Interspecies allometric analysis of the comparative pharmacokinetics of 44 drugs across veterinary and laboratory animal species.
The purpose of this study was to apply the method of allometric analysis to a study of the comparative disposition of veterinary drugs using the Food Animal Residue Avoidance Databank (FARAD) as a source of the comparative pharmacokinetic data. An initial filtration of the FARAD data was performed in order to exclude drugs for which no pharmacokinetic data were available, in at least four species the route of administration was other than intravenous, and the matrix was different from blood, plasma or serum. This process restricted the study to a total of 44 candidate drugs. The primary pharmacokinetic parameter selected for study was half-life (t1/2). As this parameter is a composite of clearance (Cl) and volume of distribution (Vd), it was considered to be the most robust for interspecies scaling. Volume of distribution at steady state (Vdss) and clearance showed weak allometric correlations with weight across species. The relationships between body weight and elimination half-life (51/2 beta) were determined for this selected group of drugs by using the empirically determined function Y = a Wb. The function Y represents the parameter of concern (half-life), a is a coefficient typical of every drug (intercept), W is the species average body weight, and b is the scaling exponent. A total of 11 drugs (tetracycline, oxytetracycline, chlortetracycline, erythromycin, diazepam, prednisolone, cephapirin, ampicillin, gentamicin, apramycin and carbenicillin) showed statistically significant correlations and consequently are excellent candidates for interspecies extrapolation of pharmacokinetic parameters (half-life) in species of relevance to veterinary medicine. The remaining 33 drugs were divided into two groups which showed various degrees of lack of correlation. Many of the drugs that showed no allometric correlation were low hepatic extraction drugs. However, some other drugs demonstrated equivocal results which could either be due to a true lack of allometric correlation, or be inconclusive due to the lack of quality data or excessive variability due to the multi-laboratory origin of the FARAD data. The results of this study show that interspecies scaling is applicable to certain veterinary drugs. The experimental determination of the coefficients of the allometric equation for relevant pharmacokinetic parameters (clearance and volume of distribution) could be an important tool in estimating dose in species where the drug has never been studied. This could have important consequences in terms of avoiding the use of dose-titration studies in Phase I of drug development, for drugs that are experimentally 'well behaved.'


Cryolipolysis for noninvasive body contouring: clinical efficacy and patient satisfaction.
In recent years, a number of modalities have become available for the noninvasive reduction of adipose tissue, including cryolipolysis, radiofrequency, low-level laser, and high-intensity focused ultrasound. Each technology employs a different mechanism of action to cause apoptosis or necrosis of the targeted adipocytes. Among these technologies, cryolipolysis has not only been commercially available for the longest time, but has also been best researched including in vitro and animal models and randomized controlled clinical trials in humans. The principle behind cryolipolysis exploits the premise that adipocytes are more susceptible to cooling than other skin cells. The precise application of cold temperatures triggers apoptosis of the adipocytes, which invokes an inflammatory response and leads to slow digestion by surrounding macrophages. In clinical studies, cryolipolysis was shown to reduce subcutaneous fat at the treatment site by up to 25% after one treatment. Improvements were seen in 86% of treated subjects. At 73%, the patient satisfaction rate is higher than with other technologies used for noninvasive lipolysis. Cryolipolysis has been proven to be a very safe method for body contouring, and is accomplished with only minimal discomfort. Expected side effects are temporary erythema, bruising, and transient numbness that usually resolve within 14 days after treatment. With a prevalence of 0.1%, the most common complaint is late-onset pain, occurring 2 weeks post-procedure, which resolves without intervention. Although no procedure has been accepted as the gold standard for noninvasive body contouring as yet, cryolipolysis is considered to be both safe and efficient with a high patient satisfaction rate.


The mtDNA legacy of the Levantine early Upper Palaeolithic in Africa.
Sequencing of 81 entire human mitochondrial DNAs (mtDNAs) belonging to haplogroups M1 and U6 reveals that these predominantly North African clades arose in southwestern Asia and moved together to Africa about 40,000 to 45,000 years ago. Their arrival temporally overlaps with the event(s) that led to the peopling of Europe by modern humans and was most likely the result of the same change in climate conditions that allowed humans to enter the Levant, opening the way to the colonization of both Europe and North Africa. Thus, the early Upper Palaeolithic population(s) carrying M1 and U6 did not return to Africa along the southern coastal route of the "out of Africa" exit, but from the Mediterranean area; and the North African Dabban and European Aurignacian industries derived from a common Levantine source.


Fluctuation of the left ventricular ejection fraction in patients with HER2-positive early breast cancer treated by 12 months of adjuvant trastuzumab.
Cardiac toxicity with a decrease of the left ventricular ejection fraction (LVEF) is the main side effect induced by trastuzumab. This study reports the fluctuation of LVEF over the 12 months of adjuvant trastuzumab in PHARE trial (NCT00381901). LVEF assessment was performed every 3 months while patients received trastuzumab and after completion of treatment over the first 2 years and then every 6 months afterwards. The fluctuations of LVEF over time were described and a logistic regression model was performed investigating associated factors to LVEF perfect recovery at baseline value. A total of 1631 patients who received 12 months of trastuzumab from PHARE trial, were considered in the analysis. A total of 13 881 LVEF measurements were assessed. Baseline mean LVEF was 66.08% (standard error (SE): 0.15) and the mean relative LVEF decrease observed at 12-month was 3.61% (SE: 0.31). No clinical characteristic was significantly associated to LVEF fluctuation. After completion of trastuzumab, the relative difference progressively disappeared with beyond 30 months a relative difference value of 0.08% (SE: 0.42). Nevertheless, at 30 months, 48.53% of patients with available measures (379/781) did not fully recover their baseline LVEF value. The LVEF decreased during treatment with trastuzumab and rose up after the completion of treatment without coming back to the initial values for a substantial subset. These results would suggest investigating some strategies aimed to improve the ability to achieve a full recovery.


Rational design of a boron-dipyrromethene-based fluorescent probe for detecting Pd2+ sensitively and selectively in aqueous media.
A novel fluorescent probe for Pd2+ based on the BODIPY fluorophore exploiting the PET (Photoinduced Electron Transfer) mechanism was designed and successfully synthesized. The fluorescent probe 1 was prepared by introducing m-bisimidazolylbenzene which was connected by phenyl acetylene to the BODIPY dye at the meso position. It exhibited a rapid response and high sensitivity and selectivity toward Pd2+. Probe 1 presented a rapid quenched fluorescence response in aqueous buffer media (pH 5.5) and the detection limit estimated from the titration results was 2.9 × 10-7 M. Meanwhile, other common metal ions did not interfere with the recognition process. The DFT calculation proved that coordination of bisimidazole ligands with Pd2+ effectively decreases the LUMO energy of m-bisimidazolylbenzene which was located between the HOMO and LUMO energies of the BODIPY dye leading to fluorescence quenching via the d-PET mechanism.


Comparison of Radiological and Functional Changes After Multi-Level Laminoplasty Between Cervical Spondylotic Myelopathy and Ossification of the Posterior Longitudinal Ligament.
To compare the radiological and functional changes after multi-level laminoplasty between patients with cervical spondylotic myelopathy (CSM) and ossification of the posterior longitudinal ligament (OPLL). This study included 75 patients consisted with 32 of CSM (group A) and 43 of OPLL (group B) presenting a preserved cervical sagittal balance who underwent multi-level laminoplasty for cervical myelopathy. The radiological outcomes were analyzed with the following radiological parameters: C2?C7 Cobb angle in neutral (C2-7AN), flexed (C2-7AF), and extended (C2-7AE) neck postures; C2?C7 range of motion (C2-7ROM); T1 slope (T1S); and C2?C7 sagittal vertical axis (C2-7SVA). The functional outcomes were analyzed with the modified Japanese Orthopedic Association (mJOA) score, Nurick grade, and recovery rate. The radiological and functional outcomes between the two groups were evaluated at 12-month postoperatively. There were statistically significance increase of C2-7SVA in group A; and decrease of C2-7AF and C2-7ROM in group A and C2-7ROM in group B postoperatively (p < 0.05). However, C2-7AN showed no statistically significant inter-group differences and postoperative intra-group changes in both groups (p > 0.05). There were no statistically significant differences in the postoperative functional outcomes including mJOA score (p=0.251), Nurick grade (p=0.316), and recovery rate (p=0.435) between the two groups. Although there were no statistically significant differences in functional outcomes between the two groups, the group A showed a greater deterioration in sagittal balance with an increase of C2-7SVA than the group B after multi-level laminoplasty.


Monte Carlo tests for associations between disease and alleles at highly polymorphic loci.
In an association analysis comparing cases and controls with respect to allele frequencies at a highly polymorphic locus, a potential problem is that the conventional chi-squared test may not be valid for a large, sparse contingency table. However, reliance on statistics with known asymptotic distribution is now unnecessary, as Monte Carlo simulations can be performed to estimate the significance level of any test statistic. We have implemented a Monte Carlo method for four 'chi-squared' test statistics, three of which involved combination of alleles, and evaluated their performance on a real data set. Combining rare alleles to avoid small expected cell counts, and considering each allele in turn against the rest, reduced the power to detect a genuine association when the number of alleles was very large. We should either not combine alleles at all, or combine them in such a way that preserves the evidence for an association.


Does delaying repair of an asymptomatic hernia have a penalty?
The incidence of hernia accident for inguinal hernias in men who are minimally symptomatic is sufficiently low that watchful waiting is an acceptable alternative to routine repair. Our aim was to determine whether a delay in hernia surgery affects short- and long-term outcomes. Patients from a multicenter randomized clinical trial of immediate tension-free repair versus watchful waiting for minimally symptomatic inguinal hernias were studied. Patients (n = 353) underwent tension-free repair and were classified as immediate repair (< or = 6 months, N = 288) or delayed repair (> 6 months, N = 65). Patients were similar at baseline with respect to age, American Society of Anesthesiologists classification, pre-existing conditions, hernia type, and hernia characteristics. Patients undergoing immediate and delayed repair had comparable surgical time, surgical complications, recurrence rates, and satisfaction with outcome. Multivariate analyses found no relation between duration until hernia repair and operative time, incidence of complications, long-term pain, or functional status. Delaying hernia repair in patients who are minimally symptomatic does not have an adverse effect on subsequent operation and on other outcomes.


