Influences of dietary sodium on functional taste receptor development: a sensitive period.
Restriction of maternal dietary sodium on or before embryonic day 8 reduced taste responses of the chorda tympani nerve to sodium chloride in the offspring. The response attenuation was substantial; responses to sodium chloride in the offspring of deprived rats were approximately 40 percent of those in control animals. Instituting the low sodium diet at embryonic day 10 or later did not produce functional changes. Thus, a sensitive period for the gustatory system exists, and the abrupt transition from maximal environmental susceptibility to no susceptibility occurs during a 2-day prenatal period. Moreover, events important in determining the developmental fate of taste membrane components occur before the initial formation of taste buds.


[The new international guidelines for cardiopulmonary resuscitation and emergency cardiovascular care].
Recently the American Heart Association and the European Resuscitation Council published new guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. These new guidelines are the result of extensive review of the scientific literature in this field by The International Liason Committee on Resuscitation. There are some important changes in the new guidelines with a major emphasis on the importance of basic life support, especially chest compressions. The guidelines also promote early defibrillation while the role of pharmacologic therapy during cardiopulmonary resuscitation is not as clear. This article discusses the highlights of the new guidelines.


Accumulation of zinc in human atherosclerotic lesions correlates with calcium levels but does not protect against protein oxidation.
Oxidized lipids and proteins, as well as decreased antioxidant levels, have been detected in human atherosclerotic lesions, with oxidation catalyzed by iron and copper postulated to contribute to lesion development. Zinc has been postulated to displace iron from critical sites and thereby protect against damage. In this study, metal ion and protein oxidation levels were quantified in human carotid and abdominal artery specimens containing early-to-advanced lesions, to determine whether zinc concentrations correlate inversely with iron levels and protein oxidation. Metal ions were quantified by EPR and inductively coupled plasma mass spectroscopy. Native and oxidized protein side-chains were quantified by high-performance liquid chromatography. Elevated levels of zinc ( approximately 6-fold) were detected in advanced lesions compared to healthy tissue or early lesions. Zinc did not correlate negatively with iron or copper levels suggesting that zinc does not displace these metal ions. Highly significant positive correlations (P<0.005) were detected between zinc and calcium levels. Zinc did not correlate with low iron levels and reduced protein oxidation. These data indicate that zinc does not prevent protein oxidation in advanced lesions. The reported protective effect of zinc accumulation is proposed to be associated with lesion calcification.


The clinical spectrum of malformations of cortical development.
Malformations of cortical development (MCD) usually manifest in childhood with epilepsy, developmental delay and focal neurological abnormalities. To evaluate the presentation and severity of epilepsy in the different types of MCD. We evaluated the first 100 consecutive patients with a neuroimaging diagnosis of MCD. They were identified among all the high resolution magnetic resonance imaging exams performed at our service between 1997 and 2001. The causes of referral were diverse, according to the routine of the neurology outpatient clinic. After magnetic resonance imaging diagnosis of the subtype of MCD a detailed clinical assessment was performed. There were 55 females and 45 males, with ages ranging from five months to 71 years old (mean=15.2 years). Seventy-seven patients presented with epilepsy. Sixty-one had partial epileptic syndromes, 13 secondary generalized syndromes, and in three, the type of epileptic syndrome could not be established. Epilepsy was less frequent in patients with the MCD subtypes of polymicrogyria and schizencephaly (p<0.001). Patients with schizencephaly and polymicrogyria had their seizures more easily controlled by antiepileptic drugs (p<0.001). That the frequency of epilepsy is lower and seizures are more easily controlled in the setting of polymicrogyria and schizencephaly. Patients with MCD frequently present with secondary generalized epilepsy early in childhood.


Intimal dissection following percutaneous transluminal carotid angioplasty for fibromuscular dysplasia.
Fibromuscular dysplasia (FMD) is an unusual form of segmental arteriopathy and may affect the internal carotid artery (ICA). We report a case of carotid FMD in which percutaneous transluminal angioplasty (PTA) was complicated by an intimal tear and required surgical exploration. PTA is a useful form of treatment, but there is a risk of intimal dissection. If this occurs, it may be necessary to excise the intimal flap surgically.


Inter-laboratory study of short time exposure (STE) test for predicting eye irritation potential of chemicals and correspondence to globally harmonized system (GHS) classification.
Short time exposure (STE) test using rabbit corneal cell line (SIRC) cells was developed as an alternative eye irritation test. STE test uses relative viability as the endpoint after cells are exposed to the test material at constant concentrations for 5 min. In this inter-laboratory study with 3 laboratories, 44 chemicals with a wide range of classes were evaluated for the transferability, between-lab reproducibility and predictive capacity of the STE test as an alternative eye irritation test. Globally harmonized system (GHS) classification based on Draize eye irritation test data was used as the comparative in vivo data. Transferability was assessed using standard chemicals (sodium lauryl sulfate, calcium thioglycolate, and Tween 80) and the coefficient variations (CVs) of relative viabilities between 3 labs were less than 0.13. The irritation category (Irritant or Non irritant) at each test concentration (5% and 0.05%) in STE test was the same in 3 laboratories for all 44 tested chemicals. The predictive capacity irritation category classification between STE test and GHS were compared, and a good correlation was confirmed (accuracy was 90.9% at all laboratories). In addition, the STE rankings of 1, 2, and 3 classified by the prediction model (PM) based on the relative viability at two concentrations (5% and 0.05%) were highly correlated with the GHS ranks of non-irritant, category 1, and category 2, respectively (accuracy was 75.0% at all laboratories). These results suggest that the STE test possessed easy transferability, reproducibility, good predictive performance.


Biomechanical variables associated with Achilles tendinopathy in runners.
The aim of this study was to investigate the kinetics, kinematics and muscle activity in runners with Achilles tendinopathy. Case-control study. Biomechanics laboratory. 21 runners free from injury and 21 runners with Achilles tendinopathy performed 10 running trials with standardised running shoes. Injured runners were diagnosed clinically according to established diagnostic criteria. Uninjured runners had been injury-free for at least 2 years. During each trial, kinetic and lower limb kinematic data were measured using a strain gauge force plate and six infrared cameras respectively. Electromyographic (EMG) data from six muscles (tibialis anterior (TA), peroneus longus (PE), lateral gastrocnemius (LG), rectus femoris (RF), biceps femoris (BF) and gluteus medius (GM)) were measured with a telemetric EMG system. Knee range of motion (heel strike to midstance) was significantly lower in injured runners than in uninjured runners. Similarly, preactivation (integrated EMG (IEMG) in 100 ms before heel strike) of TA was lower for injured runners than uninjured runners. RF and GM IEMG activity 100 ms after heel strike was also lower in the injured group. However, impact forces were not different between the two groups. Altered knee kinematics and reduced muscle activity are associated with Achilles tendinopathy in runners. Rehabilitation exercises or other mechanisms (e.g. footwear) that affect kinematics and muscle activity may therefore be beneficial in the treatment of runners with Achilles tendinopathy.


Latest Quaternary palaeoceanographic change in the eastern North Atlantic based upon a dinoflagellate cyst event ecostratigraphy.
The analyses of dinoflagellate cyst records, from the latest Quaternary sediments recovered from DSDP Core 610A taken on the Feni Ridge in the southern Rockall Trough, and part of core MD01-2461 on the continental margin of the Porcupine Seabight in the eastern North Atlantic Ocean, has provided evidence for significant oceanographic change encompassing the Last Glacial Maximum (LGM) and part of the Holocene. This together with other published records has led to a regional evaluation of oceanographic change in the eastern North Atlantic over the past 68 ka, based upon a distinctive dinoflagellate event ecostratigraphy. These changes reflect changes in the surface waters of the North Atlantic Current (NAC), and perhaps the deeper thermohaline Atlantic Meridional Overturning Circulation (AMOC), driving fundamental regime changes within the phytoplanktonic communities. Three distinctive dinoflagellate cyst associations based upon both factor and cluster analyses have been recognised. Associations characterised by Bitectatodinium tepikiense (between 61.1 ± 6.2 to 13.4 ± 1.1 ka BP), Nematosphaeropsis labyrinthus (between 10.5 ± 0.3 and 11.45 ± 0.8 ka. BP), and the cyst of Protoceratium reticulatum (between 8.5 ± 0.9 and 5.2 ± 1.3 ka. BP) indicate major change within the eastern North Atlantic oceanography. The transitions between these changes occur over a relatively short time span (c.1.5 ka), given our sampling resolution, and have the potential to be incorporated into an event stratigraphy through the latest Quaternary as recommended by the INTIMATE (INTegrating Ice core, MArine and TErrestrial records) group. The inclusion of a dinoflagellate cyst event stratigraphy would highlight changes within the phytoplankton of the North Atlantic Ocean as a fully glacial world changed to our present interglacial.


Association between celiac disease and chronic hepatitis C.
Celiac disease is characterized by a gluten-induced damage of the small bowel in sensitive individuals that may cause malabsorption. Non-intestinal inflammatory diseases may trigger immunologic gluten intolerance in susceptible people and the HCV virus may be considered as a suitable candidate. Interferon therapy could precipitate symptom onset in subjects with silent celiac disease. In fact, symptoms such as diarrhea, anemia, and weight loss may occur during interferon therapy and are associated with serological positivity of anti-tranglutaminase antibodies. To date, considering the available literature data, it is very difficult to support a firm association between HCV chronic hepatitis and celiac disease. Thus, such a serological screening in HCV patients before starting interferon therapy should not be recommended. However, serology for celiac disease must be considered in patients who develop diarrhea and/or weight loss during such therapy.


1990-2000: progress in determining high blood pressure genes.
This article attempts to summarise the genetic research that has taken place during the past decade to determine the identity of genes causing high blood pressure. Candidate gene studies and genome-wide scanning have been the methods primarily employed, and studies have been performed in both experimental models (rats and mice) and human volunteers (sibling-pairs and case-control). Key studies from the past 10 years are discussed, in addition to the congenic strains. Genome-wide scans and candidate gene studies in both rat and man have generated many chromosomal regions and loci involved in blood pressure regulation. However, much work is still required to fine map the large chromosomal regions found in the genome-wide scans and to isolate variants in candidate genes and prove that they are disease-causing. It is anticipated that within the next 5 to 10 years at least one blood pressure susceptibility gene will be identified in rat and possibly some in man. It is hoped that the identification of genes controlling blood pressure will enable investigators to determine physiological/biochemical pathways defective in hypertensive patients. This information may then be utilised to identify specific hypertensive phenotypes, to tailor therapy appropriately for patients and hopefully to develop novel therapeutic agents for hypertension.


