregistered study, we focused on stable coexistence of RhD-positive and RhD-negative subjects in a population. This is an evolutionary conundrum, because carriers of the less frequent negative allele suffer from lower fecundity due to haemolytic disease of the newborn affecting RhD-positive infants born to RhD-negative women. One explanation of persisting stability of RhD polymorphism points to heterozygote advantage. Over the past decade, numerous studies demonstrated that RhD-positive subjects score better than RhD-negative homozygotes in psychomotor tests and physical health-related variables. Still, evidence of better health and performance of heterozygotes is scarce and merely indirect. We compared the physical and mental health of 2,539 subjects whose RhD genotype was estimated based on their and their parents' RhD phenotype. We confirmed that RhD-negative homozygotes fare worse in terms of physical and mental health than subjects with RhD-positive phenotype and that RhD-positive heterozygotes enjoy better health than both homozygotes. For the first time, we demonstrated that RhD-positive homozygotes might suffer from worse health than RhD-negative homozygotes. Our results strongly support the hypothesis that RhD polymorphism is maintained by heterozygote advantage and that balancing selection may have played an important role in human evolution in this context and in general.


Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose-binding lectin, and promotes neurite outgrowth and neuronal survival when released via glia-derived exosomes.
Oligomannosidic glycans play important roles in nervous system development and function. By performing a phage display screening with oligomannose-specific antibodies, we identified an oligomannose-mimicking peptide that was functionally active in modulating neurite outgrowth and neuron-astrocyte adhesion. Using the oligomannose-mimicking peptide in crosslinking experiments, synapsin I was identified as a novel oligomannose-binding protein in mouse brain. Further analyses not only verified that synapsin I is an oligomannose-binding lectin, but also indicated that it is a glycoprotein carrying oligomannose and Lewis(x). We also found that synapsin I is expressed in glia-enriched cultures and is released from glial cells via exosomes. Incubation of glial-derived exosomes in the presence of high KCl concentrations or subjecting glial cell cultures to either oxygen/glucose deprivation or hydrogen peroxide resulted in release of synapsin I from exosomes. Application of synapsin I promoted neurite outgrowth from hippocampal neurons and increased survival of cortical neurons upon hydrogen peroxide treatment or oxygen/glucose deprivation. Coculture experiments using wild-type hippocampal neurons and wild-type or synapsin-deficient glial cells showed enhanced neurite outgrowth when synapsin was expressed by glial cells. Synapsin-induced neurite outgrowth was dependent on oligomannose on synapsin I and the neural cell adhesion molecule NCAM at the neuronal cell surface. The data indicate that, under conditions of high neuronal activity and/or oxidative stress, synapsin can be released from glial-derived exosomes and promotes neurite outgrowth and neuronal survival by modulating the interactions between glia and neurons.


Agonists that stimulate secretion promote the recruitment of CFTR into membrane lipid microdomains.
The cystic fibrosis transmembrane conductance regulator (CFTR) is a tightly regulated anion channel that mediates secretion by epithelia and is mutated in the disease cystic fibrosis. CFTR forms macromolecular complexes with many proteins; however, little is known regarding its associations with membrane lipids or the regulation of its distribution and mobility at the cell surface. We report here that secretagogues (agonists that stimulate secretion) such as the peptide hormone vasoactive intestinal peptide (VIP) and muscarinic agonist carbachol increase CFTR aggregation into cholesterol-dependent clusters, reduce CFTR lateral mobility within and between membrane microdomains, and trigger the fusion of clusters into large (3.0 µm2) ceramide-rich platforms. CFTR clusters are closely associated with motile cilia and with the enzyme acid sphingomyelinase (ASMase) that is constitutively bound on the cell surface. Platform induction is prevented by pretreating cells with cholesterol oxidase to disrupt lipid rafts or by exposure to the ASMase functional inhibitor amitriptyline or the membrane-impermeant reducing agent 2-mercaptoethanesulfonate. Platforms are reversible, and their induction does not lead to an increase in apoptosis; however, blocking platform formation does prevent the increase in CFTR surface expression that normally occurs during VIP stimulation. These results demonstrate that CFTR is colocalized with motile cilia and reveal surprisingly robust regulation of CFTR distribution and lateral mobility, most likely through autocrine redox activation of extracellular ASMase. Formation of ceramide-rich platforms containing CFTR enhances transepithelial secretion and likely has other functions related to inflammation and mucosal immunity.