The effect of Bordetella pertussis on lymphocyte cyclic AMP metabolism.
Bordetella pertussis culture fractions produce decreased metabolic responses to isoproterenol and epinephrine in mice and rats, suggesting the possibility of systemic beta adrenergic blockade. The present study was undertaken to elucidate the mechanism of the alteration in adrenergic responsiveness and to clarify its relationship to other biological effects of the organism. Lymphocytes were selected as a suitable tissue because of the marked alteration in lymphocyte distribution in pertussis-treated mice and rats, suggesting a change in the surface properties of these cells. Human peripheral blood lymphocytes, purified by nylon fiber chromatography, were studied. In short incubation experiments (20 min or less) B. pertussis did not alter the cyclic AMP response to isoproterenol, prostaglandin E (PGE(1)), or methacholine. However, when cells were preincubated with B. pertussis for 90 min at 37 degrees C, the responses to all three agents were markedly inhibited. Although these observations provide direct confirmation of the ability of B. pertussis to inhibit catecholamine responsiveness, the fact that PGE(1) and methacholine responses were also inhibited suggests that blockade at the level of the beta adrenergic receptor is doubtful. The inhibitory activity was localized in a nondialyzable, protein-rich fraction that is precipitated from B. pertussis culture fluid by ammonium sulfate at 90% of saturation. The bulk of the activity was obtained in the load volume after 50,000 g centrifugation in a cesium chloride gradient, density 1.2-1.5 (fraction 4). Fraction 4 produced a change in lymphocyte hormonal responsiveness at concentrations as low as 5 ng/ml. The relationship between cyclic AMP inhibitory activity in isolated human cells and leukocytosis-producing activity in intact mice was studied. The two activities seemed to parallel one another quite closely until the final Sephadex G-150 fractionation step, in which the two activities were obtained in the same column fraction, but a greater recovery of the leukocytosis-producing activity was obtained. Additional purification will be required to establish conclusively whether the same macromolecule is responsible for both activities. The availability of a bacterial product that markedly inhibits cyclic AMP accumulation in purified lymphocytes may help to clarify the role of cyclic AMP in lymphocyte activation by antigen and nonspecific mitogens.


Individualised care for women with assisted conception pregnancies and midwifery practice implications: An analysis of the existing research and current practice.
the aim is to explore the psychosocial needs of women who are pregnant after assisted conception, specifically in vitro Fertilisation and whether their needs are being addressed within the current maternity care service. critical review of the literature using a narrative approach. 15 papers were identified. These included both qualitative and quantitative studies, literature reviews and surveys. The findings of this limited narrative review imply that women who undergo assistive reproductive techniques to achieve pregnancy have higher levels of anxiety in pregnancy and may have some difficulties in the transition to parenthood leading to perinatal morbidity. It appears that for this group of women it is important that their history in achieving pregnancy is known to the care providers, to enable the alleviation of some of the anxieties they face. Various aspects of antenatal care have been identified as possible areas which if addressed may reduce these levels of anxiety leading to a reduction in perinatal morbidity. currently, there is insufficient evidence to suggest that providing specialist midwifery care reduces morbidity in these women. However, maternity service providers should consider offering additional antenatal and postnatal services to meet the needs of this group in advance of further research in this area.


The anatomic and radiologic basis of the circumflex scapular artery perforator flap.
Microsurgical development has recently focused upon the perforator paradigm and primary thinning. Existing perforator flaps may require intramuscular dissection or lack reliable surface markings, whereas traditional scapular/parascapular flaps have low donor morbidity and reliable anatomy, but can be excessively bulky. Clinical application of a new flap based on a perforator from the circumflex scapular axis (CSA) has recently been published, but the vessel's anatomy has not been adequately characterized. The CSA was dissected in 115 sites in 69 cadavers. The number, external vessel diameter, and site of origin of perforators were measured relative to the CSA bifurcation. Color Doppler ultrasound was used to delineate the CSA and its perforators bilaterally in 40 volunteers. The number, origin relative to CSA bifurcation, diameter, length, and flow velocity of cutaneous perforators were determined. A CSA perforator was always present, running into the subdermal plexus, arising within 2.4 cm of the bifurcation. Cadaver studies: mean perforator diameter, 1.3 mm (SD, 0.66); 13% arose at bifurcation, 36% arose proximal (mean, 1.1 mm; SD, 0.63), and 52% distal to bifurcation (mean, 1.5 mm; SD, 0.88). Ultrasound: mean perforator diameter, 1.18 mm (SD, 0.41); mean flow velocity, 16.3 cm/s (SD, 3.65); perforator arose in 36% proximal, in 40% distal to bifurcation, and in 24% from the bifurcation. We definitively describe the anatomy of the perforator from the circumflex scapular artery upon which a new flap has been based. Its origin and dimensions are anatomically and radiologically reliable. The flap has certain potential benefits over existing perforator flaps.


Effects of roasting on hazelnut lipids.
The effect of roasting on some nutritional characteristics of hazelnut lipidic fraction was investigated. Hazelnuts (Corylus avellana L.) were submitted to several different thermal treatments, comprising different temperatures (125-200 degrees C) and times of exposure (5, 15, and 30 min) and analyzed for their moisture and crude fat. Raw and roasted hazelnuts were also analyzed for their compositions in phytosterols and fatty acids (including trans isomers) by GC-FID, triacylglycerols by HPLC-ELSD, and tocopherols and tocotrienols by HPLC-DAD/fluorescence spectroscopy. Minor changes occurred in the fatty acid and triacylglycerol compositions. As temperatures and roasting periods increased, generally, a modest increase of oleic and saturated fatty acids and a decrease of linoleic acid, expressed as relative percentages, occurred. Similarly, an increase of triacylglycerols containing oleic acid moieties and a decrease of those containing linoleic acid moieties were found in the roasted samples. Roasting caused a modest decrease of the beneficial phytosterols (maximum 14.4%) and vitamin E homologues (maximum 10.0%) and a negligible increase of the trans fatty acids.


Phylogenetic Analysis of Pasteuria penetrans by 16S rRNA Gene Cloning and Sequencing.
Pasteuria penetrans is an endospore-forming bacterial parasite of Meloidogyne spp. This organism is among the most promising agents for the biological control of root-knot nematodes. In order to establish the phylogenetic position of this species relative to other endospore-forming bacteria, the 16S ribosomal genes from two isolates of P. penetrans, P-20, which preferentially infects M. arenaria race 1, and P-100, which preferentially infects M. incognita and M. javanica, were PCR-amplified from a purified endospore extraction. Universal primers for the 16S rRNA gene were used to amplify DNA which was cloned, and a nucleotide sequence was obtained for 92% of the gene (1,390 base pairs) encoding the 16S rDNA from each isolate. Comparison of both isolates showed identical sequences that were compared to 16S rDNA sequences of 30 other endospore-forming bacteria obtained from GenBank. Parsimony analyses indicated that P. penetrans is a species within a clade that includes Alicyclobacillus acidocaldarius, A. cycloheptanicus, Sulfobacillus sp., Bacillus tusciae, B. schlegelii, and P. ramosa. Its closest neighbor is P. ramosa, a parasite of Daphnia spp. (water fleas). This study provided a genomic basis for the relationship of species assigned to the genus Pasteuria, and for comparison of species that are parasites of different phytopathogenic nematodes.


Road safety in less-motorized environments: future concerns.
In the last three decades, the incidence of traffic crash fatalities and injuries has been reduced significantly in the high-income countries but not in the low- and middle-income countries. The traffic patterns in the former are not only different but are also less complex than those in the latter. Traffic in low-income countries comprises a much higher share of vulnerable road users and so vehicles, roads and the environment have to be designed for their safety. Solutions for such problems are not readily available and very innovative work needs to be done around the world to arrive at new policies and designs. In addition to crashworthiness of vehicles, transportation planning, exposure control, intelligent separation of non-motorized traffic on major roads, and traffic calming are likely to play a much more important role.


Radioresistant Cervical Cancers Are Sensitive to Inhibition of Glycolysis and Redox Metabolism.
Highly glycolytic cervical cancers largely resist treatment by cisplatin and coadministered pelvic irradiation as the present standard of care. In this study, we investigated the effects of inhibiting glycolysis and thiol redox metabolism to evaluate them as alternate treatment strategies in these cancers. In a panel of multiple cervical cancer cell lines, we evaluated sensitivity to inhibition of glycolysis (2-deoxyglucose, 2-DG) with or without simultaneous inhibition of glutathione and thioredoxin metabolism (BSO/AUR). Intracellular levels of total and oxidized glutathione, thioredoxin reductase activity, and indirect measures of intracellular reactive oxygen species were compared before and after treatment. Highly radioresistant cells were the most sensitive to 2-DG, whereas intermediate radioresistant cells were sensitive to 2-DG plus BSO/AUR. In response to 2-DG/BSO/AUR treatment, we observed increased levels of intracellular oxidized glutathione, redox-sensitive dye oxidation, and decreased glucose utilization via multiple metabolic pathways including the tricarboxylic acid cycle. 2-DG/BSO/AUR treatment delayed the growth of tumors composed of intermediate radioresistant cells and effectively radiosensitized these tumors at clinically relevant radiation doses both in vitro and in vivo Overall, our results support inhibition of glycolysis and intracellular redox metabolism as an effective alternative drug strategy for the treatment of highly glycolytic and radioresistant cervical cancers.Significance: This study suggests a simple metabolic approach to strike at an apparent Achilles' heel in highly glycolytic, radioresistant forms of cervical cancers, possibly with broader applications in cancer therapy. Cancer Res; 78(6); 1392-403. ©2018 AACR.


