Mesoscopic modeling for nucleic acid chain dynamics.
To gain a deeper insight into cellular processes such as transcription and translation, one needs to uncover the mechanisms controlling the configurational changes of nucleic acids. As a step toward this aim, we present here a mesoscopic-level computational model that provides a new window into nucleic acid dynamics. We model a single-stranded nucleic as a polymer chain whose monomers are the nucleosides. Each monomer comprises a bead representing the sugar molecule and a pin representing the base. The bead-pin complex can rotate about the backbone of the chain. We consider pairwise stacking and hydrogen-bonding interactions. We use a modified Monte Carlo dynamics that splits the dynamics into translational bead motion and rotational pin motion. By performing a number of tests, we first show that our model is physically sound. We then focus on a study of the kinetics of a DNA hairpin--a single-stranded molecule comprising two complementary segments joined by a noncomplementary loop--studied experimentally. We find that results from our simulations agree with experimental observations, demonstrating that our model is a suitable tool for the investigation of the hybridization of single strands.


Characterisation of the interaction of lactate dehydrogenase with Tween-20 using isothermal titration calorimetry, interfacial rheometry and surface tension measurements.
In this study the nature of the interaction between Tween-20 and lactate dehydrogenase (LDH) was investigated using isothermal titration calorimetry (ITC). In addition the effects of the protein and surfactant on the interfacial properties were followed with interfacial rheology and surface tension measurements in order to understand the mechanism by which the surfactant prevents protein adsorption to the air-water interface. Comparisons were made with Tween-40 and Tween-80 in order to further investigate the mechanism. ITC measurements indicated a weak, probably hydrophobic, interaction between Tween-20 and LDH. Prevention of LDH adsorption to the air-water interface by the Tween surfactants was correlated with surface energy rather than surfactant CMC. While surface pressure appears to be the main driving force for the displacement of LDH from the air-water interface by Tween-20 a solubilisation mechanism may exist for other protein molecules. More generally the results of this study highlight the value of the use of ITC and interfacial measurements in characterising the surface behaviour of mixed surfactant and protein systems.


Post-traumatic growth in mothers of children with autism: a phenomenological study.
While the adverse effects of raising a child with autism are well demonstrated, there have been few reports of the post-traumatic growth of mothers of children with autism. The purpose of this research was to explore dimensions of post-traumatic growth in this population in Mainland China and identify the factors facilitating post-traumatic growth. A total of 11 mothers of pre-school children were recruited from five rehabilitation centres of children with disabilities in Shanghai. The semi-structured interviews were conducted between August 2012 and October 2012 and analysed using thematic analysis. The data partially confirmed Tedeschi and Calhoun's model of post-traumatic growth. A new philosophy of life, appreciation of life, relating to others, personal strength and spiritual change were five domains of post-traumatic growth in mothers of children with autism. Perceived social support, peer example, effective coping style and self-efficacy enhancement were facilitating factors of post-traumatic growth. Further studies are needed to understand how to promote the post-traumatic growth of mothers of children with autism.


The de novo biosynthesis of vitamin B6 is required for disease resistance against Botrytis cinerea in tomato.
Vitamin B6 (VB6), an essential cofactor for numerous metabolic enzymes, has recently been shown to act as a potent antioxidant and play important roles in developmental processes and stress responses. However, little is known about the possible function of VB6 in plant disease resistance response against pathogen infection. In the present study, we explored the possible involvement of VB6 in defense response against Botrytis cinerea through functional analysis of tomato VB6 biosynthetic genes. Three de novo VB6 biosynthetic genes (SlPDX1.2, SlPDX1.3, and SlPDX2) and one salvage pathway gene (SlSOS4) were identified and the SlPDX1.2, SlPDX1.3, and SlPDX2 genes were shown to encode functional enzymes involved in de novo biosynthesis of VB6, as revealed by complementation of the VB6 prototrophy in yeast snz1 and sno1 mutants. Expression of SlPDX1.2, SlPDX1.3, and SlSOS4 genes was induced by infection with B. cinerea. Virus-induced gene silencing-mediated knockdown of SlPDX1.2 or SlPDX1.3 but not SlPDX2 and SlSOS4 led to increased severity of disease caused by B. cinerea, indicating that the VB6 de novo biosynthetic pathway but not the salvage pathway is involved in tomato defense response against B. cinerea. Furthermore, the SlPDX1.2- and SlPDX1.3-silenced tomato plants exhibited reduced levels of VB6 contents and reactive oxygen species scavenging capability, increased levels of superoxide anion and H2O2 generation, and increased activity of superoxide dismutase after infection by B. cinerea. Our results suggest that VB6 and its de novo biosynthetic pathway play important roles in regulation of defense response against B. cinerea through modulating cellular antioxidant capacity.


Non-adaptive phenotypic evolution of the endangered carnivore Lycaon pictus.
Decline in wild populations as a result of anthropogenic impact is widely considered to have evolutionary consequences for the species concerned. Here we examine changes in developmental stability in the painted hunting dog (Lycaon pictus), which once occupied most of sub-Saharan Africa but has undergone a dramatic population decline in the last century. Fluctuating asymmetry (FA) was used as an indicator of developmental stability and measured in museum skull specimens spanning a hundred year period. A comparison with the more ubiquitous black-backed jackal (Canis mesomelas) revealed FA in L. pictus to be high. Furthermore, the data indicate a temporal increase in FA over time in L. pictus, corresponding to the period of its population decline. The high rate of change is compatible with genetic drift although environmental factors are also likely to be important. Lowering developmental stability over time may have direct fitness consequences and as such represents an unacknowledged threat to future resilience of the population.


Judgment of the morality of an individual responsible for a fatal workplace accident involving subordinates
The aim of the study was to verify the hypothesis that additional information about the perpetrator responsible for the death of subordinates at the workplace may influence the assessment of morality. The article contains the results of an empirical study conducted among young adult working Silesians (N = 262), who were asked to evaluate the morality of the person responsible for the decision, in line with which miners had started working on 6th October 2014. On that day miners died following an explosion in the "Mysłowice-Wesoła" methane mine in the Polish Silesia region. The study explored the stories' method (from the moral psychology domain) as well as a short questionnaire. The respondents received information about the behavior of the perpetrator as well as emotions (socially desirable and undesirable) and (socially desirable and undesirable) views in the form of brief descriptions (stories). They were asked to evaluate the perpetrator's morality. The socially desirable views of the evaluated perpetrator (lack of acceptance for the situation) and the socially desirable emotions (guilt) significantly increased the level of morality according to participants. A single piece of information about the socially desirable emotions didn't significantly increase the perceived level of perpetrator's morality; neither did a single piece of information about socially desirable views. Results indicate the important role of additional information about emotions and views of the perpetrator in the process of assessing morality. It is worthwhile to implement the practical implications of this study in similar crisis situations at the workplace. Med Pr 2018;69(3):261–267.


Morphological organization of the dorsal protuberance of Linepithema humile (Mayr, 1868) ant's larvae (Hymenoptera, Formicidae).
The Argentine ant Linepithema humile is an important invasive species because of the levels of infestation that it can reach; however, there is little information about its presence, histological organization, and function of the dorsal protuberance, which is found exclusively in their larvae. The objective of this study was to describe it in L. humile through scanning electron microscopy and transmission electron microscopy, bringing information about this structure. The epidermis of these larvae have cuticles covering the whole body, and is formed by a sequence of overlapping lamellas where the inner ones were thicker and presented lower electron density, whereas the outer ones were thinner and highly electron dense. Pores or pore-like channels were not observed. A thick and acellular region composed of granular material was found under the cuticular layer. Out of this region, the flattened epidermic cells formed an epithelial layer. For the dorsal protuberance region, these cells become prismatic, and similarly to the cuticle, presents significant thickening. These cells presented extended microvilli, as well as a great amount of lamellar rough endoplasmic reticulum. Under this epithelium was observed a concentration of fat body cells, more numerous in the dorsal protuberance region. This study indicated that the dorsal protuberance present in the first segment of L. humile larvae has apparently no secretory function because no pores were found. This fact allowed to conclude that in L. humile larvae the dorsal protuberance would have the function to make it easier for the worker ants to carry them within the colony.