CpG DNA induces a class II transactivator-independent increase in class II MHC by stabilizing class II MHC mRNA in B lymphocytes.
Microbial products, such as CpG DNA and LPS, enhance class II MHC (MHC-II) expression and Ag presentation by dendritic cells, but this effect does not occur with macrophages and is largely unexplored in B cells. Although MHC-II expression is influenced by transcriptional regulation, which is governed by class II transactivator (CIITA) in all cells, microbial products enhance MHC-II expression by dendritic cells in part by increasing MHC-II protein stability. In this study, we show that the CpG-induced increase in MHC-II expression by B lymphocytes is not due to protein stabilization or changes in CIITA expression or activity, but instead is due to increased stability of MHC-II mRNA. This CIITA-independent mechanism adds a new layer of complexity to regulation of MHC-II and may increase T cell help for B cell Ab responses to microbial or vaccine Ags.


Extensive cargo identification reveals distinct biological roles of the 12 importin pathways.
Vast numbers of proteins are transported into and out of the nuclei by approximately 20 species of importin-β family nucleocytoplasmic transport receptors. However, the significance of the multiple parallel transport pathways that the receptors constitute is poorly understood because only limited numbers of cargo proteins have been reported. Here, we identified cargo proteins specific to the 12 species of human import receptors with a high-throughput method that employs stable isotope labeling with amino acids in cell culture, an in vitro reconstituted transport system, and quantitative mass spectrometry. The identified cargoes illuminated the manner of cargo allocation to the receptors. The redundancies of the receptors vary widely depending on the cargo protein. Cargoes of the same receptor are functionally related to one another, and the predominant protein groups in the cargo cohorts differ among the receptors. Thus, the receptors are linked to distinct biological processes by the nature of their cargoes.


Pathogen specific cytokine release reveals an effect of TLR2 Arg753Gln during Candida sepsis in humans.
Toll-like receptors (TLRs) are crucial pattern-recognition receptors (PRRs) for activation of innate and adapted immunity. TLR2 heterodimerizes with TLR1 or TLR6 to recognize multiple pathogen-associated molecular patterns (PAMPs) of fungi, Gram-positive pathogens, and mycobacteria. Receptor activation culminates in monocyte, T-helper (Th)1, and Th2 cytokine release. Single nucleotide polymorphisms (SNPs) Arg753Gln and Arg677Trp affect TLR2 responsiveness and may contribute to the course of sepsis, which is associated with substantial morbidity and mortality during intensive care treatment. We genotyped 325 critically ill patients with septic shock, and performed a detailed clinical follow-up with 47 of these patients. Here, we investigated whether distinct sepsis episodes result in defined plasma cytokine patterns, and whether cytokine profiles may be linked to the TLR2 polymorphisms. Blood sampling was done daily and microbiological testing was performed on a routine basis. DNA was extracted from whole blood and TLR2 SNPs were typed by pyrosequencing. Cytokines were measured by multiplexed array technologies and the leukocyte phenotype was determined by flow cytometry. Among the 325 ICU patients, 17 individuals (5.2%) were heterozygous for Arg753Gln. The SNP Arg677Trp was not found in any patient. Episodes of Gram-negative, Gram-positive, and Candida sepsis were recorded. During Gram-positive sepsis, the cytokine pattern did not differ between Arg753Gln heterozygous patients and wild type patients. By contrast, during Candida sepsis, the Arg753Gln heterozygous patients showed biomarker patterns that differed from wild type patients with elevated TNF-alpha plasma concentrations, but reduced IFN-gamma and IL-8 levels. In conclusion, TLR2 SNP Arg753Gln results in altered cytokine release in response to Candida but not to Gram-positive sepsis.