Face-sensitive processes one hundred milliseconds after picture onset.
The human face is the most studied object category in visual neuroscience. In a quest for markers of face processing, event-related potential (ERP) studies have debated whether two peaks of activity - P1 and N170 - are category-selective. Whilst most studies have used photographs of unaltered images of faces, others have used cropped faces in an attempt to reduce the influence of features surrounding the "face-object" sensu stricto. However, results from studies comparing cropped faces with unaltered objects from other categories are inconsistent with results from studies comparing whole faces and objects. Here, we recorded ERPs elicited by full front views of faces and cars, either unaltered or cropped. We found that cropping artificially enhanced the N170 whereas it did not significantly modulate P1. In a second experiment, we compared faces and butterflies, either unaltered or cropped, matched for size and luminance across conditions, and within a narrow contrast bracket. Results of Experiment 2 replicated the main findings of Experiment 1. We then used face-car morphs in a third experiment to manipulate the perceived face-likeness of stimuli (100% face, 70% face and 30% car, 30% face and 70% car, or 100% car) and the N170 failed to differentiate between faces and cars. Critically, in all three experiments, P1 amplitude was modulated in a face-sensitive fashion independent of cropping or morphing. Therefore, P1 is a reliable event sensitive to face processing as early as 100 ms after picture onset.


Control of foot and mouth disease: lessons from the experience of the outbreak in Great Britain in 2001.
An epidemic of foot and mouth disease occurred on an unprecedented scale in Great Britain in 2001. This was characterised by widespread dissemination of disease in sheep due to infection being present but unreported for at least three weeks before the first case was identified. As envisaged by the contingency plans, existing procedures dealt rapidly with disease in many parts of the country where outbreaks were reported. Elsewhere, the scale and speed of disease spread was so great that veterinary resources had to be supplemented on the operational front by a large influx of military and administrative support. At the time of writing (June 2002), the United Kingdom Government has already identified a number of key lessons, and will learn further from this experience and from the findings of inquiries, how a future outbreak of this unprecedented nature and extent could be handled. Lessons identified so far relate to the improvement of contingency plans, the wider impact on rural businesses and communities, reassessing the possible use of emergency vaccination, the availability of serological capacity, better animal identification and movement controls, carcass disposal, communications, data handling and management information. The authors present the initial lessons learned and which formed the basis of official submissions to the inquiries. Further lessons will be learned from the findings of those inquiries.


Ability of Patients to Distinguish Among Cardiac Genomic Variant Subclassifications.
Clinical genetic testing for heritable cardiovascular disease has become a widely used tool to aid in the management of patients and their families. A 5-category variant classification system is commonly used for genetic test results, but some laboratories further subclassify variants of uncertain significance. How and whether patients perceive differences among the variant categories or subclassifications of variants of uncertain significance is unknown. We tested whether participants perceived differences in genetic variant subclassifications on outcomes including risk comprehension, risk perception, worry, perceived uncertainty, and intentions. Order-randomized hypothetical cardiovascular genetic results were given to 289 participants enrolled in a genome sequencing study. Three categories of variants were presented to participants: variants of uncertain significance, possibly pathogenic, and likely pathogenic. Responses to the first variant presented were analyzed in a between-groups analysis, and responses to all 3 variants were analyzed in a within-groups analysis. When presented with all 3 results, participants distinguished among the subclassifications on all outcomes (P<0.001). When given only a possibly pathogenic result, their risk perceptions were similar to those of variants of uncertain significance, but they were more worried and intended to behave as if they had received a likely pathogenic result. Individuals depended more on their affective responses such as worry when they received only one result (P<0.05). Participants are better able to distinguish pathogenicity subclassifications when presented with multiple categories. Individuals who receive a single uncertain result in a cardiovascular disease gene may benefit from interventions to decrease worry, calibrate risk perceptions, and motivate variant-appropriate behaviors.


Chloroquine-induced Pruritus.
Chloroquine-induced pruritus remains one of the most common side-effects in the use of chloroquine in the prophylaxis and treatment of uncomplicated malaria before the advent of artemisinin-based combination therapies. It has been reported to vary from a tolerable to intolerable intensity among susceptible individuals resulting in disruption of treatment and development of resistance to the drug thus leading to therapeutic failures as reported. This scourge is quite challenging due to the complex physiologic mechanism that has not been fully elucidated. Factors observed to be responsible in the induction of pruritus such as age, race, heredity, density of parasitaemia; impurities in formulations, plasmodial specie, dosage form and metabolites have been discussed in this review. Efforts to ameliorate this burden have necessitated the use of drugs of diverse pharmacological classes such as antihistamines, corticosteroids and multivitamins either alone or as a combination. This review is to look into the use of chloroquine retrospectively, and consider its re-introduction due to its safety. Efficacy can be attained if the pruritic effect is resolved.


An optimal weighted aggregated association test for identification of rare variants involved in common diseases.
The advent of next generation sequencing technologies allows one to discover nearly all rare variants in a genomic region of interest. This technological development increases the need for an effective statistical method for testing the aggregated effect of rare variants in a gene on disease susceptibility. The idea behind this approach is that if a certain gene is involved in a disease, many rare variants within the gene will disrupt the function of the gene and are associated with the disease. In this article, we present the rare variant weighted aggregate statistic (RWAS), a method that groups rare variants and computes a weighted sum of differences between case and control mutation counts. We show that our method outperforms the groupwise association test of Madsen and Browning in the disease-risk model that assumes that each variant makes an equally small contribution to disease risk. In addition, we can incorporate prior information into our method of which variants are likely causal. By using simulated data and real mutation screening data of the susceptibility gene for ataxia telangiectasia, we demonstrate that prior information has a substantial influence on the statistical power of association studies. Our method is publicly available at http://genetics.cs.ucla.edu/rarevariants.


Progressive thermopreconditioning attenuates rat cardiac ischemia/reperfusion injury by mitochondria-mediated antioxidant and antiapoptotic mechanisms.
Progressive thermal preconditioning (PTP) provides vascular protection with less hemodynamic fluctuations, endoplasmic reticulum (ER), and oxidative stress compared with whole body hyperthermia. We suggest PTP might efficiently diminish cardiac ischemia/reperfusion-induced apoptosis and autophagy injury. A total of 67 male Wistar rats were divided into a non-PTP control group, 24 or 72 hours after a single cycle or 3 consecutive cycles of PTP in a 42°C water bath (1-24, 1-72, 3-24, and 3-72 groups). We measured the cardiac O2(-) amount in vivo in response to left anterior descending coronary artery ligation for 2 hours and reperfusion for 3 hours. Cardiac function and injury were determined by microcirculation, electrocardiography, and infarct size. The PTP-induced protective effects on nicotinamide adenine dinucleotide phosphate oxidase gp91-mediated oxidative stress, ER stress, and apoptosis- and autophagy-related mechanisms were examined using Western blot and immunohistochemistry. Coronary arterial ischemia/reperfusion depressed cardiac microcirculation, induced ST-segment elevation and increased infarct size in non-PTP and PTP rats. Ischemia/reperfusion enhanced the cardiac O2(-) levels by enhanced nicotinamide adenine dinucleotide phosphate oxidase gp91 expression, cytosolic cytochrome C release, and decreased mitochondrial Bcl-2 expression. Cardiac injury activated ER stress-78-kDa glucose-regulated protein expression, increased the Bax/Bcl-2 ratio, cleaved caspase 3 expression and poly-(ADP-ribose)-polymerase fragments, leading to apoptosis formation, and promoted LC3-II expression, resulting in autophagy formation. PTP treatment elevated heat shock protein 70, heat shock protein 32, Bcl-2, Bcl-xL, and manganese superoxide dismutase in the rat heart, especially in the 3-72 group. PTP treatment significantly restored cardiac microcirculation, decreased oxidative stress, ER stress, apoptosis, autophagy, and infarct size. PTP significantly reduced cardiac ischemia/reperfusion injury by upregulating antioxidant, antiapoptotic, and antiautophagic mechanisms.


A smooth ROC curve estimator based on log-concave density estimates.
We introduce a new smooth estimator of the ROC curve based on log-concave density estimates of the constituent distributions. We show that our estimate is asymptotically equivalent to the empirical ROC curve if the underlying densities are in fact log-concave. In addition, we empirically show that our proposed estimator exhibits an efficiency gain for finite sample sizes with respect to the standard empirical estimate in various scenarios and that it is only slightly less efficient, if at all, compared to the fully parametric binormal estimate in case the underlying distributions are normal. The estimator is also quite robust against modest deviations from the logconcavity assumption. We show that bootstrap confidence intervals for the value of the ROC curve at a fixed false positive fraction based on the new estimate are on average shorter compared to the approach by Zhou and Qin (2005), while maintaining coverage probability. Computation of our proposed estimate uses the R package logcondens that implements univariate log-concave density estimation and can be done very efficiently using only one line of code. These obtained results lead us to advocate our estimate for a wide range of scenarios.


Detection of intracranial in-stent restenosis using quantitative magnetic resonance angiography.
In-stent restenosis (ISR) after angioplasty/stenting for intracranial stenosis has been reported in up to 25% to 30% of patients. Detection and monitoring of ISR relies primarily on serial catheter angiography, because noninvasive imaging methods are typically hampered by stent-related artifact. We examined the value of serial vessel flow measurements using quantitative magnetic resonance angiography (QMRA) in detection of ISR. Records of patients undergoing stenting for intracranial symptomatic stenosis >50% between 2005 and 2009 were retrospectively reviewed. Angiographic images were graded by a blinded neurointerventionalist for stenosis pretreatment, immediately after treatment, and during follow-up. Flow in the affected vessel measured by QMRA was recorded; > 25% reduction in flow was considered indicative of an adverse change. Clinical data regarding neurological outcome were also collected. Twenty-eight patients underwent stenting during the time interval studied. Of these, 12 patients (mean age, 55.5 years; 8 female) had contemporaneous angiography and QMRA and were analyzed. Median follow-up was 9 months. Six patients (50%) demonstrated angiographic restenosis 2 to 12 months after treatment; all had an analogous decrease in flow in the vessel of interest. Of 3 patients with more severe flow decrement (> 50%), 2 experienced stroke. None of the patients without angiographic ISR demonstrated a flow decrease on QMRA. In this preliminary series, flow decrease on QMRA is highly predictive of angiographic ISR. Additionally, the degree of flow decrement correlates with symptomatic ISR. QMRA may provide a useful noninvasive tool for serial monitoring after intracranial stenting.