Isolation of pulmonary artery smooth muscle cells from neonatal mice.
Pulmonary hypertension is a significant cause of morbidity and mortality in infants. Historically, there has been significant study of the signaling pathways involved in vascular smooth muscle contraction in PASMC from fetal sheep. While sheep make an excellent model of term pulmonary hypertension, they are very expensive and lack the advantage of genetic manipulation found in mice. Conversely, the inability to isolate PASMC from mice was a significant limitation of that system. Here we described the isolation of primary cultures of mouse PASMC from P7, P14, and P21 mice using a variation of the previously described technique of Marshall et al. that was previously used to isolate rat PASMC. These murine PASMC represent a novel tool for the study of signaling pathways in the neonatal period. Briefly, a slurry of 0.5% (w/v) agarose + 0.5% iron particles in M199 media is infused into the pulmonary vascular bed via the right ventricle (RV). The iron particles are 0.2 μM in diameter and cannot pass through the pulmonary capillary bed. Thus, the iron lodges in the small pulmonary arteries (PA). The lungs are inflated with agarose, removed and dissociated. The iron-containing vessels are pulled down with a magnet. After collagenase (80 U/ml) treatment and further dissociation, the vessels are put into a tissue culture dish in M199 media containing 20% fetal bovine serum (FBS), and antibiotics (M199 complete media) to allow cell migration onto the culture dish. This initial plate of cells is a 50-50 mixture of fibroblasts and PASMC. Thus, the pull down procedure is repeated multiple times to achieve a more pure PASMC population and remove any residual iron. Smooth muscle cell identity is confirmed by immunostaining for smooth muscle myosin and desmin.


Constrained randomization and multivariate effect projections improve information extraction and biomarker pattern discovery in metabolomics studies involving dependent samples.
Analytical drift is a major source of bias in mass spectrometry based metabolomics confounding interpretation and biomarker detection. So far, standard protocols for sample and data analysis have not been able to fully resolve this. We present a combined approach for minimizing the influence of analytical drift on multivariate comparisons of matched or dependent samples in mass spectrometry based metabolomics studies. The approach is building on a randomization procedure for sample run order, constrained to independent randomizations between and within dependent sample pairs (e.g. pre/post intervention). This is followed by a novel multivariate statistical analysis strategy allowing paired or dependent analyses of individual effects named OPLS-effect projections (OPLS-EP). We show, using simulated data that OPLS-EP gives improved interpretation over existing methods and that constrained randomization of sample run order in combination with an appropriate dependent statistical test increase the accuracy and sensitivity and decrease the false omission rate in biomarker detection. We verify these findings and prove the strength of the suggested approach in a clinical data set consisting of LC/MS data of blood plasma samples from patients before and after radical prostatectomy. Here OPLS-EP compared to traditional (independent) OPLS-discriminant analysis (OPLS-DA) on constrained randomized data gives a less complex model (3 versus 5 components) as well a higher predictive ability (Q2 = 0.80 versus Q2 = 0.55). We explain this by showing that paired statistical analysis detects 37 unique significant metabolites that were masked for the independent test due to bias, including analytical drift and inter-individual variation.


Failed Disruption of Tick Feeding, Viability, and Molting after Immunization of Mice and Sheep with Recombinant Ixodes ricinus Salivary Proteins IrSPI and IrLip1.
To identify potential vaccine candidates against Ixodes ricinus and tick-borne pathogen transmission, we have previously sequenced the salivary gland transcriptomes of female ticks infected or not with Bartonella henselae. The hypothesized potential of both IrSPI (I. ricinus serine protease inhibitor) and IrLip1 (I. ricinus lipocalin 1) as protective antigens decreasing tick feeding and/or the transmission of tick-borne pathogens was based on their presumed involvement in dampening the host immune response to tick feeding. Vaccine endpoints included tick larval and nymphal mortality, feeding, and molting in mice and sheep. Whether the antigens were administered individually or in combination, the vaccination of mice or sheep elicited a potent antigen-specific antibody response. However, and contrary to our expectations, vaccination failed to afford protection against the infestation of mice and sheep by I. ricinus nymphs and larvae, respectively. Rather, vaccination with IrSPI and IrLip1 appeared to enhance tick engorgement and molting and decrease tick mortality. To the best of our knowledge, these observations represent the first report of induction of vaccine-mediated enhancement in relation to anti-tick vaccination.


An evaluation of physicians' engagement of children with asthma in treatment-related discussions.
Our objectives were to examine whether providers engage children with asthma in treatment-related discussions at the level children prefer (engagement concordance) and to determine whether engagement concordance is related to child, caregiver, and provider characteristics. Children with asthma (n = 296) aged 8-16 years were recruited at five pediatric practices in North Carolina. Using audiotaped medical visit transcripts, we documented the number of treatment-related questions the providers asked the children. Children reported their preferred level of provider engagement. A logistic generalized estimating equation was used to determine which variables predicted engagement concordance. Most children (96.6%) wanted to be involved in treatment-related discussions. One-third of the providers did not ask children any treatment-related questions. Only 36.1% of provider-child dyads were concordant. Most discordant dyads were under-engaged (83.1%). Better engagement concordance was observed among older children (odds ratio (OR) = 1.19, 95% confidence interval (CI) (1.07, 1.33)), male children (OR = 1.67, 95% CI (1.03, 2.70)), and among providers with fewer years in practice (OR = .97, 95% CI (.94, .99)). Providers engaged in treatment-related discussions with younger children and females less frequently than these children preferred. Providers should ask children how much they want to be involved in treatment-related discussions and then attempt to engage children at the level they prefer.


[HBME-1 and cyclin D1 as diagnostic markers for follicular thyroid carcinoma].
Follicular carcinomas account for 15% of thyroid malignant tumors. The differential diagnosis between adenoma and minimally invasive follicular carcinoma is difficult and lacks reproducibility especially in frozen sections. As the diagnosis depends on finding foci of capsular invasion, multiple sections must be examined. Numerous immunohistochemical markers have been studied for determining malignancy. To assess the efficacy of HBME-1 and Cyclin-D1 as diagnostic markers for follicular thyroid carcinoma. We evaluated retrospectively 21 thyroidectomy specimens of 18 women and 3 men with diagnosis of adenoma or follicular carcinomas, both by hematoxylin and eosin stain and by immunohistochemistry using the avidin biotin method for the markers HBME-1 and Cyclin D1. The sensitivity and specificity of HBME-1 for the diagnosis of follicular thyroid carcinoma, were 88.9% and 100%, respectively whereas for Cyclin D1 the sensitivity and specificity were 22.2% and 100%, respectively. There were no false positive cases. HBME-1 has excellent sensitivity and specificity for the diagnosis of follicular carcinoma.


Pliocene reversal of late Neogene aridification.
The Pliocene epoch (5.3-2.6 Ma) represents the most recent geological interval in which global temperatures were several degrees warmer than today and is therefore considered our best analog for a future anthropogenic greenhouse world. However, our understanding of Pliocene climates is limited by poor age control on existing terrestrial climate archives, especially in the Southern Hemisphere, and by persistent disagreement between paleo-data and models concerning the magnitude of regional warming and/or wetting that occurred in response to increased greenhouse forcing. To address these problems, here we document the evolution of Southern Hemisphere hydroclimate from the latest Miocene to the middle Pliocene using radiometrically-dated fossil pollen records preserved in speleothems from semiarid southern Australia. These data reveal an abrupt onset of warm and wet climates early within the Pliocene, driving complete biome turnover. Pliocene warmth thus clearly represents a discrete interval which reversed a long-term trend of late Neogene cooling and aridification, rather than being simply the most recent period of greater-than-modern warmth within a continuously cooling trajectory. These findings demonstrate the importance of high-resolution chronologies to accompany paleoclimate data and also highlight the question of what initiated the sustained interval of Pliocene warmth.


The impact of child and adolescent obesity treatment interventions on physical activity: a systematic review.
Efforts to treat obesity in childhood and adolescence would benefit from a greater understanding of evidence-based strategies to modify physical activity behaviour. A systematic review was conducted to examine the impact of child and adolescent obesity treatment interventions on physical activity. Studies included were randomized controlled trials or controlled trials, with overweight and obese youth (aged < 18 years), which reported statistical analysis of free-living physical activity at pretreatment and post-treatment. Two independent reviewers assessed each study for methodological quality. Seventeen child and three adolescent studies were retrieved, half of which were conducted in the USA. Studies were characterized by small samples of limited cultural and economic diversity. Fifteen studies reported an increase in at least one physical activity outcome at post-test or follow-up. Overall, study quality was rated as low (child median score = 3/10, range = 0-9; adolescent median score = 3/10, range = 2-5) with three child studies classified as high quality (>or=6/10). Research evaluating the effect of child and adolescent obesity treatment trials on physical activity is limited in both quantity and quality. Studies testing innovative, theoretically driven treatment approaches that use robust methodologies are required to better understand generalizable approaches for promoting physical activity participation among obese youth.


COUGER--co-factors associated with uniquely-bound genomic regions.
Most transcription factors (TFs) belong to protein families that share a common DNA binding domain and have very similar DNA binding preferences. However, many paralogous TFs (i.e. members of the same TF family) perform different regulatory functions and interact with different genomic regions in the cell. A potential mechanism for achieving this differential in vivo specificity is through interactions with protein co-factors. Computational tools for studying the genomic binding profiles of paralogous TFs and identifying their putative co-factors are currently lacking. Here, we present an interactive web implementation of COUGER, a classification-based framework for identifying protein co-factors that might provide specificity to paralogous TFs. COUGER takes as input two sets of genomic regions bound by paralogous TFs, and it identifies a small set of putative co-factors that best distinguish the two sets of sequences. To achieve this task, COUGER uses a classification approach, with features that reflect the DNA-binding specificities of the putative co-factors. The identified co-factors are presented in a user-friendly output page, together with information that allows the user to understand and to explore the contributions of individual co-factor features. COUGER can be run as a stand-alone tool or through a web interface: http://couger.oit.duke.edu.