Prevalence and characteristics of prostate cancer among participants of a community-based screening in Nigeria using serum prostate specific antigen and digital rectal examination.
Prostate cancer (CaP) is the most commonly diagnosed cancer among Nigerian men but CaP screening is not a common practice. The true burden of the disease in Nigeria is not known. The study was aimed at studying the community burden of CaP in Lagos. During a community-based prostate cancer awareness program in 13 local government areas of Lagos, men aged >40 years had serum total PSA (tPSA) test and digital rectal examination (DRE). Those with abnormal DRE or tPSA >95th percentile of the cohort or both were selected for prostate biopsy (TRPB). 4172 men were screened and complete data was available for 4110 (98.5%). The mean age was 60.8 years. DRE was abnormal in 410 men and was significantly correlated with the age of the patient and tPSA (p<0.001). The tPSA ranged from 0 to 438.3 ng/ml with a median, mean and 95th percentile of 1.5, 2.5 and 10.0 ng/ml respectively. 341 out of the 438 (78%) men selected were subjected to TRBP. Forty-three men had histological diagnosis of CaP, giving an estimated prevalence rate of at least 1.046% or 1046 per 100,000 men of age ≥40. Only 11 (26%) had organ-confined disease while 17 (40%) had locally advanced disease and 15 (35%) men had metastatic disease. The majority of the men, 32 (74%) were reported to have Gleason's score of ≥7. The prevalence rate of CaP among men aged ≥40 years in Lagos is higher than previously reported in hospital-based study. Majority have advanced and high-grade disease.


Tortuosity Effects in Garnet-Type Li7La3Zr2O12 Solid Electrolytes.
Intrinsic material microstructure features, such as pores or void spaces, grains, and defects can affect local lithium-ion concentration profiles and transport properties in solid ion conductors. The formation of lithium-deficient or -excess regions can accelerate degradation phenomena, such as dendrite formation, lithium plating, and electrode/electrolyte delamination. This paper evaluates the effects pores or void spaces have on the tortuosity of a garnet-type Li7La3Zr2O12 solid electrolyte. Synchrotron X-ray tomography is used to obtain three-dimensional reconstructions of different electrolytes sintered at temperatures between 1050 and 1150 °C. The magnitude of the electrolyte tortuosity and the tortuosity directional anisotropy is shown to increase with sintering temperature. Electrolytes with highly anisometric tortuosity have lower critical current densities. Alignment or elimination of pores within an electrolyte or composite cathode may provide a means for achieving higher critical current densities and higher power densities in all solid-state batteries.


Logistic tensor decomposition with sparse subspace learning for prediction of multiple disease types of human-virus protein-protein interactions.
Viral infection involves a large number of protein-protein interactions (PPIs) between the virus and the host, and the identification of these PPIs plays an important role in revealing viral infection and pathogenesis. Existing computational models focus on predicting whether human proteins and viral proteins interact, and rarely take into account the types of diseases associated with these interactions. Although there are computational models based on a matrix and tensor decomposition for predicting multi-type biological interaction relationships, these methods cannot effectively model high-order nonlinear relationships of biological entities and are not suitable for integrating multiple features. To this end, we propose a novel computational framework, LTDSSL, to determine human-virus PPIs under different disease types. LTDSSL utilizes logistic functions to model nonlinear associations, sets importance levels to emphasize the importance of observed interactions and utilizes sparse subspace learning of multiple features to improve model performance. Experimental results show that LTDSSL has better predictive performance for both new disease types and new triples than the state-of-the-art methods. In addition, the case study further demonstrates that LTDSSL can effectively predict human-viral PPIs under various disease types.