Petite Integration Factor 1 (PIF1) helicase deficiency increases weight gain in Western diet-fed female mice without increased inflammatory markers or decreased glucose clearance.
Petite Integration Factor 1 (PIF1) is a multifunctional helicase present in nuclei and mitochondria. PIF1 knock out (KO) mice exhibit accelerated weight gain and decreased wheel running on a normal chow diet. In the current study, we investigated whether Pif1 ablation alters whole body metabolism in response to weight gain. PIF1 KO and wild type (WT) C57BL/6J mice were fed a Western diet (WD) rich in fat and carbohydrates before evaluation of their metabolic phenotype. Compared with weight gain-resistant WT female mice, WD-fed PIF1 KO females, but not males, showed accelerated adipose deposition, decreased locomotor activity, and reduced whole-body energy expenditure without increased dietary intake. Surprisingly, PIF1 KO females did not show obesity-induced alterations in fasting blood glucose and glucose clearance. WD-fed PIF1 KO females developed mild hepatic steatosis and associated changes in liver gene expression that were absent in weight-matched, WD-fed female controls, linking hepatic steatosis to Pif1 ablation rather than increased body weight. WD-fed PIF1 KO females also showed decreased expression of inflammation-associated genes in adipose tissue. Collectively, these data separated weight gain from inflammation and impaired glucose homeostasis. They also support a role for Pif1 in weight gain resistance and liver metabolic dysregulation during nutrient stress.


Prevalence of gestational diabetes mellitus among Swampy Cree women in Moose Factory, James Bay.
Although high rates of gestational diabetes mellitus have been documented in native populations, few studies have examined rates of the disease among native Indians in Canada. The authors conducted a study to estimate the prevalence of gestational diabetes among Swampy Cree women, to identify factors predictive of the occurrence of gestational diabetes, and to identify delivery and infant outcomes related to the presence of the disease. Information on Swampy Cree women who gave birth at Weeneebayko Hospital, Moose Factory, James Bay, Ont., between 1987 and 1995 was obtained from medical charts. Patients with and without gestational diabetes were compared. Logistic regression analysis was used to identify independent predictors of gestational diabetes. Delivery and infant outcomes that occurred secondary to gestational diabetes were also identified by means of logistic regression. A total of 1401 deliveries occurred at Weeneebayko Hospital over the study period, of which 1298 were included in the study. Gestational diabetes was diagnosed in 110 (8.5% [95% confidence interval (CI) 6.9%-9.9%]) of the 1298 pregnancies. Factors predictive of gestational diabetes were age 35 years or more (relative risk [RR] 4.1, 95% CI 1.5-11.7), a history of gestational diabetes in a previous pregnancy (RR 6.4, 95% CI 3.5-11.7), diastolic blood pressure of 80 mm Hg or higher at the first prenatal visit (RR 1.7, 95% CI 1.1-2.8), weight greater than 80 kg at the first prenatal visit (RR 4.9, 95% CI 1.8-12.9) and having a first-degree relative with diabetes (RR 3.0, 95% CI 1.4-6.1). The only delivery outcome independently associated with the presence of gestational diabetes was an increased likelihood of needing assisted delivery (forceps or vacuum extraction) (RR 2.8, 95% CI 1.1-7.0). Shoulder dystocia was indirectly associated with gestational diabetes owing to increased infant birth weight. Infant outcomes associated with the presence of gestational diabetes were birth weight greater than 4500 g (RR 2.4, 95% CI 1.4-3.8), hyperbilirubinemia (RR 2.9, 95% CI 1.4-6.1), hypoglycemia (RR 7.3, 95% CI 3.7-14.4) and hypocalcemia (RR 8.9, 95% CI 2.3-33.7). Gestational diabetes occurred in a significant minority of Swampy Cree women and was associated with a number of adverse outcomes.


Primary hemangiopericytoma in the axis bone: case report and review of literature.
To the best of our knowledge, this is the first reported case of primary hemangiopericytoma in the axis bone. With this report, we attempt to better characterize this uncommon lesion in the vertebral column. This report describes a case of primary heman-giopericytoma in the axis bone of a 16-year-old female patient who presented with acute torticollis. Her neurological status was unimpaired. A lateral radiograph of the cervical spine demonstrated an odontoid neck fracture and a C1-C2 rotatory deformity. The magnetic resonance imaging study showed a hypodense lesion with moderate enhancement on T1- and T2-weighted images on the dens and body of the axis with an odontoid neck fracture. Reviewing the literature, primary hemangiopericytoma in the spine is rare; 9 cases of hemangiopericytoma with vertebral bone involvement and 44 cases of this tumor with intraspinal meningeal involvement have been reported. The patient was treated with odontoidectomy via the transoral approach, along with posterior fixation using the Halifax clamp. She was followed up 17 months after surgery, and no evidence of tumor recurrence was found. The treatment for osseous hemangiopericytoma is still controversial. At present, adequate surgical removal with postoperative radio-therapy is recommended. In addition, although hemangiopericytoma is rare in the spine, it should be kept in mind in the differential diagnosis of spinal tumors.


Treatment of ureteroarterial fistulae with covered vascular endoprostheses and ureteral occlusion.
Ureteroarterial fistulae (UAFs) are a rare entity, often difficult to identify, and associated with a high mortality rate. This fact has been attributed to a delay in diagnosis and treatment. Five conditions that can predispose to the development of this uncommon entity have been described: prior pelvic surgery, prolonged ureteral stenting, radiation therapy, previous vascular surgery and vascular pathology. We present 4 patients with UAFs and at least three of the above-mentioned conditions. Ureteral ischemia and subsequent necrosis promote the formation of these fistulae. The constant pulsation of the iliac artery is transmitted to an already compromised ureter containing a stiff intraluminal foreign body, resulting in pressure necrosis, most likely where the ureter crosses the iliac artery. Cases were managed percutaneously with a combination of the deployment of a covered prosthesis and, when needed, with mechanical occlusion of the ureter. Hematuria stopped in all the patients with no evidence of immediate rebleeding. One patient presented a new episode of vaginal bleeding 13 months after endograft placement and ureteral embolization. Arteriography showed the presence of a hypogastric artery pseudoaneurysm that was occluded using coils. No new bleeding has occurred in this patient 12 months after the second embolization. At present all 4 patients are alive with follow-up periods of 5, 9, 11 and 25 months since the first procedure.


Timing, rates and spectra of human germline mutation.
Germline mutations are a driving force behind genome evolution and genetic disease. We investigated genome-wide mutation rates and spectra in multi-sibling families. The mutation rate increased with paternal age in all families, but the number of additional mutations per year differed by more than twofold between families. Meta-analysis of 6,570 mutations showed that germline methylation influences mutation rates. In contrast to somatic mutations, we found remarkable consistency in germline mutation spectra between the sexes and at different paternal ages. In parental germ line, 3.8% of mutations were mosaic, resulting in 1.3% of mutations being shared by siblings. The number of these shared mutations varied significantly between families. Our data suggest that the mutation rate per cell division is higher during both early embryogenesis and differentiation of primordial germ cells but is reduced substantially during post-pubertal spermatogenesis. These findings have important consequences for the recurrence risks of disorders caused by de novo mutations.


BAC libraries construction from the ancestral diploid genomes of the allotetraploid cultivated peanut.
Cultivated peanut, Arachis hypogaea is an allotetraploid of recent origin, with an AABB genome. In common with many other polyploids, it seems that a severe genetic bottle-neck was imposed at the species origin, via hybridisation of two wild species and spontaneous chromosome duplication. Therefore, the study of the genome of peanut is hampered both by the crop's low genetic diversity and its polyploidy. In contrast to cultivated peanut, most wild Arachis species are diploid with high genetic diversity. The study of diploid Arachis genomes is therefore attractive, both to simplify the construction of genetic and physical maps, and for the isolation and characterization of wild alleles. The most probable wild ancestors of cultivated peanut are A. duranensis and A. ipaënsis with genome types AA and BB respectively. We constructed and characterized two large-insert libraries in Bacterial Artificial Chromosome (BAC) vector, one for each of the diploid ancestral species. The libraries (AA and BB) are respectively c. 7.4 and c. 5.3 genome equivalents with low organelle contamination and average insert sizes of 110 and 100 kb. Both libraries were used for the isolation of clones containing genetically mapped legume anchor markers (single copy genes), and resistance gene analogues. These diploid BAC libraries are important tools for the isolation of wild alleles conferring resistances to biotic stresses, comparisons of orthologous regions of the AA and BB genomes with each other and with other legume species, and will facilitate the construction of a physical map.


Increased expression of drug-metabolizing enzymes in human hepatocarcinoma FLC-4 cells cultured on micro-space cell culture plates.
Human hepatocellular carcinoma cell lines cultured in a monolayer show negligible activities of drug-metabolizing enzymes such as cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs). Here, we show that culture of human hepatocellular carcinoma FLC-4 cells on 24-well plates arrayed with uniform micro-sized compartments on the bottom of the plates (micro-space cell culture plates) resulted in increased expression of drug-metabolizing enzymes (CYP1A2, CYP2C9, CYP3A4, UGT1A1, etc.) and nuclear receptors (pregnane X receptor, constitutive androstane receptor, etc.). When cells were treated with a typical CYP3A substrate (triazolam), CYP2C9 substrate (diclofenac) or UGT1A1 substrate (SN-38), large amounts of their metabolites were detected in the medium of cells cultured on micro-space cell culture plates. The formation of metabolites from triazolam, diclofenac and SN-38 was strongly inhibited by co-treatment with a CYP3A inhibitor (ketoconazole), CYP2C9 inhibitor (sulfaphenazole) and UGT1A1 inhibitor (ketoconazole), respectively. On the other hand, formation of metabolites was not observed in the medium of cells cultured in a monolayer. Finally, the cytotoxic effect of aflatoxin B1 was more potent in cells cultured on micro-space cell culture plates than in cells cultured in a monolayer. The results suggest that FLC-4 cells cultured on micro-space cell culture plates are useful for studying drug metabolism and drug-induced hepatotoxicity.


SEROLOGICAL REACTIONS IN PNEUMONIA WITH A NON-PROTEIN SOMATIC FRACTION OF PNEUMOCOCCUS.
1. Sera from individuals acutely ill with lobar pneumonia possess the capacity to precipitate in high titre a non-protein somatic fraction derived from pneumococci (Fraction C). Following crisis the reaction is no longer demonstrable. 2. Sera obtained from cases of pneumococcus pneumonia during illness and convalescence have been tested for antibodies specifically reactive with three chemically distinct constituents of Pneumococcus. The results, when correlated with the course of disease, demonstrate differences in the occurrence of each qualitatively distinct antibody. 3. The precipitation of pneumococcus Fraction C is not limited to the sera of individuals ill with pneumococcus infection. But in the few other cases available for comparative tests, definite reactions have been obtained only in streptococcus and staphylococcus infections and in acute rheumatic fever.