Does family matter to HIV-positive men who have sex with men?
Most studies have indicated that friends or families of choice provide more support to HIV-positive men who have sex with men (MSM) than members of the family of origin. The creation of families of choice by MSM has been viewed as a means of creating a support system in the absence of traditional family. The purpose of this study is to explore if HIV-positive MSM believe family of origin is important. Data were drawn from a qualitative study of HIV disclosure to family. Responses to the question, "How important is family to you?" are explored. Results suggest that for many HIV-positive MSM, relationships with family of origin are very important. While not definitive, data to be presented are provocative and challenge notions of the significance of family of origin to marginalized populations.


Lipids of pathogenic Mycobacteria: contributions to virulence and host immune suppression.
Mycobacteria are characterized by a complex cell wall, the lipid nature of which confers to the bacilli resistance to drying, acid or alkaline conditions, and to chemical disinfectants and therapeutic agents. Pathogenic species, such as Mycobacterium tuberculosis, M. leprae and M. ulcerans, have evolved various strategies to establish residence in their hosts and provoke long-term infections. There is mounting evidence that the unique lipids composing their envelopes, strategically located at the host-pathogen interface, contribute to their escape from immune surveillance. Here, the chemical structure, host cell receptors and biological actions of this emerging class of mycobacterial virulence factors are reviewed.


Mindfulness, self-compassion, and empathy among health care professionals: a review of the literature.
The relationship between mindfulness and self-compassion is explored in the health care literature, with a corollary emphasis on reducing stress in health care workers and providing compassionate patient care. Health care professionals are particularly vulnerable to stress overload and compassion fatigue due to an emotionally exhausting environment. Compassion fatigue among caregivers in turn has been associated with less effective delivery of care. Having compassion for others entails self-compassion. In Kristin Neff's research, self-compassion includes self-kindness, a sense of common humanity, and mindfulness. Both mindfulness and self-compassion involve promoting an attitude of curiosity and nonjudgment towards one's experiences. Research suggests that mindfulness interventions, particularly those with an added lovingkindness component, have the potential to increase self-compassion among health care workers. Enhancing focus on developing self-compassion using MBSR and other mindfulness interventions for health care workers holds promise for reducing perceived stress and increasing effectiveness of clinical care.


Abnormal uterine bleeding: a management algorithm.
Abnormal uterine bleeding is a common problem, and its management can be complex. Because of this complexity, concise guidelines have been difficult to develop. We constructed a concise but comprehensive algorithm for the management of abnormal uterine bleeding between menarche and menopause that was based on a systematic review of the literature as well as the actual management of patients seen in a gynecology clinic. We started by drafting an algorithm that was based on a MEDLINE search for relevant reviews and original research. We compared this algorithm to the actual care provided to a random sample of 100 women with abnormal bleeding who were seen in a university gynecology clinic. Discrepancies between the algorithm and actual care were discussed during audiotaped meetings among the 4 investigators (2 family physicians and 2 gynecologists). The audiotapes were used to revise the algorithm. After 3 iterations of this process (total of 300 patients), we agreed on a final algorithm that generally followed the practices we observed, while maintaining consistency with the evidence. In clinic, the gynecologists categorized the patient's bleeding pattern into 1 of 4 types: irregular bleeding, heavy but regular bleeding (menorrhagia), severe acute bleeding, and abnormal bleeding associated with a contraceptive method. Subsequent management involved both diagnostic and treatment interventions, which often occurred simultaneously. The algorithm in this article is designed to help primary care physicians manage abnormal uterine bleeding using strategies that are consistent with the evidence as well as the actual practice of gynecologists.


Cross-Sectional Analysis of the Correlation Between Daily Nutrient Intake Assessed by 7-Day Food Records and Biomarkers of Dietary Intake Among Participants of the NU-AGE Study.
Methods for measuring diet composition and quantifying nutrient intake with sufficient validity are essential to study the association between nutrition and health outcomes and risk of diseases. 7-day food records provides a quantification of food actually and currently consumed and is interesting for its use in intervention studies to monitor diet in a short-term period and to guide participants toward changing their intakes. The objective of this study is to analyze the correlation/association between the daily intake of selected nutrients (collected by a 7-day food records plus a mineral/vitamin supplementation questionnaire) and estimates of energy expenditure as well as blood and urine biomarkers of dietary intakes in 1,140 healthy elderly subjects (65-79 years) at baseline of the NU-AGE intervention study (NCT01754012, clinicaltrials.gov). The results show that: the daily intake of energy correlated significantly with predicted total energy expenditure (pTEE) (ρ = 0.459, p < 0.001, and q < 0.001); protein intake correlated significantly with the ratio of 24 h urinary urea to creatinine excretion (ρ = 0.143 for total protein intake, ρ = 0.296 for animal protein intake, and ρ = 0.359 for protein intake/body weight, p < 0.001 and q < 0.001 for each correlation); vitamin B12 and folate intakes correlated significantly with their serum concentrations (ρ = 0.151 and ρ = 0.363, respectively; p < 0.001 and q < 0.001 for each correlation); sodium and potassium intakes correlated significantly with their 24 h urinary excretion (ρ = 0.298 and ρ = 0.123, respectively; p < 0.001 and q < 0.001 for each correlation); vitamin B12 and folate intakes were negatively associated with plasma homocysteine measure (p = 0.001 and p = 0.004, respectively); stratifying subjects by gender, the correlations between energy intake and pTEE and between potassium intake and its 24 h urinary excretion lost their significance in women. Even if the plasma and urinary levels of these nutrients depend on several factors, the significant correlations between daily reported intake of nutrients (protein, vitamin B12, folate, and sodium) and their blood/urinary markers confirmed that the 7-day food records (plus a supplementation questionnaire) provides reliable data to evaluate short-term current dietary intake in European elderly subjects and it can be exploited to guide and monitor NU-AGE participants through the shift of their diet according NU-AGE recommendations.


Pediatric Resuscitation: Evaluation of a Clinical Curriculum.
To assess the impact of a 6-hour pediatric resuscitation curriculum on the comfort levels of resident physicians' evaluation and treatment of critically ill pediatric patients. An evaluation instrument assessed resident comfort levels, measured on a seven digit Likert scale ranging from significantly uncomfortable to significantly comfortable, in 13 areas of pediatric resuscitation. To complete the curriculum, residents had to demonstrate proficiency in knowledge and procedural skills during mock resuscitation scenarios and on both written and oral examinations. Thirty-one residents participated in the study: 51.6% were pediatric, 12.9% were medicine/pediatric and 35.5% were emergency medicine residents. Participants in the curriculum had little previous experience with pediatric resuscitation (83% had been involved in five or fewer pediatric resuscitations). In all 13 areas of pediatric resuscitation tested, residents reported improvement in comfort levels following the course (p<0.002; Wilcoxon Signed Rank Tests). The most significant changes were observed for the following items: resuscitation of pulseless arrest, performance of cardioversion and defibrillation, performance of intraosseous needle insertion, and drug selection and dosing for rapid sequence intubation. Fewer than 48% of learners rated themselves as comfortable in these areas prior to training, but after completion, more than 80% rated themselves in the comfortable range. All residents but one received passing scores on their written examinations (97%). During the mock resuscitation scenarios and oral examination, 100% of the residents were assessed to have 'completely' met the learning objectives and critical actions Conclusion: Implementation of a pediatric resuscitation curriculum improves pediatric and emergency medicine residents' comfort with the evaluation and treatment of critically ill pediatric patients. This curriculum can be used in residency training to document the acquisition of core competencies, knowledge and procedural skills needed for the evaluation and treatment of the critically ill child. The results reported in this study support using this model of instructional design to implement educational strategies, which will meet the requirements of graduate education.


Tunable slow dynamics in a new class of soft colloids.
By means of extensive simulations, we investigate concentrated solutions of globular single-chain nanoparticles (SCNPs), an emergent class of synthetic soft nano-objects. By increasing the concentration, the SCNPs show flattening, and even reentrant behaviour, in the density dependence of their structural and dynamic correlations, as well as a soft caging regime and weak dynamic heterogeneity. The latter is confirmed by validation of the Stokes-Einstein relation up to concentrations far beyond the overlap density. Therefore SCNPs arise as a new class of soft colloids, exhibiting slow dynamics and actualizing in a real system the structural and dynamic anomalies proposed by models of ultrasoft particles. Quantitative differences in the dynamic behaviour depend on the SCNP deformability, which can be tuned through the degree of internal cross-linking.


Congenital nephrotic syndrome in mice lacking CD2-associated protein.
CD2-associated protein (CD2AP) is an 80-kilodalton protein that is critical for stabilizing contacts between T cells and antigen-presenting cells. In CD2AP-deficient mice, immune function was compromised, but the mice died at 6 to 7 weeks of age from renal failure. In the kidney, CD2AP was expressed primarily in glomerular epithelial cells. Knockout mice exhibited defects in epithelial cell foot processes, accompanied by mesangial cell hyperplasia and extracellular matrix deposition. Supporting a role for CD2AP in the specialized cell junction known as the slit diaphragm, CD2AP associated with nephrin, the primary component of the slit diaphragm.


Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging.
The hippocampus of the rat loses neurons with age, a loss which may eventuate in some of the functional impairments typical of senescence. Cumulative exposure to corticosterone (CORT) over the lifespan may be a cause of this neuronal loss, as it is prevented by adrenalectomy at mid-age. In this study, we demonstrate that prolonged exposure to CORT accelerates the process of cell loss. Rats were injected daily with sufficient CORT to produce prolonged elevations of circulating titers within the high physiological range. Animals treated for 3 months (chronic subjects) resembled aged rats in a number of ways. First, both groups had extensive and persistent depletions of CORT receptors in the hippocampus; in the case of chronic rats, no recovery of receptor concentrations occurred 4 months after the end of steroid treatment. Second, autoradiographic analysis revealed that the receptor depletion was due, in part, to a loss of CORT-concentrating cells, especially in the CA3 cell field. Remaining cells bound significantly less [3H]corticosterone than did those of control rats. Finally, analysis of size distributions of hippocampal cell bodies indicated that chronic subjects lost neurons of the same size as those lost in the aged hippocampus. Furthermore, chronic subjects also had increased numbers of small, darkly staining cells of CA3; these corresponded in size to the dark glia whose numbers increase in the aged hippocampus, and which are thought to infiltrate in response to neuronal damage or destruction. Thus, this study supports the hypothesis that cumulative exposure to CORT over the lifespan may contribute to age-related loss of neurons in the hippocampus, and that prolonged stress or exposure to CORT accelerates this process.