Comparative Study of Preoperative Airway Assessment by Conventional Clinical Predictors and Ultrasound-Assisted Predictors.
The aim of this study is to evaluate the effectiveness of airway sonographic parameters as the predictors of difficult laryngoscopy and to evaluate the validity of combined sonographic and clinical tests. This prospective and observational study analyzed a sample of 200 patients who were categorized as having easy (Grades 1 and 2) or difficult (Grades 3 and 4) laryngoscopy based on the laryngoscopic criteria of Cormack-Lahane (CL). Sonographic parameters, including the anterior neck soft-tissue thickness at the level of vocal cord (ANS-VC), ANS tissue thickness at the level of hyoid, and ratio of depth of pre-epiglottic space to distance from epiglottis to midpoint of the distance between vocal cords and clinical parameters, including modified Mallampati class, thyromental distance, and hyomental distance ratio (HMDR), were analyzed. Univariate and multivariate regression analysis was used for the statistical analysis. Twenty patients (10%) were categorized as having difficult laryngoscopy. Statistically significant differences between patients with difficult and easy laryngoscopy were noted for 5 of 6 parameters. The diagnostic validity profiles showed variable sensitivity (26.5%-87.5%) and good specificity (58.9%-94.2%) and negative predictive value (88.8%-97.03%). ANS-VC has the highest sensitivity (87.50%) and area under curve value (0.887), whereas HMDR showed highest specificity (94.2%) and highest accuracy (89.60%) which means it has low false-positive prediction rate. The combination of tests improved the diagnostic validity profile (highest area under the curve, 0.897). Sonographic predictors can help in identifying difficult laryngoscopy. Combined clinical and ultrasonographic parameters showed better validity profiles in comparison to the individual tests.


Assessment of the targeting specificity of a fluorescent albumin conceived as a preclinical agent of the liver function.
In the context of increasing liver diseases, no contrast agent is currently available in Europe and the United States to directly assess the liver function. Only neolactosylated human serum albumin is being clinically used in Asia. In order to perform preclinical studies in the context of liver diseases, we conceived a fluorescent lactosylated albumin for the quantification of liver functional cells (l-Cyal). Precise characterization was achieved in order to determine the amounts of lactose and Cyanine 5 (Cy5) coupled to the albumin. In addition, potential aggregation was characterized by asymmetrical flow field-flow fractionation hyphenated to multi-angle light scattering (AF4-MALS). The optimal functionalized albumin exhibited a mass greater than 87 kDa which corresponds to the addition of 34 lactose moieties per protein and 1-2 Cy5 labels. Also, no significant formation of aggregates could be identified due to the modification of the native albumin. In healthy mice, the accumulation of l-Cyal in the liver and its selectivity for hepatocyte cells were shown by optical imaging and flow cytometry. Administration of l-Cyal to mice bearing liver metastases showed a reduced signal in the liver related to a decrease in the number of hepatocytes. The l-Cyal bioimaging contrast agent could be particularly useful for assessing the state of liver related diseases.


Composite spheroids-laden bilayer hydrogel for engineering 3D osteochondral tissue.
Combination of hydrogels and stem cell spheroids has been used to engineer 3D osteochondral tissue, but precise zonal control directing cell fate within the hydrogel remains a challenge. In here, we developed a composite spheroids-laden bilayer hydrogel to imitate osteochondral tissue by spatially controlled differentiation of human adipose-derived stem cells. Meticulous optimization of the spheroid-size and mechanical strength of gelatin methacryloyl hydrogel enables the cells to homogeneously sprout within the hydrogel. Moreover, fibers immobilizing transforming growth factor beta-1 (TGF-β1) or bone morphogenetic protein-2 (BMP-2) were incorporated within the spheroids, which induced chondrogenic or osteogenic differentiation of cells in general media, respectively. The spheroids-filled GelMA solution was crosslinked to create the bilayer hydrogel, which demonstrated a strong interfacial adhesion between the two layers. The cell sprouting enhanced the adhesion of each hydrogel, demonstrated by increase in tensile strength from 4.8 ± 0.4 to 6.9 ± 1.2 MPa after 14 days of culture. Importantly, the spatially confined delivery of BMP-2 within the spheroids increased mineral deposition and more than 3-fold enhanced osteogenic genes of cells in the bone layer while the cells induced by TGF-β1 signals were apparently differentiated into chondrocytes within the cartilage layer. The results suggest that our composite spheroids-laden hydrogel could be used for the biofabrication of osteochondral tissue, which can be applied to engineer other complex tissues by delivery of appropriate biomolecules.