The assessment and management of inner ear barotrauma in divers and recommendations for returning to diving.
Inner ear barotrauma (IEBt) constitutes a spectrum of pressure-related pathology in the inner ear, with antecedent middle ear barotrauma (MEBt) common. IEBt includes perilymph fistula, intralabyrinthine membrane tear, inner ear haemorrhage and other rarer pathologies. Following a literature search, the pathophysiology, diagnosis, and treatment of IEBt in divers and best-practice recommendations for returning to diving were reviewed. Sixty-nine papers/texts were identified and 54 accessed. Twenty-five case series (majority surgical) provided guidance on diagnostic pathways; nine solely reported divers. IEBt in divers may be difficult to distinguish from inner ear decompression sickness (IEDCS), and requires dive-risk stratification and careful interrogation regarding diving-related ear events, clinical assessment, pure tone audiometry, a fistula test and electronystagmography (ENG). Once diagnosed, conservative management is the recommended first line therapy for IEBt. Recompression does not appear to cause harm if the diagnosis (IEBt vs IEDCS) is doubtful (limited case data). Exploratory surgery is indicated for severe or persisting vestibular symptoms or hearing loss, deterioration of symptoms, or lack of improvement over 10 days indicating significant pathology. Steroids are used, but without high-level evidence. It may be possible for divers to return to subaquatic activity after stakeholder risk acceptance and informed consent, provided: (1) sensorineural hearing loss is stable and not severe; (2) there is no vestibular involvement (via ENG); (3) high-resolution computed tomography has excluded anatomical predilection to IEBt and (4) education on equalising techniques is provided. There is a need for a prospective data registry and controlled trials to better evaluate diagnostic and treatment algorithms.


Changing immunization referral patterns among pediatricians and family practice physicians, Dallas County, Texas, 1988.
Family practice physicians and pediatricians in Dallas County, Texas, were surveyed to determine how recent vaccine price increases have changed immunization referral patterns. A total of 73% of responding physicians referred some pediatric patients for immunization in 1988. Public health clinics were the largest referral source with more responding pediatricians (84.4%) referring patients than did responding family practitioners (66.5%). Referrals to the clinics were most often made when patients were unable to afford immunizations in a private practice setting. Between 1979 and 1988, the number of responding pediatricians and family practitioners making immunization referrals increased by 193% and 391%, respectively. The percentages of children referred for immunization increased by 693% during the same decade. It was suggested by our survey of Dallas County physicians that a new influx of patients are using public sector immunizations, potentially creating additional financial stress for public health programs. In addition, this shift to the public sector may undermine the health departments' ability to provide new vaccines or protect greater numbers of children with immunization.


The peptidoglycan recognition proteins (PGRPs).
Peptidoglycan recognition proteins (PGRPs) are innate immunity molecules present in insects, mollusks, echinoderms, and vertebrates, but not in nematodes or plants. PGRPs have at least one carboxy-terminal PGRP domain (approximately 165 amino acids long), which is homologous to bacteriophage and bacterial type 2 amidases. Insects have up to 19 PGRPs, classified into short (S) and long (L) forms. The short forms are present in the hemolymph, cuticle, and fat-body cells, and sometimes in epidermal cells in the gut and hemocytes, whereas the long forms are mainly expressed in hemocytes. The expression of insect PGRPs is often upregulated by exposure to bacteria. Insect PGRPs activate the Toll or immune deficiency (Imd) signal transduction pathways or induce proteolytic cascades that generate antimicrobial products, induce phagocytosis, hydrolyze peptidoglycan, and protect insects against infections. Mammals have four PGRPs, which are secreted; it is not clear whether any are directly orthologous to the insect PGRPs. One mammalian PGRP, PGLYRP-2, is an N-acetylmuramoyl-L-alanine amidase that hydrolyzes bacterial peptidoglycan and reduces its proinflammatory activity; PGLYRP-2 is secreted from the liver into the blood and is also induced by bacteria in epithelial cells. The three remaining mammalian PGRPs are bactericidal proteins that are secreted as disulfide-linked homo- and hetero-dimers. PGLYRP-1 is expressed primarily in polymorphonuclear leukocyte granules and PGLYRP-3 and PGLYRP-4 are expressed in the skin, eyes, salivary glands, throat, tongue, esophagus, stomach, and intestine. These three proteins kill bacteria by interacting with cell wall peptidoglycan, rather than permeabilizing bacterial membranes as other antibacterial peptides do. Direct bactericidal activity of these PGRPs either evolved in the vertebrate (or mammalian) lineage or is yet to be discovered in insects.


The wake dynamics and flight forces of the fruit fly Drosophila melanogaster.
We have used flow visualizations and instantaneous force measurements of tethered fruit flies (Drosophila melanogaster) to study the dynamics of force generation during flight. During each complete stroke cycle, the flies generate one single vortex loop consisting of vorticity shed during the downstroke and ventral flip. This gross pattern of wake structure in Drosophila is similar to those described for hovering birds and some other insects. The wake structure differed from those previously described, however, in that the vortex filaments shed during ventral stroke reversal did not fuse to complete a circular ring, but rather attached temporarily to the body to complete an inverted heart-shaped vortex loop. The attached ventral filaments of the loop subsequently slide along the length of the body and eventually fuse at the tip of the abdomen. We found no evidence for the shedding of wing-tip vorticity during the upstroke, and argue that this is due to an extreme form of the Wagner effect acting at that time. The flow visualizations predicted that maximum flight forces would be generated during the downstroke and ventral reversal, with little or no force generated during the upstroke. The instantaneous force measurements using laser-interferometry verified the periodic nature of force generation. Within each stroke cycle, there was one plateau of high force generation followed by a period of low force, which roughly correlated with the upstroke and downstroke periods. However, the fluctuations in force lagged behind their expected occurrence within the wing-stroke cycle by approximately 1 ms or one-fifth of the complete stroke cycle. This temporal discrepancy exceeds the range of expected inaccuracies and artifacts in the measurements, and we tentatively discuss the potential retarding effects within the underlying fluid mechanics.


Leveraging biospecimen resources for discovery or validation of markers for early cancer detection.
Validation of early detection cancer biomarkers has proven to be disappointing when initial promising claims have often not been reproducible in diagnostic samples or did not extend to prediagnostic samples. The previously reported lack of rigorous internal validity (systematic differences between compared groups) and external validity (lack of generalizability beyond compared groups) may be effectively addressed by utilizing blood specimens and data collected within well-conducted cohort studies. Cohort studies with prediagnostic specimens (eg, blood specimens collected prior to development of clinical symptoms) and clinical data have recently been used to assess the validity of some early detection biomarkers. With this background, the Division of Cancer Control and Population Sciences (DCCPS) and the Division of Cancer Prevention (DCP) of the National Cancer Institute (NCI) held a joint workshop in August 2013. The goal was to advance early detection cancer research by considering how the infrastructure of cohort studies that already exist or are being developed might be leveraged to include appropriate blood specimens, including prediagnostic specimens, ideally collected at periodic intervals, along with clinical data about symptom status and cancer diagnosis. Three overarching recommendations emerged from the discussions: 1) facilitate sharing of existing specimens and data, 2) encourage collaboration among scientists developing biomarkers and those conducting observational cohort studies or managing healthcare systems with cohorts followed over time, and 3) conduct pilot projects that identify and address key logistic and feasibility issues regarding how appropriate specimens and clinical data might be collected at reasonable effort and cost within existing or future cohorts.


A phase demodulation method with high spatial resolution for two-dimensional single-shot X-ray Talbot interferometry.
A new phase demodulation approach is proposed that uses windowed Fourier transforms to achieve high spatial resolution in fringe pattern analysis with a high signal-to-noise ratio for single-shot X-ray grating-based interferometry. Conventionally, Fourier transforms have been used to demodulate single-fringe patterns, but this requires a fringe pattern with a long period to obtain an acceptable signal-to-noise ratio among the demodulated parameters. However, by controlling the signal-to-noise ratio, the spatial resolution of demodulated parameters is degraded below that obtained from the phase-stepping method, which requires several images to obtain these parameters. In this paper, we introduce the use of a windowed Fourier transform with a process for analyzing the objective spectrum in isolation from other spectra on the Fourier space to overcome the limitations of the Fourier transform method. It is proved that with suitable assumptions the objective spectrum is isolated theoretically, and the spatial resolution is improved by practically accepting the limitations from the assumptions. We demonstrate the validity of the proposed method by comparing the modulation transfer function of a synthetic phantom with the conventional FT method. The proposed method is also valid on practical data obtained by an experimental setup, by which it is demonstrated that a high spatial resolution with high signal-to-noise ratio can be achieved by our proposed method.


Linkage study of fibrinogen levels: the Strong Heart Family Study.
The pathogenesis of atherosclerosis involves both hemostatic and inflammatory mechanisms. Fibrinogen is associated with both risk of thrombosis and inflammation. A recent meta-analysis showed that risk of coronary heart disease may increase 1.8 fold for 1 g/L of increased fibrinogen, independent of traditional risk factors. It is known that fibrinogen levels may be influenced by demographic, environmental and genetic factors. Epidemiologic and candidate gene studies are available; but few genome-wide linkage studies have been conducted, particularly in minority populations. The Strong Heart Study has demonstrated an increased incidence of cardiovascular disease in the American Indian population, and therefore represents an important source for genetic-epidemiological investigations. The Strong Heart Family Study enrolled over 3,600 American Indian participants in large, multi-generational families, ascertained from an ongoing population-based study in the same communities. Fibrinogen was determined using standard technique in a central laboratory and extensive additional phenotypic measures were obtained. Participants were genotyped for 382 short tandem repeat markers distributed throughout the genome; and results were analyzed using a variance decomposition method, as implemented in the SOLAR 2.0 program. Data from 3535 participants were included and after step-wise, linear regression analysis, two models were selected for investigation. Basic demographic adjustments constituted model 1, while model 2 considered waist circumference, diabetes mellitus and postmenopausal status as additional covariates. Five LOD scores between 1.82 and 3.02 were identified, with the maximally adjusted model showing the highest score on chromosome 7 at 28 cM. Genes for two key components of the inflammatory response, i.e. interleukin-6 and "signal transducer and activator of transcription 3" (STAT3), were identified within 2 and 8 Mb of this 1 LOD drop interval respectively. A LOD score of 1.82 on chromosome 17 between 68 and 93 cM is supported by reports from two other populations with LOD scores of 1.4 and 1.95. In a minority population with a high prevalence of cardiovascular disease, strong evidence for a novel genetic determinant of fibrinogen levels is found on chromosome 7 at 28 cM. Four other loci, some of which have been suggested by previous studies, were also identified.