Psychotropic drugs associated with corrected QT interval prolongation.
To study whether listed putative corrected QT (QTc)-prolonging psychotropic drugs indeed prolong the QTc interval under everyday circumstances and to evaluate whether this is a class effect or an individual drug effect, we conducted a prospective population-based cohort study. This study was conducted as part of the Rotterdam Study and included 3377 men and 4845 women (>or=55 years) who had triennial electrocardiograms (ECGs). The primary end points of the study were the length of the QTc interval at each ECG, the difference in QTc interval between consecutive ECGs within one person, and the risk of an abnormally prolonged QTc interval. Drug use at the index date was obtained from automated dispensing records. The associations were examined by means of a repeated measurement analysis, adjusted for age, sex, diabetes mellitus, hypertension, myocardial infarction, heart failure, and use of class 1 QTc-prolonging drugs. Of the 8222 participants, 813 participants (9.9%) developed QTc prolongation during follow-up and 492 participants (74.4% women) used psychotropic drugs at the time of an ECG. Starting tricyclic antidepressants increased the QTc interval significantly with 6.9 milliseconds (95% confidence interval [CI], 3.1-10.7 milliseconds) between consecutive ECGs in comparison with consecutive ECGs of participants not using tricyclic antidepressants, in particular starting amitriptyline (8.5 milliseconds; 95% CI, 2.8-14.2 milliseconds), maprotiline (13.9 milliseconds; 95% CI, 3.6-24.3 milliseconds), and nortriptyline (35.3 milliseconds; 95% CI, 8.0-62.6 milliseconds). Starting lithium also increased the QTc interval significantly (18.6 milliseconds; 95% CI, 4.8-32.4 milliseconds). In this population-based prospective cohort study, we confirmed the importance of antidepressants and antipsychotics as potential contributors to QTc prolongation. Especially, starting tricyclic antidepressant drugs (as a class) is associated with a significant intraindividual increase in the QTc interval in comparison to the change in nonusers. The tricyclic antidepressants seem to prolong the QTc interval as a class effect.


Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates.
Depression is a complex, heterogeneous mental disorder. Currently available antidepressants are only effective in about one-third to one-half of all patients. The mechanisms underlying antidepressant response and treatment resistance are poorly understood. Recent clinical evidence implicates the involvement of leptin in treatment response to antidepressants. In this study, we determined the functional role of the leptin receptor (LepRb) in behavioral responses to the selective serotonergic antidepressant fluoxetine and the noradrenergic antidepressant desipramine. While acute and chronic treatment with fluoxetine or desipramine in wild-type mice elicited antidepressant-like effects in the forced swim test, mice null for LepRb (db/db) displayed resistance to treatment with either fluoxetine or desipramine. Fluoxetine stimulated phosphorylation of Akt(Thr308) and GSK-3β(Ser9) in the hippocampus and prefrontal cortex (PFC) of wild-type mice but not in db/db mice. Desipramine failed to induce measurable changes in Akt, GSK-3β or ERK1/2 phosphorylation in the hippocampus and PFC, as well as hypothalamus of either genotype of mice. Deletion of LepRb specifically from hippocampal and cortical neurons resulted in fluoxetine insensitivity in the forced swim test and tail suspension test while leaving the response to desipramine intact. These results suggest that functional LepRb is critically involved in regulating the antidepressant-like behavioral effects of both fluoxetine and desipramine. The antidepressant effects of fluoxetine but not desipramine are dependent on the presence of functional LepRb in the hippocampus and cortex.


STAT5 requires the N-domain for suppression of miR15/16, induction of bcl-2, and survival signaling in myeloproliferative disease.
Phosphorylated signal transducer and activator of transcription 5 (STAT5) is a biomarker and potential molecular target for hematologic malignancies. We have shown previously that lethal myeloproliferative disease (MPD) in mice mediated by persistently activated STAT5 (STAT5a(S711F)) requires the N-domain, but the mechanism was not defined. We now demonstrate by retrovirally complementing STAT5ab(null/null) primary mast cells that relative to wild-type STAT5a, STAT5a lacking the N-domain (STAT5aDeltaN) ineffectively protected against cytokine withdrawal-induced cell death. Both STAT5a and STAT5aDeltaN bound to a site in the bcl-2 gene and both bound near the microRNA 15b/16 cluster. However, only STAT5a could effectively induce bcl-2 mRNA and reciprocally suppress miR15b/16 leading to maintained bcl-2 protein levels. After retroviral complementation of STAT5ab(null/null) fetal liver cells and transplantation, persistently active STAT5a(S711F) lacking the N-domain (STAT5aDeltaN(S711F)) was insufficient to protect c-Kit(+)Lin(-)Sca-1(+) (KLS) cells from apoptosis and unable to induce bcl-2 expression, whereas STAT5a(S711F) caused robust KLS cell expansion, induction of bcl-2, and lethal MPD. Severe attenuation of MPD by STAT5aDeltaN(S711F) was reversed by H2k/bcl-2 transgenic expression. Overall, these studies define N-domain-dependent survival signaling as an Achilles heel of persistent STAT5 activation and highlight the potential therapeutic importance of targeting STAT5 N-domain-mediated regulation of bcl-2 family members.


Bridging the Gap between Evidence and Practice for Adults with Medically Refractory Temporal Lobe Epilepsy: Is a Change in Funding Policy Needed to Stimulate a Shift in Practice?
Objective. Surgery for medically refractory epilepsy (MRE) in adults has been shown to be effective but underutilized. Comprehensive health economic evaluations of surgery compared with continued medical management are limited. Policy changes may be necessary to influence practice shift. Methods. A critical review of the literature on health economic analyses for adults with MRE was conducted. The MEDLINE, EMBASE, CENTRAL, CRD, and EconLit databases were searched using relevant subject headings and keywords pertaining to adults, epilepsy, and health economic evaluations. The screening was conducted independently and in duplicate. Results. Four studies were identified (1 Canadian, 2 American, and 1 French). Two were cost-utility analyses and 2 were cost-effectiveness evaluations. Only one was conducted after the effectiveness of surgery was established through a randomized trial. All suggested surgery to be favorable in the medium to long term (7-8 years and beyond). The reduction of medication use was the major cost-saving parameter in favor of surgery. Conclusions. Although updated evaluations that are more generalizable across settings are necessary, surgery appears to be a favorable option from a health economic perspective. Given the limited success of knowledge translation endeavours, funder-level policy changes such as quality-based purchasing may be necessary to induce a shift in practice.


Optimism and life satisfaction as determinants for dental and general health behavior-oral health habits linked to cardiovascular risk factors.
Oral infections and cardiovascular diseases share common biological and behavioral risk factors. Psychosocial determinants could act as a link between general health behavior and dental health behavior. Our objective was to study optimism and life satisfaction as determinants of general and dental health behavior and to evaluate whether these are connected with cardiovascular risk factors and dental diseases. The 1966 Northern Finland Birth Cohort (N = 12,058) is a general population birth cohort. In a postal questionnaire, respondents (N = 8690) were asked about their health behavior and dental status. Cardiovascular risk factors were assessed in health examinations (N = 6033). Generalized linear regression models were used in analysis. The results showed that health orientation increases with strengthening life satisfaction and optimism. Dental health behavior and general health behavior were associated with both cardiovascular risk factors and self-reported dental diseases, which support the assumption that they share a common behavioral background.