Effects of McKenzie exercise, Kinesio taping, and myofascial release on the forward head posture.
[Purpose] This study aimed to investigate the effects of McKenzie exercise, Kinesio taping, and myofascial release (MFR) on forward head posture (FHP). [Participants and Methods] Twenty-eight individuals with an FHP were enrolled. participants were randomly assigned to one of three groups: Group A, Group B and Group C. Group A underwent McKenzie exercise and MFR. Group B underwent McKenzie exercise and Kinesio taping. Group C underwent McKenzie exercise, MFR, and Kinesio taping. Interventions for all three groups were provided three times per week for four weeks. The acromion and tragus of ear (A-T length), craniovertebral angle (CVA), Cranial rotation angle (CRA), and neck disability index (NDI) were measured. [Results] The A-T length significantly differed after intervention in all three groups. CVA only significantly differed after intervention in group C. All three groups showed an increase in CRA after intervention; however, these increases were not statistically significant. [Conclusion] Considering these results, these three types of exercise may be recommended as effective exercises to improve posture in adults with FHP.


Characterization of FRO1, a pea ferric-chelate reductase involved in root iron acquisition.
To acquire iron, many plant species reduce soil Fe(III) to Fe(II) by Fe(III)-chelate reductases embedded in the plasma membrane of root epidermal cells. The reduced product is then taken up by Fe(II) transporter proteins. These activities are induced under Fe deficiency. We describe here the FRO1 gene from pea (Pisum sativum), which encodes an Fe(III)-chelate reductase. Consistent with this proposed role, FRO1 shows similarity to other oxidoreductase proteins, and expression of FRO1 in yeast conferred increased Fe(III)-chelate reductase activity. Furthermore, FRO1 mRNA levels in plants correlated with Fe(III)-chelate reductase activity. Sites of FRO1 expression in roots, leaves, and nodules were determined. FRO1 mRNA was detected throughout the root, but was most abundant in the outer epidermal cells. Expression was detected in mesophyll cells in leaves. In root nodules, mRNA was detected in the infection zone and nitrogen-fixing region. These results indicate that FRO1 acts in root Fe uptake and they suggest a role in Fe distribution throughout the plant. Characterization of FRO1 has also provided new insights into the regulation of Fe uptake. FRO1 expression and reductase activity was detected only in Fe-deficient roots of Sparkle, whereas both were constitutive in brz and dgl, two mutants with incorrectly regulated Fe accumulation. In contrast, FRO1 expression was responsive to Fe status in shoots of all three plant lines. These results indicate differential regulation of FRO1 in roots and shoots, and improper FRO1 regulation in response to a shoot-derived signal of iron status in the roots of the brz and dgl mutants.


Bacopa monnieri Supplements Offset Paraquat-Induced Behavioral Phenotype and Brain Oxidative Pathways in Mice.
Parkinson's Disease (PD) is characterized by alterations in cerebellum and basal ganglia functioning with corresponding motor deficits and neuropsychiatric symptoms. Involvement of oxidative dysfunction has been implicated for the progression of PD, and environmental neurotoxin exposure could influence such behavior and psychiatric pathology. Assessing dietary supplementation strategies with naturally occurring phytochemicals to reduce behavioral anomalies associated with neurotoxin exposure would have major clinical importance. The present investigation assessed the influence of Bacopa monneri (BM) on behaviors considered to reflect anxiety-like state and motor function as well as selected biochemical changes in brain regions of mice chronically exposed to ecologically relevant herbicide, paraquat (PQ). Male mice (4-week old, Swiss) were daily provided with oral supplements of standardized BM extract (200 mg/kg body weight/day; 3 weeks) and PQ (10 mg/kg, i.p. three times a week; 3 weeks). We found that BM supplementation significantly reversed the PQ-induced reduction of exploratory behavior, gait abnormalities (stride length and mismatch of paw placement) and motor impairment (rotarod performance). In a separate study, BM administration prevented the reduction in dopamine levels and reversed cholinergic activity in brain regions important for motor (striatum) pathology. Further, in mitochondria, PQ-induced decrease in succinate dehydrogenase (SDH) activity and energy charge (MTT reduction), was restored with BM supplementation. These findings suggest that BM supplementation mitigates paraquat-induced behavioral deficits and brain oxidative stress in mice. However, further investigations would enable us to identify specific molecular mechanism by which BM influences behavioural pathology.


Education influences the association between genetic variants and refractive error: a meta-analysis of five Singapore studies.
Refractive error is a complex ocular trait governed by both genetic and environmental factors and possibly their interplay. Thus far, data on the interaction between genetic variants and environmental risk factors for refractive errors are largely lacking. By using findings from recent genome-wide association studies, we investigated whether the main environmental factor, education, modifies the effect of 40 single nucleotide polymorphisms on refractive error among 8461 adults from five studies including ethnic Chinese, Malay and Indian residents of Singapore. Three genetic loci SHISA6-DNAH9, GJD2 and ZMAT4-SFRP1 exhibited a strong association with myopic refractive error in individuals with higher secondary or university education (SHISA6-DNAH9: rs2969180 A allele, β = -0.33 D, P = 3.6 × 10(-6); GJD2: rs524952 A allele, β = -0.31 D, P = 1.68 × 10(-5); ZMAT4-SFRP1: rs2137277 A allele, β = -0.47 D, P = 1.68 × 10(-4)), whereas the association at these loci was non-significant or of borderline significance in those with lower secondary education or below (P for interaction: 3.82 × 10(-3)-4.78 × 10(-4)). The evidence for interaction was strengthened when combining the genetic effects of these three loci (P for interaction = 4.40 × 10(-8)), and significant interactions with education were also observed for axial length and myopia. Our study shows that low level of education may attenuate the effect of risk alleles on myopia. These findings further underline the role of gene-environment interactions in the pathophysiology of myopia.


Efficient miniature circular polarization analyzer design using hybrid spiral plasmonic lens.
The spin dependence of the focusing behavior of a spiral slot plasmonic lens can be utilized for a miniature circular polarization analyzer. However, the azimuthal polarization component of the incident circular polarization does not contribute to surface plasmon excitation and focusing because it is TE polarized with respect to the spiral slot. In this Letter, a hybrid metallic lens that consists of alternating spiral triangle array and spiral slot is designed to improve the plasmonic coupling efficiency. The spiral triangle array is responsible for coupling the azimuthal polarization component into surface plasmon. Numerical studies show that the field enhancement at the focus and power conversion efficiency can be increased by 39.53% and 94.69% compared to that of pure spiral slot plasmonic lens.


Losses and recovery of organic carbon from a seagrass ecosystem following disturbance.
Seagrasses are among the Earth's most efficient and long-term carbon sinks, but coastal development threatens this capacity. We report new evidence that disturbance to seagrass ecosystems causes release of ancient carbon. In a seagrass ecosystem that had been disturbed 50 years ago, we found that soil carbon stocks declined by 72%, which, according to radiocarbon dating, had taken hundreds to thousands of years to accumulate. Disturbed soils harboured different benthic bacterial communities (according to 16S rRNA sequence analysis), with higher proportions of aerobic heterotrophs compared with undisturbed. Fingerprinting of the carbon (via stable isotopes) suggested that the contribution of autochthonous carbon (carbon produced through plant primary production) to the soil carbon pool was less in disturbed areas compared with seagrass and recovered areas. Seagrass areas that had recovered from disturbance had slightly lower (35%) carbon levels than undisturbed, but more than twice as much as the disturbed areas, which is encouraging for restoration efforts. Slow rates of seagrass recovery imply the need to transplant seagrass, rather than waiting for recovery via natural processes. This study empirically demonstrates that disturbance to seagrass ecosystems can cause release of ancient carbon, with potentially major global warming consequences.


Modular development of the teleost trunk along the dorsoventral axis and zic1/zic4 as selector genes in the dorsal module.
Teleost fish exhibit remarkable diversity in morphology, such as fins and coloration, particularly on the dorsal side. These structures are evolutionary adaptive because their back is highly visible to other individuals. However, owing to the late phenotypic appearance (from larva to adult) and lack of appropriate mutants, the genetic mechanisms that regulate these dorsoventrally asymmetric external patterns are largely unknown. To address this, we have analyzed the spontaneous medaka mutant Double anal fin (Da), which exhibits a mirror-image duplication of the ventral half across the lateral midline from larva to adult. Da is an enhancer mutant for zic1 and zic4 in which their expression in dorsal somites is lost. We show that the dorsoventral polarity in Da somites is lost and then demonstrate using transplantation techniques that somites and their derived tissues globally determine the multiple dorsal-specific characteristics of the body (fin morphology and pigmentation) from embryo to adult. Intriguingly, the zic1/zic4 expression in the wild type persists throughout life in the dorsal parts of somite derivatives, i.e. the myotome, dermis and vertebrae, forming a broad dorsal domain in the trunk. Comparative analysis further implies a central role for zic1/zic4 in morphological diversification of the teleost body. Taken together, we propose that the teleost trunk consists of dorsal/ventral developmental modules and that zic1/zic4 in somites function as selector genes in the dorsal module to regulate multiple dorsal morphologies.


Neutrophil extracellular trap formation is associated with IL-1β and autophagy-related signaling in gout.
Gout is a prevalent inflammatory arthritis affecting 1-2% of adults characterized by activation of innate immune cells by monosodium urate (MSU) crystals resulting in the secretion of interleukin-1β (IL-1β). Since neutrophils play a major role in gout we sought to determine whether their activation may involve the formation of proinflammatory neutrophil extracellular traps (NETs) in relation to autophagy and IL-1β. Synovial fluid neutrophils from six patients with gout crisis and peripheral blood neutrophils from six patients with acute gout and six control subjects were isolated. MSU crystals, as well as synovial fluid or serum obtained from patients with acute gout, were used for the treatment of control neutrophils. NET formation was assessed using immunofluorescence microscopy. MSU crystals or synovial fluid or serum from patients induced NET formation in control neutrophils. Importantly, NET production was observed in neutrophils isolated from synovial fluid or peripheral blood from patients with acute gout. NETs contained the alarmin high mobility group box 1 (HMGB1) supporting their pro-inflammatory potential. Inhibition of phosphatidylinositol 3-kinase signaling or phagolysosomal fusion prevented NET formation, implicating autophagy in this process. NET formation was driven at least in part by IL-1β as demonstrated by experiments involving IL-1β and its inhibitor anakinra. These findings document for the first time that activation of neutrophils in gout is associated with the formation of proinflammatory NETs and links this process to both autophagy and IL-1β. Modulation of the autophagic machinery may represent an additional therapeutic study in crystalline arthritides.