Reproducibility of tract segmentation between sessions using an unsupervised modelling-based approach.
This work describes a reproducibility analysis of scalar water diffusion parameters, measured within white matter tracts segmented using a probabilistic shape modelling method. In common with previously reported neighbourhood tractography (NT) work, the technique optimises seed point placement for fibre tracking by matching the tracts generated using a number of candidate points against a reference tract, which is derived from a white matter atlas in the present study. No direct constraints are applied to the fibre tracking results. An Expectation-Maximisation algorithm is used to fully automate the procedure, and make dramatically more efficient use of data than earlier NT methods. Within-subject and between-subject variances for fractional anisotropy and mean diffusivity within the tracts are then separated using a random effects model. We find test-retest coefficients of variation (CVs) similar to those reported in another study using landmark-guided single seed points; and subject to subject CVs similar to a constraint-based multiple ROI method. We conclude that our approach is at least as effective as other methods for tract segmentation using tractography, whilst also having some additional benefits, such as its provision of a goodness-of-match measure for each segmentation.


Measuring young people's attitudes to breastfeeding using the Theory of Planned Behaviour.
The focus of this study was to design and pilot a questionnaire to measure young people's attitudes to breastfeeding using the Theory of Planned Behaviour (TPB). This is intended for subsequent use in a large-scale attitude survey, which in turn will inform the design of a breastfeeding intervention programme with adolescents. The first three phases of a research programme employing the theory are described: belief elicitation, questionnaire development and a pilot study. Firstly, an elicitation study to identify the modal salient beliefs underlying young peoples' motivations to breastfeed, using six semi-structured focus groups with 48 young people, was performed. Secondly, the measurement instrument was constructed, incorporating all the key theoretical constructs and both direct and belief-based measures. The questionnaire was then piloted on a sample of 121 female and male schoolchildren to identify and assess the relative importance of the determinants of breastfeeding intention. The questionnaire proved to be reliable, and preliminary analysis provided strong support for the predictive power of the TPB. Some key issues involved in the operationalization of the theory are highlighted, which may be of interest to researchers involved in the design of TPB questionnaires for use in other intervention programmes.


Rural-urban differences in objective and subjective measures of physical activity: findings from the National Health and Nutrition Examination Survey (NHANES) 2003-2006.
Lower levels of physical activity among rural relative to urban residents have been suggested as an important contributor to rural-urban health disparity; however, empirical evidence is sparse. We examined rural-urban differences in 4 objective physical activity measures (2 intensity thresholds by 2 bout lengths) and 4 subjective measures (total, leisure, household, and transportation) in a nationally representative sample of participants in the National Health and Nutrition Examination Survey (NHANES) 2003-2006. The sample comprised 5,056 adults aged 20 to 75 years. Rural-Urban Commuting Area (RUCA) codes were matched with NHANES subjects to identify urban status and 2 types of rural status. Rural-urban and within-rural differences in physical activity were estimated without and with controls for demographic and socioeconomic variables. Rural residents were less active than urban residents in high-intensity long bout (2,020 counts per minute threshold and 10 miniutes or longer bout length) accelerometer-measured physical activity (42.5 ± 6.2 min/wk vs 55.9 ± 2.8 min/wk) but the difference disappeared with a lower-intensity threshold (760 counts per minute). Rural residents reported more total physical activity than urban residents (438.3 ± 35.3min/wk vs 371.2 ± 12.5 min/wk), with differences primarily attributable to household physical activity. Within rural areas, micropolitan residents were less active than residents in smaller rural areas. Controlling for other variables reduced the size of the differences. The direction and significance of rural-urban difference in physical activity varied by the method of physical activity measurement, likely related to rural residents spending more time in low-intensity household physical activity but less time in high-intensity physical activity. Micropolitan residents were substantially less active than residents in smaller rural areas, indicating that physical activity did not vary unidirectionally with degree of urbanization.


Deep Eutectic Solvents as Efficient Solvents in Biocatalysis.
'Ideal' solvents in biocatalysis have to fulfill a large number of requirements, such as high substrate solubility, high enzyme activity and stability, and positive effects on reaction equilibrium. In the past decades, many enzymatic synthesis routes in water-based and nonaqueous (organic solvents, ionic or supercritical fluids) reaction media have been developed. However, no solvent meets every demand for different reaction types at the same time, and there is still a need for novel solvents suited for different reaction types and applications. Deep eutectic solvents (DESs) have recently been evaluated as solvents in different biocatalytic reactions. They can improve substrate supply, conversion, and stability. The best results were obtained when the DES is formed by the substrates of an enzymatic reaction.


Matrix metalloproteinase protein expression profiles cannot distinguish between normal and early osteoarthritic synovial fluid.
Osteoarthritis (OA) and rheumatoid arthritis (RA) are diseases which result in the degeneration of the joint surface articular cartilage. Matrix metalloproteinases (MMPs) are enzymes that aid in the natural remodelling of tissues throughout the body including cartilage. However, some MMPs have been implicated in the progression of OA and RA as their expression levels and activation states can change dramatically with the onset of disease. Yet, it remains unknown if normal and arthritic joints demonstrate unique MMPs expression profiles, and if so, can the MMP expression profile be used to identify patients with early OA. In this study, the synovial fluid protein expression levels for MMPs 1, 2, 3, 7, 8, 9, 12 & 13, as well as those for the Tissue Inhibitors of MMPs (TIMPs) 1, 2, 3, & 4 were examined in highly characterized normal knee joints, and knee joints with clinically diagnosed OA (early and advanced) or RA. The purpose of this study was to determine if normal, OA, and RA patients exhibit unique expression profiles for a sub-set of MMPs, and if early OA patients have a unique MMP expression profile that could be used as an early diagnostic marker. Synovial fluid was aspirated from stringently characterized normal knee joints, and in joints diagnosed with either OA (early and advanced) or RA. Multiplexing technology was employed to quantify protein expression levels for 8 MMPs and 4 TIMPs in the synovial fluid of 12 patients with early OA, 17 patients diagnosed with advanced OA, 15 with RA and 25 normal knee joints. Principle component analysis (PCA) was used to reveal which MMPs were most influential in the distinction between treatment groups. K - means clustering was used to verify the visual grouping of subjects via PCA. Significant differences in the expression levels of MMPs and TIMPs were observed between normal and arthritic synovial fluids (with the exception of MMP 12). PCA demonstrated that MMPs 2, 8 & 9 can be used to effectively separate individuals diagnosed with advanced arthritis from early osteoarthritic and normal individuals, however, these MMP profiles do not separate early OA from normal synovial fluid. An apparent separation between advanced OA and RA subjects was also revealed through PCA. K-means clustering verified the presence of 3 clusters: normal joints clustered with early OA, and separate clusters of advanced OA or RA. This study demonstrates that unique MMP and TIMP expression profiles are present within normal, advanced OA and RA synovial fluid. These MMP profiles can be used to distinguish advanced OA & RA synovial fluid from early OA & normal synovial fluid, and even between synovial fluid samples from OA and RA joints. Although this methodology cannot be used for the diagnosis of early OA, high throughput multiplex technology of MMPs and TIMPs in synovial fluid may prove useful in determining the severity of the disease state, and/or quantifying the response of individuals to disease interventions.


Climate change, habitat loss, protected areas and the climate adaptation potential of species in mediterranean ecosystems worldwide.
Mediterranean climate is found on five continents and supports five global biodiversity hotspots. Based on combined downscaled results from 23 atmosphere-ocean general circulation models (AOGCMs) for three emissions scenarios, we determined the projected spatial shifts in the mediterranean climate extent (MCE) over the next century. Although most AOGCMs project a moderate expansion in the global MCE, regional impacts are large and uneven. The median AOGCM simulation output for the three emissions scenarios project the MCE at the end of the 21(st) century in Chile will range from 129-153% of its current size, while in Australia, it will contract to only 77-49% of its current size losing an area equivalent to over twice the size of Portugal. Only 4% of the land area within the current MCE worldwide is in protected status (compared to a global average of 12% for all biome types), and, depending on the emissions scenario, only 50-60% of these protected areas are likely to be in the future MCE. To exacerbate the climate impact, nearly one third (29-31%) of the land where the MCE is projected to remain stable has already been converted to human use, limiting the size of the potential climate refuges and diminishing the adaptation potential of native biota. High conversion and low protection in projected stable areas make Australia the highest priority region for investment in climate-adaptation strategies to reduce the threat of climate change to the rich biodiversity of the mediterranean biome.


Protective effect of yellow tea extract on N-nitrosodiethylamine-induced liver carcinogenesis.
Context Yellow tea containing the same catechins as other types of tea but in different proportions has been suggested to possess potent anticancer activities. Objective This study investigates the chemopreventive effect of yellow tea aqueous extract against N-nitrosodiethylamine (NDEA)-induced liver carcinogenesis in rats by employing histological and biochemical methods. Materials and methods Wistar rats were divided randomly into four groups: control (I), yellow tea (II), NDEA (III), and yellow tea + NDEA (IV). Groups II and IV were exposed via a diet to yellow tea extract in a concentration of 10 g/kg feed; groups III and IV received 0.01% NDEA in drinking water. The experiment lasted for 13 weeks. Results Daily intake of yellow tea in an average dose of 800 mg/kg b.w. alleviated the carcinogenic effect of NDEA as evidenced by reversed histopathological changes towards normal hepatocellular architecture and decreased lipid peroxidation, protein carbonyl formation, and DNA degradation by 64%, 37% and 15%, respectively, as compared with values obtained in NDEA alone-treated rats. Treatment with yellow tea extract caused protection of superoxide dismutase (SOD) and catalase (CAT); their activity was recovered by 47% and 12%, respectively, as compared with the NDEA-treated rats. Moreover, the extract normalized the NDEA-induced activity of paraoxonase 1 (PON1) and glutathione peroxidase (GPx), while a further increase in the level of reduced glutathione (GSH) was noticed. Conclusions On the basis of these findings, it can be concluded that treatment with yellow tea partially protected the livers of rats from NDEA-induced hepatocarcinogenesis and that its antioxidant activity contributed to this effect.