Apolipoprotein A-I mimetics mitigate intestinal inflammation in COX2-dependent inflammatory bowel disease model.
Cyclooxygenase 2 (Cox2) total knockout and myeloid knockout (MKO) mice develop Crohn's-like intestinal inflammation when fed cholate-containing high fat diet (CCHF). We demonstrated that CCHF impaired intestinal barrier function and increased translocation of endotoxin, initiating TLR/MyD88-dependent inflammation in Cox2 KO but not WT mice. Cox2 MKO increased pro-inflammatory mediators in LPS-activated macrophages, and in the intestinal tissue and plasma upon CCHF challenge. Cox2 MKO also reduced inflammation resolving lipoxin A4 (LXA4) in intestinal tissue, while administration of an LXA4 analog rescued disease in Cox2 MKO mice fed CCHF. The apolipoprotein A-I (APOA1) mimetic 4F mitigated disease in both the Cox2 MKO/CCHF and piroxicam-accelerated Il10-/- models of inflammatory bowel disease (IBD) and reduced elevated levels of pro-inflammatory mediators in tissue and plasma. APOA1 mimetic Tg6F therapy was also effective in reducing intestinal inflammation in the Cox2 MKO/CCHF model. We further demonstrated that APOA1 mimetic peptides: i) inhibited LPS and oxidized 1-palmitoyl-2-arachidonoyl-sn-phosphatidylcholine (oxPAPC) dependent pro-inflammatory responses in human macrophages and intestinal epithelium; and ii) directly cleared pro-inflammatory lipids from mouse intestinal tissue and plasma. Our results support a causal role for pro-inflammatory and inflammation resolving lipids in IBD pathology and a translational potential for APOA1 mimetic peptides for the treatment of IBD.


Effect of modest alcohol consumption over 1-2 weeks on the coronary microcirculation of normal subjects.
It has been reported that imbibing red wine increases coronary blood flow reserve acutely. In the absence of changes in coronary driving pressure, any increases in coronary blood flow reserve should occur through a decrease in capillary resistance, which in turn is determined by capillary dimensions and whole-blood viscosity. Since alcohol intake is unlikely to acutely change capillary dimensions, we hypothesized that it must increase coronary blood flow reserve by reducing whole-blood viscosity. Forty-five normal subjects were randomly assigned to water (n = 12), vodka (n = 11), white wine (n = 11), and red wine (n = 11). Myocardial blood flow reserve was measured at baseline and after up to 2 weeks of beverage consumption using myocardial contrast echocardiography. In addition, whole-blood viscosity and its principal determinants (haematocrit; erythrocyte deformability, mobility, and charge; plasma fibrinogen; and total serum protein, glucose, and lipids) were also measured. Systolic and diastolic blood pressure and heart rate did not change between the two examinations either at rest or following dipyridamole infusion. Neither did myocardial blood flow reserve nor whole-blood viscosity or any of its determinants. Only high-density lipoprotein-2 increased for all alcohol consumers (12.4 +/- 5.3 vs. 10.9 +/- 4.7, P = 0.007). It is concluded that modest alcohol consumption for up to 2 weeks does not increase myocardial blood flow reserve. It also does not alter whole-blood viscosity or any of its principal determinants. Therefore, the beneficial cardiovascular effects of modest alcohol consumption over 1-2 weeks cannot be attributed either to its effect on the coronary microcirculation or haemorheology.


Spontaneous and Excellent Healing of Bilateral Brown Tumors in Mandible after Endocrinal Therapy and Subtotal Parathyroidectomy: Case Report with 4-Year Follow-Up.
Primary hyperparathyroidism is an endocrine disorder occurring due to increased secretion of parathormone resulting in a complex of clinical, anatomical, and biochemical alterations. On the other hand, excision of a parathyroid adenoma can normalize the metabolic status. A 24-year-old man was referred to the hospital with bilateral swelling and spontaneous gingival bleeding from posterior of the mandible also with radiolucent well-demarcated lesions bilaterally in the mandibular third molar regions. After consultations, the patient was hospitalized in the endocrinology department where further tests were performed due to highly increased PTH level as 714 pg/ml. Bilateral brown tumors started to regress spontaneously, and no additional surgery was required after subtotal parathyroidectomy was performed. The presented case is the first patient whose bilateral brown tumors in the jaws spontaneously and totally healed after subtotal parathyroidectomy and endocrinal therapy who was strictly followed up for 4 years even though the lesions were associated with impacted third molars.


Judgement analysis of case severity and future risk of disability regarding chronic low back pain by general practitioners in Ireland.
Chronic low back pain is a major healthcare burden that has wide ranging effects on the individual, their family, society and the workplace. However, appropriate management and treatment is often difficult, as a majority of cases are non-specific in terms of underlying pathology. As a result, there are extensive differences in both individual patient preferences for treatment and treatment decisions amongst general practitioners. The current study examined the clinical judgements of GPs in Ireland, regarding fictional patients' case severity and future risk of disability, through judgement analysis. Judgement analysis (JA) is an idiographic regression modelling technique that has been utilised in extant healthcare research for the purpose of allocating weighting to judgement criteria, or cues, observed by professionals in their clinical decision-making. The primary aim of the study was to model two critical information utilisation tasks performed by GPs with regard to CLBP-in combining information cues to form a judgement about current case severity and a judgement about the same patient's risk of future disability. It was hypothesised that the judgement weighting would differ across the two judgements and that judgements regarding future risk of disability would be less consistent among GPs than judgements about case severity. Results from the regression-based judgement analysis and subsequent follow-up statistical analysis provided support for both study hypotheses. Study findings are discussed in light of theory and research on judgement, clinical decision-making and chronic low back pain.


Sequestering the standard model vacuum energy.
We propose a very simple reformulation of general relativity, which completely sequesters from gravity all of the vacuum energy from a matter sector, including all loop corrections and renders all contributions from phase transitions automatically small. The idea is to make the dimensional parameters in the matter sector functionals of the 4-volume element of the Universe. For them to be nonzero, the Universe should be finite in spacetime. If this matter is the standard model of particle physics, our mechanism prevents any of its vacuum energy, classical or quantum, from sourcing the curvature of the Universe. The mechanism is consistent with the large hierarchy between the Planck scale, electroweak scale, and curvature scale, and early Universe cosmology, including inflation. Consequences of our proposal are that the vacuum curvature of an old and large universe is not zero, but very small, that w(DE) ≃ -1 is a transient, and that the Universe will collapse in the future.


Association of Dietary Intakes and Genetically Determined Serum Concentrations of Mono and Poly Unsaturated Fatty Acids on Chronic Kidney Disease: Insights from Dietary Analysis and Mendelian Randomization.
Polyunsaturated fatty acid (PUFA) intake is generally associated with better renal function, while the association of monounsaturated fatty acids (MUFAs) remains unconfirmed. Mendelian randomization (MR) analysis was used to obtain unconfounded estimates of the causal association of dietary intake and genetically determined serum PUFA and MUFA levels with measures of renal function. Data from participants of the National Health and Nutrition Examination Surveys (NHANES) from 2005 to 2010 were used. Data from the largest genome-wide association studies (GWAS) on MUFAs, PUFAs, eGFR, and chronic kidney disease (CKD) were analysed for the entire sample. A total of 16,025 participants were included. eGFR improved across increasing quartiles of total PUFA intake from 86.3 ± 0.5 (Q1) to 96.2 ± 0.5 mL/min/1.73 m² (Q4), (p < 0.001). Conversely, there was no association between MUFA intake and measures of renal function (all p > 0.21). In multivariable models, the top quartile of PUFA intake had a 21% lower risk for CKD, but there was no significant association between CKD risk and MUFA intake. Genetically determined serum MUFA (heptadecenoate (17:1), myristoleic acid (14:1), and palmitoleic acid (16:1)) and PUFA (α-linolenic acid and eicosapentaenoic acid) concentrations had no significant association with eGFR and CKD risk. Additionally, no association was found in the analyses stratified by diabetes status. Higher dietary PUFA intake is associated with lower risk of CKD, while there was no association with serum levels of MUFAs or PUFAs. Additional studies including clinical trials are warranted.