Relations Between Brain Alterations and Clinical Pain Measures in Chronic Musculoskeletal Pain: A Systematic Review.
Compelling evidence has shown chronic widespread and exaggerated pain experience in chronic musculoskeletal pain (MSKP) conditions. In addition, neuroimaging research has revealed morphological and functional brain alterations in these patients. It is hypothesized that brain alterations play a role in the persistent pain complaints of patients with chronic MSKP. Nevertheless, lack of overview exists regarding the relations between brain alterations and clinical measures of pain. The present systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines, to investigate the relations between structural or functional brain alterations, using magnetic resonance imaging scans, and clinical pain measures in patients with chronic MSKP. PubMed, Web of Science, Cinahl, and Cochrane databases were searched. First, the obtained articles were screened according to title and abstract. Second, the screening was on the basis of full-text. Risk of bias in included studies was investigated according to the modified Newcastle-Ottawa Scale. Twenty studies met the inclusion criteria. Moderate evidence shows that higher pain intensity and pressure pain sensitivity are related to decreased regional gray matter (GM) volume in brain regions encompassing the cingulate cortex, the insula, and the superior frontal and temporal gyrus. Further, some evidence exists that longer disease duration in fibromyalgia is correlated with decreased total GM volume. Yet, inconclusive evidence exists regarding the association of longer disease duration with decreased or increased regional GM volume in other chronic MSKP conditions. Inconclusive evidence was found regarding the direction of the relation of pain intensity and pressure pain sensitivity with microstructural white matter and functional connectivity alterations. In conclusion, preliminary to moderate evidence demonstrates relations between clinical pain measures, and structural and functional connectivity alterations within brain regions involved in somatosensory, affective, and cognitive processing of pain in chronic MSKP. Nevertheless, inconclusive results exist regarding the direction of these relations. Further research is warranted to unravel whether these brain alterations are positively or negatively correlated to clinical pain measures. Structural and functional brain alterations within regions involved in somatosensory, affective, and cognitive pain processing play a crucial role in the persistent pain of chronic MSKP patients. Accordingly, these brain alterations have to be taken into account when assessing and treating patients with chronic MSKP.


The effect of correct and consistent condom use on chlamydial and gonococcal infection among urban adolescents.
To evaluate the relationship between self-reported correct and consistent condom use and chlamydial and gonococcal infection. Cross-sectional study. An urban adolescent health care clinic. Patients A total of 509 adolescent girls tested for Chlamydia trachomatis and Neisseria gonorrhoeae infection by urine nucleic acid amplification tests. Main Outcome Measure Effect of condom use on infection rates of chlamydia and gonorrhea. Consistent condom use was defined as using condoms for every act of vaginal sex and correct use as consistent use without any of the following: beginning sex without a condom, taking it off before finishing sex, flipping it over, condom breakage, or condom slippage. A total of 95% of the participants were African American, with a mean age of 16.6 years. Chlamydia prevalence was 21% (105/509) and gonorrhea prevalence was 7% (36/509). Condom errors were reported by 316 (71%) of 442 participants who had reported using a condom at least once in the previous 3 months. Consistent use was reported by 176 patients (35%); however, both correct and consistent use was reported by only 80 patients (16%). After adjusting for confounders, correct and consistent use was protective for chlamydia (odds ratio, 0.4; 95% confidence interval, 0.2-1.0) and highly protective for gonorrhea (odds ratio, 0.1; 95% confidence interval, 0-0.7). Our findings indicate that assessing both correctness and consistency of use is important for evaluation of condom effectiveness.


Can parasites really reveal environmental impact?
This review assesses the usefulness of parasites as bioindicators of environmental impact. Relevant studies published in the past decade were compiled; factorial meta-analysis demonstrated significant effects and interactions between parasite levels and the presence and concentration of various pollutants and/or environmental stressors. These effects and interactions were also evident in subsets of studies that used different methods such as field surveys or experimental exposure. From this meta-analysis we conclude that parasites are useful bioindicators of environmental impact. Further, by examining aspects of study design, we put forward recommendations for the design of future studies to evaluate anthropogenic impact on host-parasite interactions and increase the efficiency of environmental monitoring programs.


Clinical and serological study of myasthenia gravis in HuBei Province, China.
Ocular and childhood myasthenia gravis (MG) cases seem relatively more common in Oriental than in Caucasian populations, but there have been no comprehensive serological studies on patients from mainland China. 391 unselected patients with MG attending Tongji Hospital in WuHan (the largest hospital in the province of HuBei, China) were studied during a 15-month period; most had already received treatment for their condition. The male to female ratio was 0.8. 50% of the patients were children (<15 years), and age at onset showed a single peak at between 5 and 10 years of age. 64% of the children and 66% of the adults were positive for acetylcholine receptor (AChR) antibodies but the antibody titres were lower than in similar Caucasian studies, although this was partly due to the high incidence of ocular MG. Of the 43 patients with generalised MG without AChR antibodies, only 1 had muscle-specific kinase antibodies (2.5%) and 2 had voltage-gated calcium channel antibodies indicating probable Lambert-Eaton myasthenic syndrome. 75% of the children, compared with only 28% of the adults, had ocular MG. Thymoma was evident by MRI in 1.5% of children and in 20% of adults. Despite most patients having received prednisone, very few had obtained full clinical remission. This study emphasises the frequency of early childhood onset with ocular symptoms and shows that many of these patients have AChR antibodies. By contrast, patients presenting in later age seem to be very uncommon in comparison with recent studies in Caucasian populations.


Conservative management of abnormally invasive placentation.
Due to the growing number of cesarean deliveries, the frequency of abnormally invasive placentation is increasing. The optimal management of this condition remains unclear. This article reviews the efficacy and safety of conservative management of abnormally invasive placentation. We performed a MEDLINE and Embase search and reviewed all articles on conservative management of abnormally invasive placentation published from 1985 through 2006. Over the past 20 years, 48 reports have described outcomes of 60 women who were treated conservatively for abnormally invasive placentation. Twenty-six women were managed without any additional interventions. In most of these patients (19/26), the placenta had been partially removed. In 4 of these 26, conservative therapy failed. Twenty-two women received adjuvant methotrexate. In most of these women (19/22), the entire placenta was left in situ. In 5, therapy failed. Twelve women were managed with arterial embolization. In most of these (9/12), the diagnosis was made antepartum and the placenta was completely left in situ. In 3, therapy failed. Overall, 11 women experienced infection (11/60), 21 women experienced vaginal bleeding (21/60), and 4 suffered disseminated intravascular coagulopathy (4/60). Spontaneous loss of placental tissue was noted in 16 women. Subsequent pregnancies were reported in 8 women. Conservative management of abnormally invasive placentation can be effective and fertility can be preserved. It should only be considered in highly selected cases when blood loss is minimal and there is desire for fertility preservation. Whether adjuvant methotrexate or selective arterial embolization is beneficial is uncertain. Undetectable hCG values do not seem to guarantee complete resorption of retained placental tissue.


Comparison of PCR with culture for detection of Ureaplasma urealyticum in clinical samples from patients with urogenital infections.
PCR was compared with culture for the detection of Ureaplasma urealyticum in 50 specimens, including sperm, urine, and prostate secretions, from hospital patients with urogenital infections. Five positive and a further four doubtful diagnoses were made by culture, whereas PCR detected U. urealyticum in 12 samples. PCR also was faster than culturing. The increased sensitivity and shorter time requirement of PCR support its further development for the diagnosis of U. urealyticum infection.


The physiological significance of pulsatile LHRH secretion in man: gonadotrophin responses to physiological doses of pulsatile versus continuous LHRH administration.
This study tested whether pulsatile LHRH stimulation of the pituitary is required for normal gonadotrophin secretion in man. Four men with idiopathic hypogonadotrophic hypogonadism (IHH) and presumed endogenous LHRH deficiency were taken off all hormonal replacement for 5-6 weeks, then 5 micrograms LHRH was administered every 2 h for 1 week in order to prime pituitary gonadotrophin responsiveness. A physiological dose of LHRH (10 micrograms every 2 h) was then administered in both pulsatile and continuous regimens, in varying order, to each man. Pulsatile LHRH was capable of stimulating LH (as measured by bioassay) and FSH secretion, while continuous administration of LHRH was not. Serum LH, measured by RIA and bioassay, and FSH and free alpha-subunit levels, measured by RIA, increased significantly (P less than 0.05) over pretreatment levels during pulsatile LHRH administration. In contrast, bioactive LH and immunoactive FSH did not change significantly compared to pretreatment values during continuous infusion of the same total LHRH dose, although immunoactive LH and free alpha-subunit levels did increase significantly (P less than 0.05). The ratio of LH bioactivity to immunoactivity was significantly lower during the continuous compared to pulsatile LHRH regimen (P less than 0.001). Similar serum LHRH levels were achieved during pulsatile and continuous infusions. Serum testosterone and oestradiol levels did not increase significantly from pretreatment levels during either regimen of LHRH administration. It is concluded that a pulsatile LHRH signal pattern is essential for normal pituitary gonadotrophin secretion in men with IHH. Continuous infusion of a physiological dose of LHRH, which produced serum LHRH levels which were indistinguishable from those found during pulsatile administration, failed to stimulate FSH or bioactive LH secretion.


A molecular boron cluster-based chromophore with dual emission.
Bromination of the luminescent borane, anti-B18H22, via electrophilic substitution using AlCl3 and Br2, yields the monosubstituted derivative 4-Br-anti-B18H21 as an air-stable crystalline solid. In contrast to the unsubstituted parent compound, 4-Br-anti-B18H21 possesses dual emission upon excitation with UV light and exhibits fluorescence at 410 nm and phosphorescence at 503 nm, with Φtotal = 0.07 in oxygen-free cyclohexane. Increased oxygen content in cyclohexane solution quenches the phosphorescence signal. The fluorescent signal intensity remains unaffected by oxygen, suggesting that this molecule could be used as a ratiometric oxygen probe.