Indirect hemagglutination test for human antibody to typhus and spotted fever group rickettsiae.
An indirect hemagglutination (IHA) test is described that uses glutaraldehyde-stabilized erythrocytes treated with a rickettsial erythrocyte-sensitizing substance obtained from Rickettsia typhi or Rickettsia rickettsii. The serological reagent was stable for at least 3 months at room temperature and 6 months at 4 C. It exhibited group specificity and no group cross-reactivity. At a minimum dilution of 1:40, acute and early convalescent epidemic and murine typhus antisera showed 86% positive reactors, whereas similar spotted fever antisera had 74% positive reactors. In comparison with the indirect fluorescent antibody test, the IHA procedure gave lower titers but showed comparable detection of seroconversion with most paired sera. The IHA test demonstrated significantly higher titers than the complement fixation test and was more sensitive than either the complement fixation or Weil-Felix test in identifying seroconversion. No agglutination was observed when sensitized erythrocytes were tested with rodent sera known to contain rickettsial antibodies.


Application of an adaptive control grid interpolation technique to morphological vascular reconstruction.
The problem of interslice magnetic resonance (MR) image reconstruction arises in a broad range of medical applications. In such cases, there is a need to approximate information present in the original subject that is not reflected in contiguously acquired MR images because of hardware sampling limitations. In the context of vascular morphology reconstruction, this information is required in order for subsequent visualization and computational analysis of blood vessels to be most effective. Toward that end we have developed a method of vascular morphology reconstruction based on adaptive control grid interpolation (ACGI) to function as a precursor to visualization and computational analysis. ACGI has previously been implemented in addressing various problems including video coding and tracking. This paper focuses on the novel application of the technique to medical image processing. ACGI combines features of optical flow-based and block-based motion estimation algorithms to enhance insufficiently dense MR data sets accurately with a minimal degree of computational complexity. The resulting enhanced data sets describe vascular geometries. These reconstructions can then be used as visualization tools and in conjunction with computational fluid dynamics (CFD) simulations to offer the pressure and velocity information necessary to quantify power loss. The proposed ACGI methodology is envisioned ultimately to play a role in surgical planning aimed at producing optimal vascular configurations for successful surgical outcomes.


Low-temperature, highly efficient growth of carbon nanotubes on functional materials by an oxidative dehydrogenation reaction.
In many applications like photovoltaics, fuel cells, batteries, or interconnects in integrated circuits carbon nanotubes (CNTs) have the role of charge transport electrodes. The building of such devices requires an in situ growth of CNTs at temperatures where the structure or chemical composition of the functional materials is unaltered. We report that in a chemical vapor deposition process involving an oxidative dehydrogenation reaction of C2H2 with CO2 growth temperatures below 400 degrees C are achieved. Furthermore, the growth can be performed on versatile materials ranging from metals through oxides to organic materials.