Simultaneous augmentation/mastopexy: a retrospective 5-year review of 332 consecutive cases.
Of all mastopexies performed in the authors' facility, approximately 77 percent of patients have an implant placed simultaneously. The unique challenges and safety concerns associated with the simultaneous augmentation/mastopexy procedure merit a deeper evaluation of its use and associated risks. A retrospective analysis of 430 mastopexy operations, including 332 simultaneous augmentation mastopexies, was performed. Patient demographics, patient selection, and operative approach were evaluated and correlated with surgical outcomes. Complications and reoperation rates were measured and compared with published reports in the literature. For simultaneous augmentation/mastopexy procedures, the overall complication rate was 22.9 percent (primary cases, 20.4 percent; secondary cases, 28.9 percent). Tissue- and implant-related complication rates were 15.1 and 7.8 percent, respectively. The overall reoperation rate was 23.2 percent (primary cases, 20.0 percent; secondary cases, 30.9 percent). Tissue- and implant-related reoperation rates were 13.3 and 9.9 percent, respectively. The most common complications were capsular contracture (13 of 332), poor scarring (11 of 332), and recurrent ptosis (11 of 332). They were also the most common indications for reoperation (11 of 332 for each one). The mastopexy-only reoperation rate of 10.2 percent was comparable to the tissue-related reoperation rate of 13.3 percent. Although the measured reoperation rate (23.2 percent) may be higher than that of either procedure performed independently, the revision rate of combining the procedures was not more than additive. With appropriate patient selection and a carefully planned operative approach, the authors believe a one-stage procedure can be safely performed with acceptable complication and reoperation rates. Therapeutic, III.


Role of advanced glycation end-products in obesity-related ovarian dysfunction.
Obesity affects ovarian function, one of the main regulators of female fertility. Tissue levels of the proinflammatory advanced glycation end-products (AGEs) and their receptors (RAGE) are elevated in obesity. AGEs are key contributors to perturbations in the ovarian microenvironment. On this basis, the present review focuses on clinical and experimental studies supporting the role of AGE-RAGE system as a contributor to obesity-related ovarian dysfunction. Particular emphasis has been given to changes in AGEs, RAGE and the anti-inflammatory soluble receptor (sRAGE) levels in obesity state and following dietary interventions (high-fat diet and weight loss). Ovarian sensitivity, in particular granulosa cell function and oocyte meiosis, to the pro-inflammatory AGE-RAGE system as well as the relationship of follicular fluid AGEs and sRAGE to in vitro fertilization outcome are also discussed. Overall, obesity, with its alterations in the AGE-RAGE system, can disrupt the ovarian microenvironment potentially compromising oocyte competence and fertility. This review underscores a critical need to uncover the mechanistic actions of AGE-RAGE system in obesity-related ovarian dysfunction. Clinical and basic studies focusing on elucidating the patterns of accumulation and role of the AGE-RAGE system in human ovarian follicles are key steps in understanding their contribution to the health of human oocytes and embryos.


Function of mitochondrial Stat3 in cellular respiration.
Cytokines such as interleukin-6 induce tyrosine and serine phosphorylation of Stat3 that results in activation of Stat3-responsive genes. We provide evidence that Stat3 is present in the mitochondria of cultured cells and primary tissues, including the liver and heart. In Stat3(-/-) cells, the activities of complexes I and II of the electron transport chain (ETC) were significantly decreased. We identified Stat3 mutants that selectively restored the protein's function as a transcription factor or its functions within the ETC. In mice that do not express Stat3 in the heart, there were also selective defects in the activities of complexes I and II of the ETC. These data indicate that Stat3 is required for optimal function of the ETC, which may allow it to orchestrate responses to cellular homeostasis.


Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection.
Data from randomized trials are lacking on the benefits and risks of initiating antiretroviral therapy in patients with asymptomatic human immunodeficiency virus (HIV) infection who have a CD4+ count of more than 350 cells per cubic millimeter. We randomly assigned HIV-positive adults who had a CD4+ count of more than 500 cells per cubic millimeter to start antiretroviral therapy immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells per cubic millimeter or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy (deferred-initiation group). The primary composite end point was any serious AIDS-related event, serious non-AIDS-related event, or death from any cause. A total of 4685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12,759 copies per milliliter, and the median CD4+ count was 651 cells per cubic millimeter. On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001). Hazard ratios for serious AIDS-related and serious non-AIDS-related events were 0.28 (95% CI, 0.15 to 0.50; P<0.001) and 0.61 (95% CI, 0.38 to 0.97; P=0.04), respectively. More than two thirds of the primary end points (68%) occurred in patients with a CD4+ count of more than 500 cells per cubic millimeter. The risks of a grade 4 event were similar in the two groups, as were the risks of unscheduled hospital admissions. The initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter. (Funded by the National Institute of Allergy and Infectious Diseases and others; START ClinicalTrials.gov number, NCT00867048.).


Self-care for minor illness.
To describe experiences with and knowledge of minor illness, self-care interventions used in minor illness and channels of information used when providing self-care for minor illness. Although minor illness is self-limiting, symptoms can be substantial and have a great impact on the affected person's wellbeing. Possibilities to seek and find information about health and self-care have significantly increased through internet-based communities, forums, and websites. Still, a considerable number of consultations with general practitioners are for conditions that are potentially self-treatable. Seeking advanced care for minor illnesses is costly for society and can create discomfort for patients as they are down-prioritized at emergency departments. Study participants were recruited randomly from the Swedish Address Register. A questionnaire was sent out, and the final sample included 317 randomly selected persons aged 18-80 and living in Sweden. Having experienced a specific illness correlated with self-reported knowledge. Preferred self-care interventions differed between different conditions, but resting and self-medicating were commonly used, along with consulting health care facilities. Compliance to advice was the highest for official information channels, and family members were a popular source of advice.


Streamer branching rationalized by conformal mapping techniques.
Spontaneous branching of discharge channels is frequently observed, but not well understood. We recently proposed a new branching mechanism based on simulations of a simple continuous discharge model in high fields. We here present analytical results for such streamers in the Lozansky-Firsov limit where they can be modeled as moving equipotential ionization fronts. This model can be analyzed by conformal mapping techniques which allow the reduction of the dynamical problem to finite sets of nonlinear ordinary differential equations. Our solutions illustrate that branching is generic for the intricate head dynamics of streamers in the Lozansky-Firsov limit.


Treatment options for chronic myeloid leukemia.
The bcr-abl tyrosine kinase inhibitors (TKIs) are the cornerstone treatment for chronic myeloid leukemia (CML). However, there are many topics related to therapy that remain debated. The aim of this paper is to give the reader a comprehensive review of how to treat CML at diagnosis, how to monitor the disease and a brief read of special populations and case scenarios. It describes the first-line (imatinib) and second-line (nilotinib and dasatinib) TKIs currently used for the treatment of CML, including landmark studies proving their efficacy, side effect profile, dosage and use in special populations. It also reviews the current guidelines regarding treatment and monitoring of the disease while on TKIs, along with an overview of treatment in advanced stages, the role of allogeneic stem cell transplantation and investigational drugs. Although imatinib represented a mayor therapeutic advancement over conventional chemotherapy, second-generation TKIs offer higher rates of optimal response and should be used as the frontline therapy. Patients with the T315I mutation carry a worse prognosis and should be offered allogeneic stem cell transplantation. The treatment in advanced stages of CML remains suboptimal and bench, translational and clinical research is encouraged.