Robust magnetic domains in fluorinated ReS2₂monolayer.
Transition metal dichalcogenides are layered materials that are typically bound together by van der Waals forces. An exception in the family is ReS2; the geometrical distortion of its lattice structure due to Peierls distortion dimerizes Re atoms to form zigzag chains, thus decoupling the layers electronically and vibrationally. This in turn reduces the layer dependence of its physical and chemical properties. In order to tailor the properties of ReS2 monolayer, an alternative way by fluorination above and between Re chains in the lattice is investigated. The results of density functional theory calculations show the site-dependent electronic properties of fluorinated ReS2: (i) F atoms above the Re chains induce metallic mid-gap states which are ferromagnetically-coupled within the Re chains, and antiferromagnetically-coupled between chains; (ii) F atoms between the Re chains induce semiconducting mid-gap states which are non-magnetic. Unlike other states observed, the mid-gap states associated with top sites above the Re chains are generally insusceptible to the external electric field. The electron localization and negative Laplacian plots show that not only bonds between F and S atoms are ionic in character, the Re chains are also coupled ionically. The emergence of these robust metallic mid-gap states in the localized domains suggest that electrons could conduct along the Re chains by hopping. The electron conduction in such functionalized ReS2 is anisotropic in nature, and hence could be applied in spintronic devices, such as spin-transfer torque and spin-wave logic devices.


Myocardial performance index by tissue Doppler in bronchopulmonary dysplasia survivors.
Bronchopulmonary dysplasia (BPD) survivors from the surfactant era were evaluated by echocardiography in a few studies and no significant differences were found between BPD and non-BPD children. In this study, we evaluated these children with myocardial performance index (MPI), which was obtained by tissue Doppler echocardiography (TDE) in addition to the conventional methods. Fifteen children with BPD who did not have any cardiopulmonary symptoms at the time of the study were examined. All children were studied with M-mode, two-dimensional and DE. Pulmonary artery systolic pressures (PAPs) were estimated from tricuspid regurgitant velocity, and MPI for both ventricles were obtained by TDE. Results were compared with those of term-born, age- and sex-matched control children. While the variables obtained by M-mode and DE did not differ between the groups, the right and left ventricular MPI were found to be significantly higher in the BPD group compared with the control group (mean right ventricular MPI 0.48 +/- 0.04 vs. 0.41 +/- 0.05; mean left ventricular MPI 0.47 +/- 0.05 vs. 0.39 +/- 0.06). In addition, mean PAPs values of the patients were found to be significantly higher than those of the controls (30.4 +/- 6.9 mmHg vs. 23.3 +/- 5.3 mmHg), and there was a positive correlation between PAPs and right ventricular MPI values in the BPD group (r = 0.5). While routine echocardiographic examinations revealed no difference between the groups, MPI measurements by TDE technique yielded significantly higher values in the BPD group. To this extent, our study is the first to show that survivors of BPD may, in fact, have a subclinical ventricular dysfunction.


Heparan sulfate, an endogenous TLR4 agonist, promotes acute GVHD after allogeneic stem cell transplantation.
Graft-versus-host disease (GVHD) remains the most common cause of nonrelapse-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although T-cell depletion and intensive immunosuppression are effective in the control of GVHD, they are often associated with higher rates of infection and tumor recurrence. In this study, we showed that heparan sulfate (HS), an extracellular matrix component, can activate Toll-like receptor 4 on dendritic cells in vitro, leading to the enhancement of dendritic cell maturation and alloreactive T-cell responses. We further demonstrated in vivo that serum HS levels were acutely elevated at the onset of clinical GVHD in mice after allo-HSCT. Treatment with the serine protease inhibitor α1-antitrypsin decreased serum levels of HS, leading to a reduction in alloreactive T-cell responses and GVHD severity. Conversely, an HS mimetic that increased serum HS levels accelerated GVHD. In addition, in patients undergoing allo-HSCT for hematologic malignancies, serum HS levels were elevated and correlated with the severity of GVHD. These results identify a critical role for HS in promoting acute GVHD after allo-HSCT, and they suggest that modulation of HS release may have therapeutic potential for the control of clinical GVHD.


A comparison of adenosine A2A agonism and methylprednisolone in attenuating neuronal damage and improving functional outcome after experimental traumatic spinal cord injury in rabbits.
Steroid agents remain the lone pharmacological treatment in widespread use for acute spinal cord injury (SCI), although their utility remains in dispute in the neurotrauma literature. Adenosine A2A receptor activation with ATL-146e, a selective A2A agonist, has shown potential benefit in treating SCI; however, it has not been compared with the gold standard, methylprednisolone. The authors of this study evaluated ATL-146e and methylprednisolone for their ability to preserve neuronal viability and motor function in experimental SCI. New Zealand White rabbits sustained SCI or sham injury via the Allen weight-drop technique. Ten minutes postinjury, animals received ATL-146e (ATL group, 0.06 microg/kg/min intravenously for 3 hours), methylprednisolone (steroid group, 30 mg/kg intravenously), or saline (trauma control group). Hindlimb motor function was recorded every 12 hours using the Tarlov motor grading scale (0, paralysis-5, normal hop). At 48 hours, fixed spinal cord tissue was evaluated for neuronal viability. Hindlimb motor function in animals treated with ATL-146e was equivalent to that of sham-injured animals and was significantly better than that of trauma control animals at all time points and that of steroid-treated animals at 12 hours (p = 0.05). Motor function in steroid-treated animals was worse than in those given ATL-146e and better than that of trauma control animals at later time points, but was not statistically significant (both p > 0.05). Neuronal viability (measured in neurons/hpf) was significantly higher in both treatment groups compared with the trauma control group (12.1 +/- 1.4 neurons/hpf for the ATL and 13.3 +/- 1.4 neurons/hpf for the steroid group compared with 7.5 +/- 1.5 neurons/hpf for the trauma control group; both p < 0.04). Neuronal viability did not differ among ATL-146e-treated, steroid-treated, and sham-injured groups. The use of ATL-146e is at least as effective as methylprednisolone in preserving function and is equivalent to methylprednisolone in preserving the structure of spinal cord tissue after blunt SCI. Adenosine A2A receptor activation may be an effective treatment for acute SCI while avoiding the adverse effects of steroid agents.


MAGELLAN: a cognitive map-based model of human wayfinding.
In an unfamiliar environment, searching for and navigating to a target requires that spatial information be acquired, stored, processed, and retrieved. In a study encompassing all of these processes, participants acted as taxicab drivers who learned to pick up and deliver passengers in a series of small virtual towns. We used data from these experiments to refine and validate MAGELLAN, a cognitive map-based model of spatial learning and wayfinding. MAGELLAN accounts for the shapes of participants' spatial learning curves, which measure their experience-based improvement in navigational efficiency in unfamiliar environments. The model also predicts the ease (or difficulty) with which different environments are learned and, within a given environment, which landmarks will be easy (or difficult) to localize from memory. Using just 2 free parameters, MAGELLAN provides a useful account of how participants' cognitive maps evolve over time with experience, and how participants use the information stored in their cognitive maps to navigate and explore efficiently.


In conversation with Janet Thornton.
Professor Dame Janet Thornton is a pioneer in structural bioinformatics who has developed an extensive computational toolkit for the analysis of protein structure and inference of function and evolution. She began her career in science as a physicist, following an undergraduate degree in physics from the University of Nottingham with a Master's and PhD in biophysics in London. After undertaking a postdoctoral position in the group of Sir David Phillips at the University of Oxford, Janet returned to London where she eventually held professorial appointments at both University College London and Birkbeck College. During this period, she formed a number of long-standing and fruitful collaborations that, amongst other advances, led to the development of a software that revolutionised protein structure validation - PROCHECK - as well as a unique classification system for protein structures, CATH. Janet was Director of the European Bioinformatics Institute EMBL-EBI between 2001 until 2015 and played a pivotal role in launching ELIXIR, a pan-European infrastructure for biological data. She remains at EMBL-EBI as a senior scientist, and her group primarily focuses on understanding protein structure and function and how these contribute to our understanding of diseases and ageing. Her contributions to the life sciences have been distinguished through numerous awards and honours, and in 2012, she was appointed a Dame Commander of the Order of the British Empire for services to bioinformatics.


Hyperbaric oxygen therapy may improve symptoms in autistic children.
Autism is a neurodevelopmental disorder that currently affects as many as 1 out of 166 children in the United States. Recent research has discovered that some autistic individuals have decreased cerebral perfusion, evidence of neuroinflammation, and increased markers of oxidative stress. Multiple independent single photon emission computed tomography (SPECT) and positron emission tomography (PET) research studies have revealed hypoperfusion to several areas of the autistic brain, most notably the temporal regions and areas specifically related to language comprehension and auditory processing. Several studies show that diminished blood flow to these areas correlates with many of the clinical features associated with autism including repetitive, self-stimulatory and stereotypical behaviors, and impairments in communication, sensory perception, and social interaction. Hyperbaric oxygen therapy (HBOT) has been used with clinical success in several cerebral hypoperfusion syndromes including cerebral palsy, fetal alcohol syndrome, closed head injury, and stroke. HBOT can compensate for decreased blood flow by increasing the oxygen content of plasma and body tissues and can even normalize oxygen levels in ischemic tissue. In addition, animal studies have shown that HBOT has potent anti-inflammatory effects and reduces oxidative stress. Furthermore, recent evidence demonstrates that HBOT mobilizes stem cells from human bone marrow, which may aid recovery in neurodegenerative diseases. Based upon these findings, it is hypothesized that HBOT will improve symptoms in autistic individuals. A retrospective case series is presented that supports this hypothesis.


Efficient Bloch-Siegert B1 (+) mapping using spiral and echo-planar readouts.
The Bloch-Siegert (B-S) B1 (+) mapping technique is a fast, phase-based method that is highly SAR limited especially at 7T, necessitating the use of long repetition times. Spiral and echo-planar readouts were incorporated in a gradient-echo based B-S sequence to reduce specific absoprtion rate (SAR) and improve its scan efficiency. A novel, numerically optimized 4 ms B-S off-resonant pulse at + 1960 Hz was used to increase sensitivity and further reduce SAR compared with the conventional 6 ms Fermi B-S pulse. Using echo-planar and spiral readouts, scan time reductions of 8-16 were achieved. By reducing the B-S pulse width by a factor of 1.5, SAR was reduced by a factor of 1.5 and overall sensitivity was increased by a factor of 1.33 due to the nearly halved resonance offset of the new B-S pulse. This was validated on phantoms and volunteers at 7 T.