First Twin in Breech Presentation and Neonatal Mortality and Morbidity According to Planned Mode of Delivery.
To compare neonatal mortality and morbidity of first twins according to the planned mode of delivery when the first twin is in breech presentation, in a country where planned vaginal delivery is an option. This is a planned secondary analysis of the JUMODA (JUmeaux MODe d'Accouchement) cohort, a national prospective population-based study of twin deliveries conducted in 176 French hospitals. We analyzed pregnancies with first twins in breech presentation and applied the inclusion criteria of the Twin Birth Study (except the criterion for first-twin presentation): both fetuses alive, with a birth weight between 1,500 g and 4,000 g, at or after 32 0/7 weeks of gestation. The primary outcome was a composite of neonatal mortality and morbidity. We used multivariate Poisson regression models to control for potential confounders and propensity score analyses, that is, matching and inverse probability of treatment weighting to control for indication bias. Among the 1,467 women with a breech-presenting first twin included in this analysis, 1,169 (79.7%) had planned cesarean and 298 (20.3%) planned vaginal births, of whom 185 (62.1%) delivered both twins vaginally. The neonatal mortality and severe morbidity rate for first twins was 1.7% (5/298) in the planned vaginal and 1.9% (22/1,169) in the planned cesarean delivery groups (crude relative risk [RR] 0.90, 95% CI 0.34-2.34). Planned vaginal delivery was not associated with higher neonatal mortality and morbidity than planned cesarean delivery, regardless of the statistical method used: adjusted RR 0.71, 95% CI 0.27-1.86; RR 0.61, 95% CI 0.20-1.83 after matching for propensity score; RR 0.63, 95% CI 0.23-1.74 with inverse probability of treatment weighting. Analyses of neonatal mortality and morbidity of second twins yielded similar results. Although our sample size precluded a robust assessment for small differences in outcomes between planned cesarean and planned vaginal delivery in twin pregnancies in which the first twin was in breech presentation, in our cohort planned vaginal delivery was not associated with higher neonatal mortality and morbidity for either twin.


Neurological consults on the renal unit.
Neurological symptoms commonly occur in chronic kidney disease and may result from its treatments and complications. Impaired renal function also influences treatments for other neurological conditions, requiring various cautions, dose adjustments and timing considerations, particularly in the context of renal replacement therapy. In this review, we present six illustrative clinical vignettes to highlight these challenges.


Multiple metabolic functions of glucose in rat pancreatic islets.
Metabolic interactions between glucose and amino acids were studied with isolated rat islets using glucose utilization and lactate formation as indicators. Certain amino acids (8-10 mM) are capable of greatly stimulating lactate formation from 5mM glucose. On a molar basis L-isoleucine is the most potent stimulator in a group of twenty-six amino acids. Aphysiological amino acid mixture (7.5-14 mM) or L-isoleucine (8 mM) profoundly altered the basic sigmoidal relation between glucose concentration in the medium and the rate of glucose utilization and lactate formation: with basal glucose (5 mM) both glucose utilization and lactate production were stimulated by the amino ACID MIXTURE and by L-isoleucine; at high glucose levels utilization was decreased by the amino acid mixture, but was unaffected by L-isoleucine, whereas lactate formation was decreased by both additions. The data indicate that amino acids may play a significant role in regulating the extent to which glucose serves as a fuel of pancreatic islet cells and in determining the pathways of glucose metabolism. In order to elucidate the mechanisms of the amino acid effect, studies with phloridzin, ouabain, iodoacetate, cytochalasin B, and Na+-deficiency were performed with the most effective amino acid, L-isoleucine. Each of these agents and Na+-deficiency substantially reduced or completely blocked the extra lactate formation induced by L-isoleucine (8-10 mM). The intracellular uptake of 14-CL-isoleucine by isolated islets was found to be Na+-independent, and uphill transport of this amino acid was not detectable, whether basal glucose was present in the medium or not. The action of iodoacetate in blocking glycolysis was reinvestigated. After forty-five minutes of exposure, 0.2mM iodoacetate completely blocks lactate formation as well as glucose utilization. Thisconfirms and extends earlier data for this laboratory and suggests that this SH-reagent indeed allows dissociation of the fuel and releasing functions of glucose.