Cost to government health-care services of treating acute self-poisonings in a rural district in Sri Lanka.
To estimate the direct financial costs to the Sri Lanka Ministry of Health of treating patients after self-poisoning, particularly from pesticides, in a single district. Data on staff, drug, laboratory and other inputs for each patient admitted for self-poisoning were prospectively collected over a one-month period from one general hospital (2005) and five peripheral hospitals (2006) in the Anuradhapura district. Data on transfers to secondary- and tertiary-level facilities were obtained for a 6-month period from 30 peripheral hospitals. The cost of the inputs in United States dollars (US$), using 2005 figures, was derived from hospital accounts. The average total cost of treating a self-poisoned patient at the general hospital was US$ 31.83, with ward staff input and drugs being the highest expenditure category and only US$ 0.19 of this sum related to capital and maintenance costs. The average total cost of treatment was highest for self-poisoning with pesticides (US$ 49.12). The patients placed in the intensive care unit, who comprised 5% of the total, took up 75% of the overall treatment cost for all self-poisoned patients at the general hospital. The average total cost of treating self-poisoned patients at peripheral hospitals was US$ 3.33. The average patient cost per transfer was US$ 14.03. In 2006, the total cost of treating self-poisoned patients in the Anuradhapura district amounted to US$ 76,599, of which US$ 53,834 were comprised of pesticide self-poisonings. Based on the total treatment cost per self-poisoned patient estimated in this study, the cost of treating self-poisoned patients in all of Sri Lanka in 2004 was estimated at US$ 866,304. The cost of treating pesticide self-poisonings may be reduced by promoting the use of less toxic pesticides and possibly by improving case management in primary care hospitals. Additional research is needed to assess if increasing infrastructure and staff at peripheral hospitals could reduce the overall cost to the government, optimize case management and reduce pressure on secondary services.


Influence of Mouth Pressure on Measurement of Diffusing Capacity in the Clinical Pulmonary Function Laboratory.
Current American Thoracic Society/European Respiratory Society guidelines recommend that patients hold their breath with minimum effort at total lung capacity during measurement of the single-breath diffusing capacity of the lung for carbon monoxide (DLCO) to avoid excessively positive or negative mouth pressures. We asked to what extent do these pressures range during single-breath DLCO testing and whether mouth pressures are associated with single-breath DLCO. We analyzed mouth pressures measured during clinical single-breath DLCO testing in an academic pulmonary function laboratory over a 3-month period. We compared mouth pressures with single-breath DLCO and determined the influence of obesity, restriction, and emphysema on mouth pressures. We used multiple linear regression to evaluate whether mouth pressure was an independent determinant of single-breath DLCO. We analyzed data from 336 subjects who presented with a variety of diseases, the most common of which were unexplained dyspnea, interstitial lung disease, sarcoidosis, and emphysema. The median mouth pressure was 4.5 cm H2O, with a range of -13 to 31 cm H2O. The single-breath DLCO did not correlate with mouth pressure (P = .08). There was no difference in mouth pressures between individuals with and without obesity, with and without restriction, and with and without interstitial lung disease. Mouth pressure was lower among the subjects with emphysema. There was no difference in single-breath DLCO % predicted between individuals who were obese and individuals who were not obese. Multiple linear regression demonstrated that only age and FEV1, but not mouth pressure, were independently associated with single-breath DLCO % predicted (ß-coefficient: age, -0.35 [P = .003]; FEV1%, 0.26 [P = .004]; adjusted R2, 0.16). Mouth pressures varied widely during single-breath DLCO measurement but were not associated with the measurement of single-breath DLCO in the clinical setting of pulmonary function testing. Overall, these findings indicate that pulmonary function technologists need not discard efforts made during measurement of single-breath DLCO if only mild changes in mouth pressure occur.


Elevated blood ketone and glucagon levels cannot account for 1,3-butanediol induced cerebral protection in the Levine rat.
1,3-Butanediol is an ethanol dimer that induces systemic ketosis. It has previously been shown to increase hypoxic survival time and reduce neurologic deficit in several experimental preparations. The aim of this study was to determine if the mechanism of 1,3-butanediol-induced cerebral protection was elevation of blood ketone levels, blood glucagon levels, or both. Blood beta-hydroxybutyrate levels, glucagon levels, or both produced by a previously reported protective dose of 1,3-butanediol (47 mmol/kg) were simulated by direct i.v. infusion of the ketone beta-hydroxybutyrate and glucagon separately and in combination, and the effect on hypoxic survival time in instrumented Levine rats (unilateral carotid ligation and hypoxic exposure) was determined. To test if the mechanism was a direct or osmotic effect of the alcohol, an equimolar dose of ethanol (47 mmol/kg) was administered and the effect on hypoxic survival time was compared with that produced by 1,3-butanediol. As in previous studies, 1,3-butanediol significantly increased hypoxic survival time (241% of control, Scheffe p less than 0.05). Various doses of beta-hydroxybutyrate and glucagon were infused to approximate the blood levels of beta-hydroxybutyrate and glucagon produced by a protective dose of 1,3-butanediol. Although beta-hydroxybutyrate or glucagon infusions produced blood levels of these substances that were comparable with those produced by administering butanediol, they failed to prolong hypoxic survival time as long as 1,3-butanediol. No correlation was detected between hypoxic survival time and blood levels of beta-hydroxybutyrate, glucagon, insulin, or glucose. An equimolar dose of ethanol did not significantly increase hypoxic survival time.(ABSTRACT TRUNCATED AT 250 WORDS)


Isolation and characterization of the native glycoprotein from pig small-intestinal mucus.
Glycoprotein from pig small-intestinal mucus was isolated free of non-covalently bound protein and nucleic acid with a yield of over 60%. No non-covalently bound protein could be detected by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis or by equilibrium centrifugation in a density gradient of CsCl with 4 M-guanidinium chloride. The intrinsic viscosity and reduced viscosity of the glycoprotein preparations rose with the removal of non-covalently bound protein and nucleic acid from the glycoprotein, evidence that non-covalently bound protein does not contribute to the rheological properties of the glycoprotein in the mucus. The pure glycoprotein, in contrast with impure preparations, gelled at the same concentration of glycoprotein as that present in the gel in vivo. The glycoprotein was a single component, as judged by gel filtration and analytical ultracentrifugation. The distribution of sedimentation coefficients was polydisperse but unimodal with an s025,w of 14.5S and a molecular weight of 1.72 X 10(6). The chemical composition of the glycoprotein was 77% carbohydrate and 21% protein, 52% of which was serine, threonine and proline. The glycoprotein had a strong negative charge and contained 3.1% and 18.3% by weight ester sulphate and sialic acid respectively. The molar proportion of N-acetylgalactosamine was nearly twice that of any of the other sugars present, the glycoprotein had A and H blood-group activity and the average maximum length of the carbohydrate chains was deduced to be six to eight sugar residues.


mRNA expression analysis and the molecular basis of neonatal testis defects in Dmrt1 mutant mice.
Transcriptional regulators containing the DM domain DNA binding motif have been found to control sexual differentiation in a diverse group of metazoan animals including vertebrates, insects, and nematodes, suggesting that these proteins may comprise a very ancient group of sexual regulators. Dmrt1, 1 of 7 mammalian DM domain genes, is essential for several aspects of testicular differentiation in mice. The Dmrt1 mutant phenotype becomes apparent shortly after birth, and culminates in severe testicular dysgenesis. To better understand the roles of Dmrt1 in testicular development we have performed a more detailed analysis of its mutant phenotypes, and we have used mRNA expression profiling to identify genes misregulated in the neonatal Dmrt1 mutant testis. We find that Dmrt1 mutant germ cells fail to undergo several of the normal postnatal events of germ cell development, including radial movement, mitotic proliferation, differentiation into spermatogonia, and initiation of meiosis, and they die by P14. During this period Dmrt1 mutant Sertoli cells fail to polarize and form tight junctions, and fail to cease proliferation, eventually filling the seminiferous tubules. Expression profiling at P1 and P2 in Dmrt1 mutant testes indicates defects in several important testicular signaling pathways (Gdnf, retinoic acid, TGFbeta, FSH), and detects elevated expression of the pluripotency marker Stella/Dppa3/Pgc7, providing insight into the molecular basis of Dmrt1 testis defects. This work also identifies a number of new candidate testicular regulators for further investigation.