Modelling the implications of moving towards universal coverage in Tanzania.
A model was developed to assess the impact of possible moves towards universal coverage in Tanzania over a 15-year time frame. Three scenarios were considered: maintaining the current situation ('the status quo'); expanded health insurance coverage (the estimated maximum achievable coverage in the absence of premium subsidies, coverage restricted to those who can pay); universal coverage to all (government revenues used to pay the premiums for the poor). The model estimated the costs of delivering public health services and all health services to the population as a proportion of Gross Domestic Product (GDP), and forecast revenue from user fees and insurance premiums. Under the status quo, financial protection is provided to 10% of the population through health insurance schemes, with the remaining population benefiting from subsidized user charges in public facilities. Seventy-six per cent of the population would benefit from financial protection through health insurance under the expanded coverage scenario, and 100% of the population would receive such protection through a mix of insurance cover and government funding under the universal coverage scenario. The expanded and universal coverage scenarios have a significant effect on utilization levels, especially for public outpatient care. Universal coverage would require an initial doubling in the proportion of GDP going to the public health system. Government health expenditure would increase to 18% of total government expenditure. The results are sensitive to the cost of health system strengthening, the level of real GDP growth, provider reimbursement rates and administrative costs. Promoting greater cross-subsidization between insurance schemes would provide sufficient resources to finance universal coverage. Alternately, greater tax funding for health could be generated through an increase in the rate of Value-Added Tax (VAT) or expanding the income tax base. The feasibility and sustainability of efforts to promote universal coverage will depend on the ability of the system to contain costs.


The Supreme Court limits lawsuits against managed care organizations.
In Aetna Health Inc. v. Davila, the United States Supreme Court revisited the question of whether the Employee Retirement Income Security Act (ERISA) precludes state lawsuits against ERISA plans. The Court held that ERISA preempts damage actions brought against managed care organizations under the Texas Health Care Liability Act because ERISA itself provides the exclusive remedy for challenging ERISA plans' coverage decisions. The Court suggested, however, that health plans might be liable for treatment decisions made by employed physicians. It also volleyed back to Congress the question of whether ERISA beneficiaries should have any remedy for damages caused by coverage decisions.


CLIC1-mediated autophagy confers resistance to DDP in gastric cancer.
Gastric cancer has been a constant concern to researchers as one of the most common malignant tumors worldwide. The treatment options for gastric cancer include surgery, chemotherapy and traditional Chinese medicine. Chemotherapy is an effective treatment for patients with advanced gastric cancer. Cisplatin (DDP) has been approved as a critical chemotherapy drug to treat various kinds of solid tumors. Although DDP is an effective chemotherapeutic agent, many patients develop drug resistance during treatment, which has become a severe problem in clinical chemotherapy. This study aims to investigate the mechanism of DDP resistance in gastric cancer. The results show that intracellular chloride channel 1 (CLIC1) expression was increased in AGS/DDP and MKN28/DDP, and as compared to the parental cells, autophagy was activated. In addition, the sensitivity of gastric cancer cells to DDP was decreased compared to the control group, and autophagy increased after overexpression of CLIC1. On the contrary, gastric cancer cells were more sensitive to cisplatin after transfection of CLIC1siRNA or treatment with autophagy inhibitors. These experiments suggest that CLIC1 could alter the sensitivity of gastric cancer cells to DDP by activating autophagy. Overall, the results of this study recommend a novel mechanism of DDP resistance in gastric cancer.


Critical molecular determinants of voltage-gated sodium channel sensitivity to mu-conotoxins GIIIA/B.
GIIIA/B mu-conotoxins block the rat skeletal muscle sodium channel (rNa(v)1.4) with high affinity by binding to specific residues in the pore. However, human Na(v)1.4 (hNa(v)1.4) channels, which are resistant to block by GIIIA/B, have these same pore residues. We used chimera constructs, site-directed mutagenesis, and electrophysiological techniques to investigate which residues determine GIIIA/B selectivity. Exchange of serine 729 in the D2/S5-S6 linker of rat Na(v)1.4 with leucine (S729L), the corresponding residue in hNa(v)1.4, reduces the sensitivity of rNa(v)1.4 by approximately 20-fold and largely accounts for the differential sensitivity of rNa(v)1.4 and hNa(v)1.4 to both GIIIA and GIIIB. To determine whether D2/S5-S6 linker residues might contribute to the resistance of neuronal channels to GIIIA/B, we exchanged residues in this linker that differed between rNa(v)1.4 and neuronal channels. Substitution of aspargine 732 with lysine (N732K), the corresponding residue in rNa(v)1.1a and rNa(v)1.7, reduced the GIIIB sensitivity of rNa(v)1.4 by approximately 20-fold. The N732K substitution, however, only reduced GIIIA sensitivity of rNa(v)1.4 by approximately 4-fold, demonstrating that GIIIA and GIIIB have distinct interactions with the D2/S5-S6 linker. Our data indicate that naturally occurring variants in the extra-pore region of the D2/S5-S6 linker contribute to the isoform-specific sensitivity of sodium channels to GIIIA/B. Because S729 and N732 are not part of the high-affinity binding site for mu-conotoxins, these extra-pore residues probably influence the accessibility of the toxin to the binding site within the pore and/or the stability of the toxin-channel complex. Our results should aid the development of toxins that block specific neuronal sodium channel isoforms.


Device complications and inappropriate implantable cardioverter defibrillator shocks in patients with hypertrophic cardiomyopathy.
Although the benefit of implantable cardioverter defibrillator (ICD) therapy in patients with hypertrophic cardiomyopathy (HCM) at risk for sudden cardiac arrest is well established, there may be a higher risk for device complications and inappropriate shocks. To determine the incidence of inappropriate ICD shocks and device complications in HCM patients and the impact of young age at ICD implant and atrial fibrillation. HCM patients who underwent ICD implantation between January 1988 and December 2005 were included. The frequency of device complications, including pneumothorax, pericardial effusion, haematoma, lead revisions, infection and rate of inappropriate shocks, was determined. ICD shocks were characterised as inappropriate if triggered by sinus tachycardia, atrial fibrillation or device malfunction. A total of 181 patients were included (mean age 44 (SD 17) years; 62% males). During a mean follow-up of 59 (42) months (4.92 years; 830.75 patient-years), 65 patients (36%) had a total of 88 device complications, including 42 (23%) patients with inappropriate shocks. The rate of inappropriate shocks was 5.3% per year (vs 4% risk of appropriate shocks), and the likelihood of inappropriate ICD shocks per 100 patient-years was 5.1. Younger age and atrial fibrillation were associated with an increased risk of inappropriate ICD discharges. The rate of inappropriate ICD shocks and frequency of device complications in HCM patients are not insignificant and are most common in younger patients and those with atrial fibrillation. Inappropriate ICD shocks are the most common device complication and should be accounted for when counselling high-risk HCM patients for ICD implantation.


A New Method to Measure the Subpubic Arch Angle Using 3-D Ultrasound.
The aim of this study was to assess the reproducibility of both a new contrast-enhancing technique (Oblique View eXtended Imaging, OVIX; Samsung) and the recently reported 3-D multiplanar technique (MPT) in the measurement of the subpubic angle (SPA) among a group of women at term gestation. In addition, we aimed to study the intermethod agreement between the OVIX technique and MPT. We acquired a transperineal 3-D ultrasound volume from 155 women with a singleton uncomplicated term pregnancy before the onset of labor. Each 3-D dataset was analyzed by the MPT and OVIX algorithm. The angle formed by the lower edges of the pubic rami (SPA) was measured twice by an operator and once by another operator for each technique in order to assess intra- and interobserver reproducibility. Reproducibility and intermethod agreement were studied by means of the intraclass correlation coefficient (ICC) and Bland-Altman method. SPA measurements performed with OVIX showed high intraobserver [ICC 0.912, 95% confidence interval (CI) 0.882-0.935] and good interobserver (ICC 0.791, 95% CI 0.724-0.844) agreement, while those measured with MPT showed moderate intraobserver (ICC 0.573, 95% CI 0.457-0.670) and good interobserver (ICC 0.640, 95% CI 0.537-0.724) agreement. Whereas the intermethod analysis showed good agreement between the MPT and the OVIX techniques (ICC 0.614, 95% CI 0.414-0.757), the SPA measured by MPT were significantly wider than those measured by OVIX (125 ± 12 vs. 120 ± 11°, p = 0.006). OVIX is a reliable technique for SPA measurement. MPT overestimates the SPA in comparison with OVIX. Further studies are needed to assess its clinical utility.


α-Costic acid, a plant sesquiterpene with acaricidal activity against Varroa destructor parasitizing the honey bee.
The organic extract of the aerial parts of Dittrichia viscosa, a perennial native plant of the Mediterranean basin, showed a significant acaricidal activity against Varroa destructor, the parasite mite of Apis mellifera, commonly called honey bee. Among the metabolites isolated from the organic extract of this Asteraceae, α-costic acid showed to be one of the compounds responsible for the toxic activity exhibited by the crude plant extract on this parasite mite species. In addition to the toxic effect a clear acaricidal response has been recorded when the parasitic mite was exposed to 1 mg/mL concentration of α-costic acid while no effects have been showed on honey bees using the same compound at the same concentration. This finding suggests a potential use of α-costic acid to control Varroa mites. The possibility to reliably achieve absolute configuration of α-costic acid by DFT computational analysis of chiroptical spectra has been also demonstrated.†.


An interview with Enrico Coen.
Enrico Coen CBE FRS is a Project Leader at the John Innes Centre in Norwich, UK, who uses a variety of approaches to study patterning and morphogenesis in plants. We met with Enrico at the Spring Meeting of the British Society for Developmental Biology, where he was awarded the Waddington Medal, to ask him more about his career and his passion for art and book-writing.