Comorbidity between depressive symptoms and migraine: preliminary data from the Zabút Aging Project.
We evaluated the association between depressive symptoms and migraine using cross-sectional data from the Zabút Aging Project, a population-based study including subjects aged > or =50 years. A total of 1285 nonmigraineurs and 151 migraineurs were included. Diagnosis of migraine was carried out using the criteria of the International Headache Society. The Center for Epidemiologic Studies Depression scale (CES-D) was used to score depressive symptoms. Depressive symptoms were clustered in four groups: depressed and positive affects, somatic activity and intrapersonal feelings. Migraineurs showed higher total and specific depressive symptoms than controls (p from 0.005 to <0.0001). Mild-to-moderate depressive symptoms (CES-D score of > or =16) were present in 47.2% of migraineurs compared to 15.8% of controls (p<0.0001). After adjustment for demographics, mild-to-moderate depressive symptoms were strongly associated with migraine (OR [95% CI]=4.7 [3.1-7.0]). This association significantly increased in males (OR [95% CI]=6.2 [2.8-14.6]). Depressive features represent highly frequent comorbid symptoms of adult-to-elderly migraineurs.


Catalytically active and thermally stable core-shell gold-silica nanorods for CO oxidation.
Deactivation based on sintering phenomena is one of the most costly issues for the industrial application of metal nanoparticle catalysts. To address this drawback, mesoporous silica encapsulation is reported as a promising strategy to stabilize metallic nanoparticles towards use in high temperature catalytic applications. These protective shells provide significant structural support to the nanoparticles, while the mesoporosity allows for efficient transport of the reactants to the catalytically active surface of the metallic nanoparticle in the core. Here, we extend the use of gold nanorods with mesoporous silica shells by investigating their stability in the CO oxidation reaction as an example of high temperature gas phase catalysis. Gold nanorods were chosen as the model system due to the availability of a simple, high yield synthesis method for both the metallic nanorods and the mesoporous silica shells. We demonstrate the catalytic activity of gold nanorods with mesoporous silica shells at temperatures up to 350 °C over several cycles, as well as the thermal stability up to 500 °C, and compare these results to surfactant-stabilized gold nanorods of similar size, which degrade, and lose most of their catalytic activity, before reaching 150 °C. These results show that the gold nanorods protected by the mesoporous silica shells have a significantly higher thermal stability than surfactant-stabilized gold nanorods and that the mesoporous silica shell allows for stable catalytic activity with little degradation at high temperatures.


The Epistemic Risk in Representation.
Both the distinction between the 'internal' and 'external' phases of science and the concept of 'inductive risk' are core constructs in the values in science literature. However, both constructs have shortcomings, which, we argue, have concealed the unique significance of values in scientific representation. We defend three closely-related proposals to rectify the problem: i) to draw a conceptual distinction between endorsing a 'fact' and making a decision about representation; ii) to employ a conception of inductive risk that aligns with this distinction, not one between internal/external phases in science; iii) to conceptualize 'representational risk' as a unique epistemic risk, no less significant than inductive risk. We outline the implications of each proposal for current debates in the values in science literature.


Recovery of uncommon bacteria from blood: association with neoplastic disease.
Table 6 is a summary of the organisms discussed with a listing of the environmental source, the endogenous source, the predisposing factors including neoplasms, and the postulated mechanisms by which the organism can gain access to the circulation. The evidence considered indicates that the entrance of one of these microorganisms into the bloodstream of a human being depends on the presence of multiplicity of predisposing factors. In the majority of cases of bacteremia due to one of these unusual organisms, two or more predisposing factors are present. Certain predisposing factors, such as cancer chemotherapy or intravenous catheterization, often provide a barrier break, while others, such as liver disease, may render the host immune system less capable of clearing organisms from the circulation. For organisms such as Campy-lobacter, Listeria, and Salmonella spp., attributes that allow the invasion of a healthy host are present and seem to be enhanced by the simultaneous presence of a predisposing condition, such as liver disease, in the host. Although somewhat fragmentary, a number of individual case reports describe bacteremia due to one of these organisms occurring weeks to years after surgery and after other therapeutic measures had effected a supposed cure of a cancer. It may be speculated that cancer patients, even after a cure, are still susceptible to bloodstream invasion by one of the aforementioned organisms by virtue of the presence of one or more predisposing metabolic, physiologic, or immunologic factors, even though these factors may be cryptic. The predominance of hematologic malignancies among cases of bacteremia due to these unusual organisms is also apparent. Although, as pointed out by Keusch (169), the reduction in the performance of immune function in hematologic malignancies compared with solid tumors is likely to be responsible, other associations of certain organisms with specific neoplasms warrant further examination. The frequency of bloodstream infections of Salmonella typhimurium and Capno-cytophaga canimorsus in Hodgkin's disease patients seems likely due to a particular mechanism which infection by these species is favored. The specific nature of these mechanisms remains to be determined. The recovery of any unusual bacterium from blood should warrant a careful consideration of the possibility of underlying disease, especially cancer. Microbiologists should advise clinicians of the unusual nature of the identified organism and provide the counsel that certain neoplastic processes, often accompanied by neutropenia, render the human host susceptible to invasion by almost any bacterium. The recovery of such organisms as C. septicum or S. bovis should prompt the clinician to aggressively seek to identify an occult neoplasm if one has not yet been diagnosed.


Contrasting Age Effects on Complexity of Tracking Force and Force Fluctuations During Monorhythmic Contraction.
This study contrasted the stochastic force component between young and older adults, who performed pursuit tracking/compensatory tracking by exerting in-phase/antiphase forces to match a sinusoidal target. Tracking force was decomposed into the force component containing the target frequency and the nontarget force fluctuations (stochastic component). Older adults with inferior task performance had higher complexity (entropy across time; p = .005) in total force. For older adults, task errors were negatively correlated with force fluctuation complexity (pursuit tracking: r = -.527 to -.551; compensatory tracking: r = -.626 to -.750). Notwithstanding an age-related increase in total force complexity (p = .004), older adults exhibited lower complexity of the stochastic force component than young adults did (low frequency: p = .017; high frequency: p = .035). Those older adults with a higher complexity of stochastic force had better task performance due to the underlying use of a richer gradation strategy to compensate for impaired oscillatory control.


A molecular diagnostic algorithm to guide pollen immunotherapy in southern Europe: towards component-resolved management of allergic diseases.
Correct identification of the culprit allergen is an essential part of diagnosis and treatment in immunoglobulin E (IgE)-mediated allergic diseases. In recent years, molecular biology has made important advances facilitating such identification and overcoming some of the drawbacks of natural allergen extracts, which consist of mixtures of various proteins that may be allergenic or not, specific for the allergen source or widely distributed (panallergens). New technologies offer the opportunity for a more accurate component-resolved diagnosis, of benefit especially to polysensitized allergic patients. The basic elements of molecular diagnostics with potential relevance to immunotherapy prescription are reviewed here, with a focus on Southern European sensitization patterns to pollen allergens. We propose a basic algorithm regarding component-resolved diagnostic work-up for pollen allergen-specific immunotherapy candidates in Southern Europe; this and similar algorithms can form the basis of improved patient management, conceptually a 'Component-Resolved Allergy Management'.


Plant extracts from stinging nettle (Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-kappaB.
Activation of transcription factor NF-kappaB is elevated in several chronic inflammatory diseases and is responsible for the enhanced expression of many proinflammatory gene products. Extracts from leaves of stinging nettle (Urtica dioica) are used as antiinflammatory remedies in rheumatoid arthritis. Standardized preparations of these extracts (IDS23) suppress cytokine production, but their mode of action remains unclear. Here we demonstrate that treatment of different cells with IDS23 potently inhibits NF-kappaB activation. An inhibitory effect was observed in response to several stimuli, suggesting that IDS23 suppressed a common NF-kappaB pathway. Inhibition of NF-kappaB activation by IDS23 was not mediated by a direct modification of DNA binding, but rather by preventing degradation of its inhibitory subunit IkappaB-alpha. Our results suggests that part of the antiinflammatory effect of Urtica extract may be ascribed to its inhibitory effect on NF-kappaB activation.


An international cohort study of cancer in systemic lupus erythematosus.
There is increasing evidence in support of an association between systemic lupus erythematosus (SLE) and malignancy, but in earlier studies the association could not be quantified precisely. The present study was undertaken to ascertain the incidence of cancer in SLE patients, compared with that in the general population. We assembled a multisite (23 centers) international cohort of patients diagnosed as having SLE. Patients at each center were linked to regional tumor registries to determine cancer occurrence. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers. Cancers expected were determined by multiplying person-years in the cohort by the geographically matched age, sex, and calendar year-specific cancer rates, and summing over all person-years. The 9,547 patients from 23 centers were observed for a total of 76,948 patient-years, with an average followup of 8 years. Within the observation interval, 431 cancers occurred. The data confirmed an increased risk of cancer among patients with SLE. For all cancers combined, the SIR estimate was 1.15 (95% confidence interval [95% CI] 1.05-1.27), for all hematologic malignancies, it was 2.75 (95% CI 2.13-3.49), and for non-Hodgkin's lymphoma, it was 3.64 (95% CI 2.63-4.93). The data also suggested an increased risk of lung cancer (SIR 1.37; 95% CI 1.05-1.76), and hepatobiliary cancer (SIR 2.60; 95% CI 1.25, 4.78). These results support the notion of an association between SLE and cancer and more precisely define the risk of non-Hodgkin's lymphoma in SLE. It is not yet known whether this association is mediated by genetic factors or exogenous exposures.