Identification and characterization of areas of high and low risk for asymptomatic malaria infections at sub-village level in Ratanakiri, Cambodia.
Malaria elimination needs a concentration of activities towards identification of residual transmission foci and intensification of efforts to eliminate the last few infections, located in so-called 'malaria hotspots'. Previous work on characterizing malaria transmission hotspots has mainly focused on falciparum malaria and especially on symptomatic cases, while the malaria reservoir is expected to be mainly concentrated in the asymptomatic human population when transmission is low. For Plasmodium vivax, there has been less effort in identifying transmission hotspots. The main aim of this study was to uncover micro-epidemiological mechanisms of clustering of malaria infections at a sub-village level, based on geographical or behavioural features. A cross-sectional survey was performed in three villages within the highest malaria endemic province of Cambodia. The survey took place in the dry season, when the malaria reservoir is expected to be low and residing in the asymptomatic part of the population. Village and field locations of households were georeferenced, blood samples were taken from as many residents as possible and a short questionnaire probing for individual risk factors was taken. Asymptomatic malaria carriers were detected by PCR, and geographical clustering analysis (SaTScan) as well as risk factor analysis were performed. A total of 1540 out of 1792 (86%) individuals were sampled. Plasmodial DNA was detected in 129 individuals (8.4%). P. vivax was most prevalent (5.5%) followed by Plasmodium malariae (2.1%) and Plasmodium falciparum (1.6%). Mixed infection occurred in 12 individuals. In two out of three villages geographical clustering of high and low malaria infection risk was clearly present. Cluster location and risk factors associated with the infection differed between the parasite species. Age was an important risk factor for the combined Plasmodium infections, while watching television at evenings was associated with increased odds of P. vivax infections [OR (CI): 1.86 (0.95-3.64)] and bed net use was associated with reduced odds of P. falciparum infections [OR (CI): 0.25 (0.077-0.80)]. Clusters of malaria carriers were malaria species specific and often located remotely, outside village centres. As such, at micro-epidemiological level, malaria is not a single disease. Further unravelling the micro-epidemiology of malaria can enable programme managers to define the interventions likely to contribute to halt transmission in a particular hotspot location.


Improved WDM performance of a fibre optical parametric amplifier using Raman-assisted pumping.
We experimentally demonstrate a Raman-Assisted Fibre Optical Parametric Amplifier (RA-FOPA) with 20dB net gain using wavelength division multiplexed signals. We report amplification of 10x58Gb/s 100GHz-spaced QPSK signals and show that by appropriate tuning of the parametric pump power and frequency, gain improvement of up to 5dB can be achieved for the RA-FOPA compared with combined individual contributions from the parametric and Raman pumps. We compare the RA-FOPA with an equivalent-gain conventional FOPA and find that four-wave mixing crosstalk is substantially reduced by up to 5.8 ± 0.4dB using the RA-FOPA. Worst-case performance penalty of the RA-FOPA is found to be only 1.0 ± 0.2dB over all measured OSNRs, frequencies and input powers, making it an attractive proposal for future communications systems.


Survival and lifetime costs associated with first-line bevacizumab use in older patients with metastatic colorectal cancer.
The objective of this study was to investigate clinical effectiveness and incremental lifetime costs associated with first-line bevacizumab in older patients with metastatic colorectal cancer (mCRC). Patients diagnosed with mCRC in 2004-2007 were identified from the Surveillance, Epidemiology, and End Results-Medicare database and stratified by first-line treatment (no chemotherapy [CTx], CTx alone, CTx plus bevacizumab). The impact of first-line bevacizumab on survival was investigated using a propensity score adjusted multivariate Cox proportional hazards model. Mean lifetime costs for each cohort were calculated using Medicare claims for all services rendered between diagnosis and end of follow-up, adjusting for death and censoring. A total of 4,414 patients (mean age: 77.3 years) were identified, of whom 15% received first-line bevacizumab. Among first-line-treated patients, bevacizumab receipt was associated with improved overall survival (hazard ratio: 0.85 [95% confidence interval: 0.75-0.97]; p = .013), and this benefit was limited to patients who received >1 month of bevacizumab therapy. Median and mean survival were greatest in patients treated with CTx plus bevacizumab relative to CTx alone (CTx plus bevacizumab median 19.4 months [mean 28.0 months] vs. CTx alone median 15.1 months [mean 22.9 months]; p < .001), as were mean lifetime costs (mean per patient cost $143,284 vs. $111,280). Compared with CTx alone, CTx plus bevacizumab was associated with a 5.1-month increase in mean survival and a $32,004 increase in mean lifetime treatment costs, with an incremental cost of $75,303 per life-year gained. Bevacizumab use is associated with longer survival than CTx alone in older patients treated in real-world clinical settings, at an incremental cost of $75,303 per life-year gained.


Tear ferning in contact lens wearers.
Tear ferning (TF) has shown good sensitivity and specificity in the diagnosis of dry eye, but is a relatively uncommon test, especially in contact lens wearers. The aim of this study was to investigate the relationship between TF, ocular comfort and tear film stability amongst contact lens (CL) wearers and non-contact lens (NCL) wearers. Subjects (36 NCL, 24 CL; mean age 23.2 +/- 4.8 years) underwent assessment of non-invasive tear break up time (NIBUT), fluorescein tear break up time (FBUT) and completed the Ocular Comfort Index (OCI) questionnaire. Non-stimulated tears were collected from the inferior tear meniscus with a glass capillary. Samples of 1.5 microL were air dried, observed by light microscopy and the TF pattern quantified according to Rolando's grading scale. Significantly higher grades of TF pattern and discomfort (higher OCI scores) were observed in CL wearers compared to NCL wearers (Mann-Whitney U-test; p < 0.005 and p < 0.05 respectively). Differences in tear film stability were not significant between groups. Even when asymptomatic (low OCI scores) CL and NCL subjects were compared, TF remained significantly different (p < 0.005). In both CL and NCL subjects, TF displayed poor correlation with tear film stability tests and OCI scores. Higher TF grades in CL wearers, even if asymptomatic, indicate an unfavourable ratio of salt to macromolecule concentration within the tear film of such subjects. The lack of significant difference in TF between symptomatic CL and NCL wearers could suggest similar aetiology (tear film hyperosmolarity) in each cohort. The TF technique demonstrates limited sensitivity and specificity for the prediction of ocular surface comfort in both CL and NCL wearers.


Label-free analysis of cellular biochemistry by Raman spectroscopy and microscopy.
We review the biomedical applications of Raman spectroscopy at the single cell and tissue level. Raman scattering is the inelastic scattering of light by molecular bonds resulting in a wealth of spectral bands, which enable the identification of biological materials and the nondestructive analysis of dynamic changes in their biochemistry. We briefly review the basics behind highly sensitive Raman spectroscopy and highlight recent applications to biomedical research. We discuss advanced chemometrics methods that are utilized to analyze Raman spectral data and which permit one, for example, to distinguish between normal and diseased cells or which enable one to follow the differentiation of stem cells without perturbing the cellular biochemistry. We also discuss advanced coherent Raman scattering techniques, such as coherent anti-Stokes Raman scattering and stimulated Raman scattering, which allow for the molecularly specific imaging of cells, tissues, and entire organisms in vitro and in vivo.