Role of spinal GABA receptors in depressor responses to chemical stimulation of the A5 area in normal and hypertensive rats.
Chemical stimulation of neurons in the pontine A5 area by microinjection of L-glutamate lowers arterial blood pressure. The mechanism of this 'A5 depressor response' is not well-established. Here, we examine the involvement of spinal cord gamma-aminobutyric acid (GABA) receptors in this depressor response in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Experiments were conducted in male WKY and age-matched SHR anaesthetised with sodium pentobarbitone and chloral hydrate. An intrathecal catheter was implanted with the tip located between T9 and L2. Three days later, rats were re-anaesthetised and 10 nl of 40 mM L-glutamate was injected into the A5 area before, during and after, blockade of spinal cord GABA-A receptors by intrathecal injection of bicuculline methiodide (1 mM in 10 microliters phosphate-buffered saline). Injection of L-glutamate (10, 20, 40, 80 mM in 10 nl) produced depressor responses that were similar in WKY (n = 6) and SHR (n = 6). Intrathecal injection of bicuculline elicited a pressor response that was greater in SHR (n = 7, 28.5 +/- 7.6% increase in mean arterial pressure) than WKY (n = 11, 11.6 +/- 3.6%, p < 0.05). After bicuculline, the depressor response to injection of L-glutamate into the A5 area was eliminated in both WKY (n = 7) and SHR (n = 6). Intrathecal injection of vehicle had no effect on either resting arterial blood pressure or the depressor response to A5 stimulation. Basal blood pressure and control responses to A5 stimulation were fully restored by around 90 min after bicuculline injection in each animal. In separate groups of rats, intrathecal injection of muscimol elicited depressor responses that were greater in SHR (n = 6, -32.0 +/- 6.2%) than WKY (n = 6, -17.3 +/- 1.5%, p < 0.05). Our results suggest that the A5 depressor response is due to a projection from the A5 area to the spinal cord. This projection acts directly, or through a spinal interneuron and uses GABA as a neurotransmitter. Furthermore, our results indicate a hyper-responsiveness to GABA-A receptor stimulation in SHR since intrathecal bicuculline elicited much greater increases and intrathecal muscimol elicited much greater decreases, in blood pressure in SHR than in WKY. Finally, it seems likely that the A5-spinal depressor pathway is less effective in SHR than WKY under physiological conditions since chemical stimulation of the A5 area with L-glutamate produced a comparable depressor response in both strains.


Testing the efficacy of theoretically derived improvements in the treatment of social phobia.
Recent theoretical models of social phobia suggest that targeting several specific cognitive factors in treatment should enhance treatment efficacy over that of more traditional skills-based treatment programs. In the current study, 195 people with social phobia were randomly allocated to 1 of 3 treatments: standard cognitive restructuring plus in vivo exposure, an "enhanced" treatment that augmented the standard program with several additional treatment techniques (e.g., performance feedback, attention retraining), and a nonspecific (stress management) treatment. The enhanced treatment demonstrated significantly greater effects on diagnoses, diagnostic severity, and anxiety during a speech. The specific treatments failed to differ significantly on self-report measures of social anxiety symptoms and life interference, although they were both significantly better than the nonspecific treatment. The enhanced treatment also showed significantly greater effects than standard treatment on 2 putative process measures: cost of negative evaluation and negative views of one's skills and appearance. Changes on these process variables mediated differences between the treatments on changes in diagnostic severity.


A case-control study of diet and gastric cancer in northern Italy.
Dietary factors in the aetiology of stomach cancer were investigated using data from a case-control study conducted in Northern Italy on 206 histologically confirmed carcinomas and 474 control subjects in hospital for acute, non-digestive conditions, unrelated to any of the potential risk factors for gastric cancer. Dietary histories concerned the frequency of consumption per week of 29 selected food items (including the major sources of starches, proteins, fats, fibres, vitamins A and C, nitrates and nitrites in the Italian diet) and subjective scores for condiments and salt intake. Pasta and rice (the major sources of starch), polenta (a porridge made of maize) and ham were positively related with gastric cancer risk, whereas green vegetables and fresh fruit as a whole (and specifically citrus fruit) and selected fibre-rich aliments (such as whole-grain bread or pasta) showed protective effects on gastric cancer risk. Allowance for major identified potential distorting factors (chiefly indicators of socio-economic status) reduced the positive association with pasta or rice consumption, but did not appreciably modify any of the other risk estimates. When a single logistic model was fitted including all food items significant in univariate analysis, the 3 items remaining statistically significant were green vegetables (relative risk, RR = 0.27 for upper vs. lower tertile), polenta (RR = 2.32) and ham (RR = 1.60). Indices of beta-carotene and ascorbate intake were negatively and strongly related with gastric cancer risk, but the association with these micronutrients was no longer evident after simultaneous allowance for various food items. An approximately 7-fold difference in risk was found between extreme quintiles of a scale measuring major positive and negative associations.


Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer.
Cisplatin and carboplatin are the primary first-line therapies for the treatment of ovarian cancer. However, resistance to these platinum-based drugs occurs in the large majority of initially responsive tumors, resulting in fully chemoresistant, fatal disease. Although the precise mechanism(s) underlying the development of platinum resistance in late-stage ovarian cancer patients currently remains unknown, CpG-island (CGI) methylation, a phenomenon strongly associated with aberrant gene silencing and ovarian tumorigenesis, may contribute to this devastating condition. To model the onset of drug resistance, and investigate DNA methylation and gene expression alterations associated with platinum resistance, we treated clonally derived, drug-sensitive A2780 epithelial ovarian cancer cells with increasing concentrations of cisplatin. After several cycles of drug selection, the isogenic drug-sensitive and -resistant pairs were subjected to global CGI methylation and mRNA expression microarray analyses. To identify chemoresistance-associated, biological pathways likely impacted by DNA methylation, promoter CGI methylation and mRNA expression profiles were integrated and subjected to pathway enrichment analysis. Promoter CGI methylation revealed a positive association (Spearman correlation of 0.99) between the total number of hypermethylated CGIs and GI50 values (i.e., increased drug resistance) following successive cisplatin treatment cycles. In accord with that result, chemoresistance was reversible by DNA methylation inhibitors. Pathway enrichment analysis revealed hypermethylation-mediated repression of cell adhesion and tight junction pathways and hypomethylation-mediated activation of the cell growth-promoting pathways PI3K/Akt, TGF-beta, and cell cycle progression, which may contribute to the onset of chemoresistance in ovarian cancer cells. Selective epigenetic disruption of distinct biological pathways was observed during development of platinum resistance in ovarian cancer. Integrated analysis of DNA methylation and gene expression may allow for the identification of new therapeutic targets and/or biomarkers prognostic of disease response. Finally, our results suggest that epigenetic therapies may facilitate the prevention or reversal of transcriptional repression responsible for chemoresistance and the restoration of sensitivity to platinum-based chemotherapeutics.


Large amplitude excitations traveling along the interface in bistable catalytic methanol oxidation on Rh(110).
Traveling interface modulations have been observed in catalytic methanol oxidation on an unpromoted Rh(110) and a partially vanadium oxide covered (θV = 0.1 MLE) Rh(110) surface. The front instabilities have been followed with photoemission electron microscopy (PEEM) in the 10-4 mbar range at T ≈ 800 K where the reaction is bistable. Near the equistability point large amplitude excursions (up to 300 μm) from the average interface position occur which travel in a pulse-like manner along the interface.


Predictors of surgery in patients with severe acute pancreatitis managed by the step-up approach.
Initial management of severe acute pancreatitis (SAP) is conservative. As a step-up approach, percutaneous catheter drainage (PCD) with saline irrigation is reported to be effective. Factors leading to surgery are unclear. In this ongoing prospective study, 70 consecutive patients with SAP were recruited. As a step-up approach, all patients initially received medical management and later underwent PCD and surgery as per the indication. Of the 70 consecutive patients with SAP, 14 were managed medically, 29 managed with PCD alone, whereas 27 required surgery after initial PCD. Sepsis reversal was achieved with PCD alone in 62.5%. The curative efficacy of PCD alone was in 27 patients (48%). Overall mortality in the whole group was 24%. On univariate analysis, factors significantly affecting surgical intervention included initial acute physiology and chronic health evaluation (APACHE) II score, APACHE II score at first intervention, sepsis reversal by PCD within a week, number of organs failed, organ failure within a week of the onset of disease, number of bacteria isolated per patient, renal failure, respiratory failure, Escherichia coli, computerized tomography severity index score at admission, parenteral nutrition requirement before or after radiological intervention, maximum extent of necrosis of more than 50% of the pancreas, and extrapancreatic necrosis. On multivariate analysis, renal failure (P = -0.03), APACHE II score at first intervention (P = -0.006), and the number of bacteria isolated per patient (P = -0.01) remained independent predictors of surgery. An APACHE II score of more than 7.5 at first intervention (PCD) had the ability to predict surgery with a sensitivity of 88.9% and a specificity of 69%. PCD reversed sepsis in 62% and avoided surgery in 48% of the patients. Reversal of sepsis within a week of PCD, APACHE II score at first intervention (PCD), and organ failure within a week of the onset of disease could predict the need for surgery in the early course of disease.


Functional consequences of compartmentalization of synaptic input.
Intra-axonal recordings of stomatogastric nerve axon 1 (SNAX1) indicate that there are synaptic inputs onto the SNAX1 terminals in the stomatogastric ganglion (STG) of the crab Cancer borealis (Nusbaum et al., 1992b). To determine whether this synaptic input only influenced SNAX1 activity within the STG, we identified the SNAX1 soma in the commissural ganglion (CoG). We found that this neuron has a neuropilar arborization in the CoG and also receives synaptic inputs in this ganglion. Based on its soma location, we have renamed this neuron modulatory commissural neuron 1 (MCN1). While intracellular stimulation of MCN1soma and MCN1SNAX has the same excitatory effects on the STG motor patterns, MCN1 receives distinct synaptic inputs in the STG and CoG. Moreover, the synaptic input that MCN1 receives within the STG compartmentalizes its activity. Specifically, the lateral gastric (LG) neuron synaptically inhibits MCN1SNAX-initiated activity within the STG (Nusbaum et al., 1992b), and while LG did not inhibit MCN1soma-initiated activity in the CoG, it did inhibit these MCN1 impulses when they arrived in the STG. As a result, during MCN1soma-elicited gastric mill rhythms, MCN1soma is continually active in the CoG but its effects are rhythmically inhibited in the STG by LG neuron impulse bursts. One functional consequence of this local control of MCN1 within the STG is that the LG neuron thereby controls the timing of the impulse bursts in other gastric mill neurons. Thus, local synaptic input can functionally compartmentalize the activity of a neuron with arbors in distinct regions of the nervous system.