Social inequalities in mental disorders and substance misuse in young adults : A birth cohort study in Southern Brazil.
To investigate the association between mental disorders and substance misuse at 30 years of age with gender, socioeconomic position at birth, and family income trajectories. The 1982 Pelotas Birth Cohort was used; all 5914 children born alive at hospital were originally enrolled (99.2% of all city births). In 2012, 3701 subjects were located and interviewed (68% retention rate). Mental disorders and substance misuse were assessed, and their prevalence analysed according to gender, socioeconomic status at birth, and four different income trajectories: always poor, never poor, poor at birth/non-poor at age 30, and non-poor at birth/poor at age 30. While women presented higher prevalence of mental disorders, substance misuse was much more frequent among men. Individuals in the lowest income quintile at birth presented 2-5 times more mental disorders and substance misuse than those in the highest quintile. Young adults who were always poor or were not poor at birth but were poor at 30 years of age had a higher prevalence of mental disorders than the other groups. The high rates of mental disorders and lifetime suicide attempts in young adults, especially those who were always poor or became poor after childhood, suggest that recent socioeconomic-related stressful situations may have a higher impact on the current mental health than events earlier in life. However, we could not identify at what specific ages socioeconomic changes were more important.


Low energy electron-induced decomposition of (η5-Cp)Fe(CO)2Mn(CO)5, a potential bimetallic precursor for focused electron beam induced deposition of alloy structures.
The production of alloyed nanostructures presents a unique problem in focused electron beam induced deposition (FEBID). Deposition of such structures has historically involved the mixing of two or more precursor gases in situ or via multiple channel gas injection systems, thereby making the production of precise, reproducible alloy compositions difficult. Promising recent efforts to address this problem have involved the use of multi-centred, heterometallic FEBID precursor species. In this vein, we present here a study of low-energy electron interactions with cyclopentadienyl iron dicarbonyl manganese pentacarbonyl ((η5-Cp)Fe(CO)2Mn(CO)5), a bimetallic species with a polyhapto ligand (Cp) and seven terminal carbonyl ligands. Gas phase studies and coupled cluster calculations of observed low-energy electron-induced reactions were conducted in order to predict the performance of this precursor in FEBID. In dissociative electron attachment, we find single CO loss and cleavage of the Fe-Mn bond, leading to the formation of [Mn(CO)5]-, to be the two dominant channels. Contributions through further CO loss from the intact core and the formation of [Mn(CO)4]- are minor channels. In dissociative ionization (DI), the fragmentation is significantly more extensive and the DI spectra are dominated by fragments formed through the loss of 5 and 6 CO ligands, and fragments formed through cleavage of the Fe-Mn bond accompanied by substantial CO loss. The gas phase fragmentation channels observed are discussed in relation to the underlying processes and their energetics, and in context to related surface studies and the likely performance of this precursor in FEBID.


Third-Trimester Prenatal Syphilis Screening: A Cost-Effectiveness Analysis.
To estimate the cost to prevent one case of congenital syphilis or fetal or neonatal death with universal third-trimester syphilis rescreening in the United States and to estimate the incidence of syphilis seroconversion at which rescreening becomes cost-effective. We created a decision model comparing universal third-trimester syphilis rescreening in women who screened negative in the first trimester with no rescreening. The assumed base case incidence of seroconversion was 0.012%. The primary outcome was the cost to prevent one case of congenital syphilis. Secondary outcomes included the cost to prevent one fetal or neonatal death and the number needed to rescreen to prevent one adverse outcome. A strategy was considered cost-effective if it cost less than $285,000 to prevent one case of congenital syphilis (the estimated long-term care cost). Under our assumptions, universal third-trimester rescreening would cost an additional $419,842 for each case of congenital syphilis prevented and $3,621,144 and $6,052,534, respectively, for each fetal and neonatal death prevented. Rescreening 4,000,000 women would prevent 60 cases of congenital syphilis and seven fetal and four neonatal deaths. Prevention of one case of congenital syphilis would require 65,790 women be rescreened. Seroconversion incidence of 0.017% would make third-trimester rescreening cost-effective. Universal third-trimester syphilis rescreening requires a large number of women be rescreened at a high health care cost to prevent one adverse outcome from maternal syphilis. Seroconversion incidence must be 19-fold higher than the national average of primary and secondary syphilis in women for universal third-trimester rescreening to be cost-effective.


[Aging by the perspective of elderly caregivers].
This study reports elderly caregivers' perception in charge of giving assistance to three benefiting institutions in elderly care, in the city of Araçatuba, São Paulo, Brazil. Questions were approached regarding aging, caregivers' personal motivation in the search of working with this sector of population, relationship with elderly, most common difficulties found during work and caregivers' satisfaction. An interview was done with caregivers and the collected verbal material was analyzed through the Collective Subject Discursive Technique. It was possible to realize through the reports the emotional involvement of caregivers with their work as well as the emotional and physical overload which they are exposed to. Reports related to aging could also be collected as well as social questions which motivated caregivers to search for this kind of job. The several eyes of caregivers lead us to search for new strategies of theoretical capability and psychological support for this group, thinking of their well-being along with the elderly well-being.


Studying multiple protein profiles over time to assess biomarker validity.
Protein profile analysis is increasingly used for identification of disease biomarkers. The approaches vary from surface-enhanced laser desorption/ionization to protein arrays. Newer platforms are constantly being developed. Almost all are based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and are often coupled with sophisticated software tools. Protein profiling has been applied to a variety of samples including plasma, urine, cerebrospinal fluid, saliva and solid tissue. This article focuses on those instances where it is possible to obtain sequential samples from the same individual. In the authors use of a profile method, many protein changes with highly significant correlations to disease have been found. The main challenge lies in the validation of the marker to demonstrate its adequacy for use in the clinical setting. The latter requires a methodology that is robust and amenable to high-throughput. One problem is that interindividual variability among the healthy population can mask major changes that occur on an intraindividual basis. Often, a large change for an individual may remain within the range of healthy individuals. Thus, one strategy to optimize biomarker discovery is to examine serial samples from a given individual, where a disease biomarker is established by comparison with the individual's own baseline sample. The focus of this review is to illustrate the principle and value of serial protein profiling using a rapid protein extraction method.


Overexpression and hyperactivity of breast cancer-associated fatty acid synthase (oncogenic antigen-519) is insensitive to normal arachidonic fatty acid-induced suppression in lipogenic tissues but it is selectively inhibited by tumoricidal alpha-linolenic and gamma-linolenic fatty acids: a novel mechanism by which dietary fat can alter mammary tumorigenesis.
Activity and expression of fatty acid synthase (FAS), a critical enzyme in the de novo biosynthesis of fatty acids in mammals, is exquisitely sensitive to nutritional regulation of lipogenesis in liver or adipose tissue. Surprisingly, a number of studies have demonstrated hyperactivity and overexpression of FAS (oncogenic antigen-519) in a biologically aggressive subset of human breast carcinomas, suggesting that FAS-dependent neoplastic lipogenesis is unresponsive to nutritional regulation. We have assessed the role of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) on the enzymatic activity and protein expression of tumor-associated FAS in SK-Br3 human breast cancer cells, an experimental paradigm of FAS-overexpressing tumor cells in which FAS enzyme constitutes up to 28%, by weight, of the cytosolic proteins. Of the omega-3 PUFAs tested, alpha-linolenic acid (ALA) dramatically reduced FAS activity in a dose-dependent manner (up to 61%). omega-3 PUFA docosahexaenoic acid (DHA) demonstrated less marked but still significant inhibitory effects on FAS activity (up to 37%), whereas eicosapentaenoic acid (EPA) was not effective. Of the omega-6 fatty acids tested, gamma-linolenic acid (GLA) was the most effective dose-dependent inhibitor of FAS activity, with a greater than 75% FAS activity reduction. Remarkably, omega-6 PUFAs linoleic acid (LA) and arachidonic acid (ARA), suppressors of both hepatic and adipocytic FAS-dependent lipogenesis, had no significant inhibitory effects on the activity of tumor-associated FAS in SK-Br3 breast cancer cells. Western blotting studies showed that down-regulation of FAS protein expression tightly correlated with previously observed inhibition of FAS activity, suggesting that ALA-, DHA-, and GLA-induced changes in FAS activity resulted from effects at the protein level. We investigated whether the FAS inhibitory effect of GLA and omega-3 PUFAs correlated with a cytotoxic effect related to a peroxidative mechanism. Measurement of cell viability by MTT assay indicated a significant cellular toxicity after ALA and GLA exposures. Furthermore, we observed a significant correlation between the ability of PUFAs to repress FAS and cause cell toxicity. In the presence of anti-oxidants (vitamin E), ALA and GLA dramatically lost their ability to inhibit FAS activity. Interestingly, a combination of ALA and GLA was FAS inhibitory in an additive manner, and this FAS repression was only partially reversible by vitamin E. In examining the molecular mechanisms underlying resistance of breast cancer-associated FAS to normal dietary fatty acid-induced suppression, a dramatic decrease of FAS accumulation was found after exposure of SK-Br3 cells to mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (MAPK ERK1/2) inhibitor U0126, phosphatidylinositol-3'-kinase (PI-3'K) blocker LY294002, and/or anti-HER-2/neu antibody trastuzumab. Interestingly, a long-term exposure to pharmacological inhibitors of FAS activity cerulenin [(2S,3R) 2,3-epoxy-4-oxo-7E,10E-dodecadienamide] or C75 also resulted in a significant reduction of FAS accumulation. These data indicate that: a) GLA- and omega-3 PUFA-induced repression of tumor-associated FAS may result, at least in part, from a non-specific cytotoxic effect due to peroxidative mechanisms; b) alternatively, GLA and omega-3 PUFAs have a suppressive effect on FAS expression and activity that can result in the accumulation of toxic fluxes of the FAS substrate malonyl-CoA; c) GLA- and/or omega-3 PUFA-induced repression of tumor-associated FAS may represent a novel mechanism of PUFA-induced cytotoxicity clinically useful against breast carcinomas carrying overexpression of FAS enzyme; d) fundamental differences in the ability of FAS gene to respond to normal fatty acid's regulatory actions in lipogenic tissues may account for the observed extremely high levels of FAS in breast carcinoma; and e) FAS overexpression in SK-Br3 breast cancer cells is driven by increases in HER-2/neu signaling, acting in major part through a constitutive downstream art through a constitutive downstream activation of the MAPK ERK1/2 and PI-3'K/AKT transduction cascades.