Effects of direct-to-consumer advertising and clinical guidelines on appropriate use of human papillomavirus DNA tests.
Both clinical guidelines and direct-to-consumer (DTC) advertising influence the use of new health care technologies, but little is known about their relative effects. The introduction of a cervical cancer screening test in 2000 offered a unique opportunity to assess the 2 strategies. To evaluate the effects of clinical guidelines and a targeted DTC advertising campaign on overall and appropriate use of human papillomavirus (HPV) DNA tests. Quasi-experimental study using difference-in-differences analysis. Data were MarketScan private insurance claims for 500,000 women aged 21 to 64 enrolled at least 12 consecutive months from January 2001 through December 2005. Both clinical guidelines and DTC advertising were associated with increases in overall HPV DNA test use. DTC advertising was associated with a statistically significant increase in HPV DNA test use in 2 groups of DTC cities (+5.57%, P < 0.0001; +2.54%, P < 0.0001). DTC advertising was associated with comparable increases in the probability of appropriate and inappropriate use of the HPV DNA test in primary screening. Clinical guideline releases from the American College of Obstetricians and Gynecologists, and by a cosponsored panel, were associated with greater increases in HPV DNA tests for appropriate primary screening than for inappropriate primary screening (β = 0.3347, P < 0.05 and β = 0.4175, P < 0.01). DTC advertising was associated with increased overall use of a cervical cancer screening test, whereas clinical guidelines were differentially associated with increased appropriate use. These findings suggest distinct influences of consumer marketing and professional guidelines on the use of health care products and services.


Colloidal supramolecular aggregates for therapeutic application in neuromedicine.
Neuromedicine has recently been emerging on the research scene and presents interesting challenges in therapeutics. The range of therapies generally used to treat neurological disorders are limited in their efficacy and degree of patient compliance because of the necessity of multiple drug dosages, low drug concentration in the central nervous system and side effects. Moreover, therapeutics require standard drug dosages which cannot be personalized. The limiting obstacle in neuromedicine is still the blood-brain barrier, which prevents the accumulation of endogenous and exogenous compounds inside the brain. Various transporters located on the blood-brain barrier modulate the crossing of endogenous compounds. It has been discovered that these transporters can be used as pathways for the transport of therapeutic agents and macromolecules that pass the blood-brain barrier allowing the uptake of bioactive compounds into the central nervous system. Several attempts have recently been made to develop forms of nanomedicine capable of overcoming the limitations of conventional therapy, above all the crossing of the blood-brain barrier. An outstandingly promising option could be the use of colloidal supramolecular aggregates. These nanodrugs are safe, biodegradable, and biocompatible and can combine biomaterials useful for diagnostic and therapeutical applications. They can be modified using monoclonal antibodies, proteins, peptides and macromolecules, thus providing personalized neuromedicine, which can be used in the treatment of various neurological disorders. In this review, recent advancements of supramolecular colloidal devices as neuromedicines are discussed, with particular focus on the latest developments.


Soy milk oleosome behaviour at the air-water interface.
Soy milk is a highly stable emulsion mainly due to the presence of oleosomes, which are oil bodies and function as lipid storage organelles in plants, e.g., in seeds. Oleosomes are micelle-like structures with an outer phospholipid monolayer, an interior filled with triacylglycerides (TAGs), and oleosins anchored hairpin-like into the structure with their hydrophilic parts remaining outside the oleosomes, completely covering their surface (K. Hsieh and A. H. C. Huang, Plant Physiol., 2004, 136, 3427-3434). Oleosins are alkaline proteins of 15-26 kDa (K. Hsieh and A. H. C. Huang, Plant Physiol., 2004, 136, 3427-3434) which are expressed during seed development and maturation and play a major role in the stability of oil bodies. Additionally, the oil bodies of seeds seem to have the highest impact on coalescence, probably due to the required protection against environmental stress during dormancy and germination compared to, e.g., vertebrates' lipoproteins. Surface pressure investigations and Brewster angle microscopy of oleosomes purified from raw soy milk were executed to reveal their diffusion to the air-water interface, rupture, adsorption and structural modification over time at different subphase conditions. Destroying the surface portions of the oleosins by tryptic digestion induced coalescence of oleosomes (J. Tzen and A. Huang, J. Cell. Biol., 1992, 117, 327-335) and revealed severe changes in their adsorption kinetics. Such investigations will help to determine the effects behind oleosome stability and are necessary for a better understanding of the principal function of oleosins and their interactions with phospholipids.