Cementless total hip arthroplasty in patients fifty years of age or younger: a minimum ten-year follow-up.
The durability of total hip arthroplasty in younger patients has been reported to be less than that in older patients. The purpose of this study was to evaluate the results of cementless total hip arthroplasty performed in a consecutive series of patients fifty years of age or younger who were followed for a minimum of ten years. We prospectively followed 100 consecutive patients (115 hips) who were fifty years of age or younger when they were treated with primary cementless total hip arthroplasty with use of a second-generation, extensively porous-coated femoral stem and a cementless acetabular component. The patients were followed for a minimum of ten years, and the results were compared with our patients in the same age group who had total hip arthroplasty with cement. Evaluation included the need for revision, activity questionnaires, six-minute walks, activity level monitoring with an accelerometer, and radiographic evaluation for evidence of loosening, wear, and osteolysis. Seventy-three patients (eighty-two hips) were available for follow-up at ten years (mean, twelve years). Seventeen patients (twenty-three hips) had died, and ten patients (ten hips) were lost to follow-up. The average age at the time of surgery was 40.1 years. Three femoral stems were revised for periprosthetic fracture. No acetabular shell or femoral stem was revised for loosening, and none were loose on radiographs made at the time of a minimum ten-year follow-up. This compares favorably with the cemented cohort, which had poorer survivorship of the implant with regard to revision for aseptic loosening and radiographic loosening. Reoperation for any reason was similar between the two cohorts at ten years, primarily because of the relatively large numbers of revisions for polyethylene wear in the cementless group. Cementless total hip arthroplasty with use of a second-generation, extensively porous-coated stem demonstrated durable fixation in an active, younger population at a minimum follow-up of ten years and had better survivorship with respect to fixation compared with our previously reported cemented cohort.


Durability of Gadolinium Zirconate/YSZ Double-Layered Thermal Barrier Coatings under Different Thermal Cyclic Test Conditions.
Higher durability in thermal barrier coatings (TBCs) is constantly sought to enhance the service life of gas turbine engine components such as blades and vanes. In this study, three double layered gadolinium zirconate (GZ)-on-yttria stabilized zirconia (YSZ) TBC variants with varying individual layer thickness but identical total thickness produced by suspension plasma spray (SPS) process were evaluated. The objective was to investigate the role of YSZ layer thickness on the durability of GZ/YSZ double-layered TBCs under different thermal cyclic test conditions i.e., thermal cyclic fatigue (TCF) at 1100 °C and a burner rig test (BRT) at a surface temperature of 1400 °C, respectively. Microstructural characterization was performed using SEM (Scanning Electron Microscopy) and porosity content was measured using image analysis technique. Results reveal that the durability of double-layered TBCs decreased with YSZ thickness under both TCF and BRT test conditions. The TBCs were analyzed by SEM to investigate microstructural evolution as well as failure modes during TCF and BRT test conditions. It was observed that the failure modes varied with test conditions, with all the three double-layered TBC variants showing failure in the TGO (thermally grown oxide) during the TCF test and in the ceramic GZ top coat close to the GZ/YSZ interface during BRT. Furthermore, porosity analysis of the as-sprayed and TCF failed TBCs revealed differences in sintering behavior for GZ and YSZ. The findings from this work provide new insights into the mechanisms responsible for failure of SPS processed double-layered TBCs under different thermal cyclic test conditions.


Non-invasive measurement of respiratory rate in children using the photoplethysmogram.
Respiratory rate is recognised as a valuable predictor of the severity of illness in children, but it is not currently feasible to measure this automatically in a triage environment. Autoregressive modelling on data from the pulse oximeter photoplethysmogram has the potential to introduce automated breathing measurement into the realm of paediatric triage. Using autoregressive modelling, it is shown that respiratory rate can be extracted from the paediatric photoplethysmogram with a mean error of 3.4 breaths per minute.


Inhibitory effect of exogenous oxytocin on ACTH and cortisol secretion during labour.
Complex mechanisms which are still not completely defined, are responsible for the spontaneous onset of labour: an essential role is attributed to endocrine factors. A massive increase, even three times higher than normal physiological values of ACTH and cortisol, has been reported during labour. Similar behaviour has also been recorded for oxytocin at the end of pregnancy as well as during labour. The relationship between oxytocin and the adrenal axis are still debated thus the goal of our study was to attempt to clarify this rapport. Sixty-two women at the end of a term-pregnancy agreed to participate in this study: 46 were innoculated with oxytocin (syntocinon) every 20 minutes for 1 hour; 16 were administered a natural placebo every 20 minutes for 1 hour (control group). ACTH and cortisol values from plasma samples were taken every 20 minutes and analyzed. Our results demonstrated an inhibitory effect of exogenous oxytocin on ACTH and cortisol release. This inhibitory effect, as shown by our results, is time and dose-related. High oxytocin levels, as during exogenous infusion, could induce an effect opposite a normal physiologic one.


Neural correlates of lyrical improvisation: an FMRI study of freestyle rap.
The neural correlates of creativity are poorly understood. Freestyle rap provides a unique opportunity to study spontaneous lyrical improvisation, a multidimensional form of creativity at the interface of music and language. Here we use functional magnetic resonance imaging to characterize this process. Task contrast analyses indicate that improvised performance is characterized by dissociated activity in medial and dorsolateral prefrontal cortices, providing a context in which stimulus-independent behaviors may unfold in the absence of conscious monitoring and volitional control. Connectivity analyses reveal widespread improvisation-related correlations between medial prefrontal, cingulate motor, perisylvian cortices and amygdala, suggesting the emergence of a network linking motivation, language, affect and movement. Lyrical improvisation appears to be characterized by altered relationships between regions coupling intention and action, in which conventional executive control may be bypassed and motor control directed by cingulate motor mechanisms. These functional reorganizations may facilitate the initial improvisatory phase of creative behavior.


Advancing Cardiovascular, Neurovascular, and Renal Magnetic Resonance Imaging in Small Rodents Using Cryogenic Radiofrequency Coil Technology.
Research in pathologies of the brain, heart and kidney have gained immensely from the plethora of studies that have helped shape new methods in magnetic resonance (MR) for characterizing preclinical disease models. Methodical probing into preclinical animal models by MR is invaluable since it allows a careful interpretation and extrapolation of data derived from these models to human disease. In this review we will focus on the applications of cryogenic radiofrequency (RF) coils in small animal MR as a means of boosting image quality (e.g., by supporting MR microscopy) and making data acquisition more efficient (e.g., by reducing measuring time); both being important constituents for thorough investigational studies on animal models of disease. This review attempts to make the (bio)medical imaging, molecular medicine, and pharmaceutical communities aware of this productive ferment and its outstanding significance for anatomical and functional MR in small rodents. The goal is to inspire a more intense interdisciplinary collaboration across the fields to further advance and progress non-invasive MR methods that ultimately support thorough (patho)physiological characterization of animal disease models. In this review, current and potential future applications for the RF coil technology in cardiovascular, neurovascular, and renal disease will be discussed.


Nasal patency and lavage biomarkers in relation to settled dust and cleaning routines in schools.
This study determined the relations between settled dust and cleaning routines in classrooms on one hand, and nasal symptoms, nasal cavity dimensions, and the concentration of selected biomarkers of inflammation in nasal lavage on the other. Measurements of settled dust via standardized vacuum cleaning and an investigation of the cleaning routines were performed in 12 randomly selected primary schools in the municipality of Uppsala. Clinical examinations including acoustic rhinometry and nasal lavage were performed in the school environment among 279 school personnel working in the main buildings of the schools. Eosinophil cationic protein (ECP), myeloperoxidase (MPO), lysozyme, and albumin were analyzed in the lavage fluid. The relationships between the medical and hygienic data were analyzed both bivariately and with a multiple regression model controlling for age, gender, smoking, atopy, room temperature, and urban vicinity of the school. The amount of settled dust was positively related to subjective nasal obstruction and smaller nasal cavity dimensions measured with acoustic rhinometry. The noses were less patent, and the levels of ECP or lysozyme in the lavage were increased for the subjects in schools with a lower frequency of floor mopping, a lower frequency of desk cleaning, and where wet mopping was used. Our results indicate that the actual dust levels in Swedish classrooms can affect the occurrence of nasal obstruction among school personnel. A beneficial effect on the clinical signs of the nasal mucosa was observed for a higher frequency of both floor mopping and desk cleaning, whereas the use of wet mopping seemed disadvantageous in comparison with dry mopping. These findings illustrate the need for adequate cleaning procedures to minimize the environmental effects on the airway mucosa.


BapE DNA endonuclease induces an apoptotic-like response to DNA damage in Caulobacter.
In the presence of extensive DNA damage, eukaryotes activate endonucleases to fragment their chromosomes and induce apoptotic cell death. Apoptotic-like responses have recently been described in bacteria, but primarily in specialized mutant backgrounds, and the factors responsible for DNA damage-induced chromosome fragmentation and death have not been identified. Here we find that wild-type Caulobacter cells induce apoptotic-like cell death in response to extensive DNA damage. The bacterial apoptosis endonuclease (BapE) protein is induced by damage but not involved in DNA repair itself, and mediates this cell fate decision. BapE fragments chromosomes by cleaving supercoiled DNA in a sequence-nonspecific manner, thereby perturbing chromosome integrity both in vivo and in vitro. This damage-induced chromosome fragmentation pathway resembles that of eukaryotic apoptosis. We propose that damage-induced programmed cell death can be a primary stress response for some bacterial species, providing isogenic bacterial communities with advantages similar to those that apoptosis provides to multicellular organisms.


A 6-months assessment of the alcohol-related clinical burden at emergency rooms (ERs) in 11 acute care hospitals of an urban area in Germany.
The purpose of the study was to identify and to profile alcohol-related attendances to emergency rooms (ERs) of 11 hospitals of various medical specialties covering a large urban population, to assess risk factors associated with short-stay cases, repeat attendances and higher degree of alcohol consumption and to estimate their impact on the alcohol-related burden at ERs. A 6-months study was carried out to obtain clinical and administrative data on single and multiple attendances at ERs in 11 governmental acute hospitals in a large city in Germany. All alcohol-related attendances at ERs of study hospitals were eligible. A broad definition of alcohol-related attendances independently from alcohol diagnosis and various demographic, clinical and administrative measures were used. Odds ratios for the associations of these measures with duration of stay, repeat attendances and higher degrees of alcohol consumption were derived from multivariate binomial and multinomial logistic regression models. 1,748 patients with symptoms of alcohol consumption or withdrawal (inclusion rate 83.8%) yielded 2,372 attendances (3% of all medical admissions), and resulted in 12,629 inpatient-days. These patients accounted for 10.7 cases per 1,000 inhabitants. The average duration of inpatient stay was 10 days. 1,451 of all patients (83%) presented once, whereas the median of repeat attendances was three for the remaining 297 patients. Short-stay cases (<24 hours) were significantly linked with male gender, alcohol misuse, trauma (or suspicion of a trauma) and medical specialties. Increased levels of alcohol consumption at first attendance were significantly associated with repeat attendances in due course. In a multinomial logistic regression model higher degrees of alcohol consumption were significantly associated with male gender, trauma, short-stays, attendance outside regular working time, and with repeat attendances and self-discharge. Apart from demographic factors, the alcohol-related clinical burden is largely determined by short-stay cases, repeat attendances and cases with higher levels of alcohol consumption at first attendance varying across medical specialties. These findings could be relevant for the planning of anti-alcoholic interventions at ERs.


Cell cycle effects of nonsteroidal anti-inflammatory drugs and enhanced growth inhibition in combination with gemcitabine in pancreatic carcinoma cells.
Increased cyclooxygenase-2 (COX-2) expression in human pancreatic adenocarcinomas, as well as the growth-inhibitory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro, suggests that NSAIDs may be an effective treatment for pancreatic cancer. Gemcitabine is currently the most effective chemotherapeutic drug available for patients with pancreatic cancer, but is only minimally effective against this aggressive disease. Clearly, other treatment options must be identified. To design successful therapeutic strategies involving compounds either alone or in combination with others, it is necessary to understand their mechanism of action. In the present study, we evaluated the effects of three NSAIDs (sulindac, indomethacin, and NS-398) or gemcitabine in two human pancreatic carcinoma cell lines, BxPC-3 (COX-2-positive) and PaCa-2 (COX-2-negative), previously shown to be growth-inhibited by these NSAIDs. Effects on cell cycle and apoptosis were investigated by flow cytometry or Western blotting. Treatment with NSAIDs or gemcitabine altered the cell cycle phase distribution as well as the expression of multiple cell cycle regulatory proteins in both cell lines, but did not induce substantial levels of apoptosis. Furthermore, we demonstrated that the combination of the NSAID sulindac or NS-398 with gemcitabine inhibited cell growth to a greater degree than either compound alone. These results indicate that the antiproliferative effects of NSAIDs and gemcitabine in pancreatic tumor cells are primarily due to inhibition of cell cycle progression rather than direct induction of apoptotic cell death, regardless of COX-2 expression. In addition, NSAIDs in combination with gemcitabine may hold promise in the clinic for the treatment of pancreatic cancer.


Are molecular tools clarifying or confusing our understanding of the public health threat from zoonotic enteric protozoa in wildlife?
Emerging infectious diseases are frequently zoonotic, often originating in wildlife, but enteric protozoa are considered relatively minor contributors. Opinions regarding whether pathogenic enteric protozoa may be transmitted between wildlife and humans have been shaped by our investigation tools, and have led to oscillations regarding whether particular species are zoonotic or have host-adapted life cycles. When the only approach for identifying enteric protozoa was morphology, it was assumed that many enteric protozoa colonized multiple hosts and were probably zoonotic. When molecular tools revealed genetic differences in morphologically identical species colonizing humans and other animals, host specificity seemed more likely. Parasites from animals found to be genetically identical - at the few genes investigated - to morphologically indistinguishable parasites from human hosts, were described as having zoonotic potential. More discriminatory molecular tools have now sub-divided some protozoa again. Meanwhile, some infection events indicate that, circumstances permitting, some "host-specific" protozoa, can actually infect various hosts. These repeated changes in our understanding are linked intrinsically to the investigative tools available. Here we review how molecular tools have assisted, or sometimes confused, our understanding of the public health threat from nine enteric protozoa and example wildlife hosts (Balantoides coli - wild boar; Blastocystis sp. - wild rodents; Cryptosporidium spp. - wild fish; Encephalitozoon spp. - wild birds; Entamoeba spp. - non-human primates; Enterocytozoon bieneusi - wild cervids; Giardia duodenalis - red foxes; Sarcocystis nesbitti - snakes; Toxoplasma gondii - bobcats). Molecular tools have provided evidence that some enteric protozoa in wildlife may infect humans, but due to limited discriminatory power, often only the zoonotic potential of the parasite is indicated. Molecular analyses, which should be as discriminatory as possible, are one, but not the only, component of the toolbox for investigating potential public health impacts from pathogenic enteric protozoa in wildlife.


Temporal evolution of both premotor and motor cortical tuning properties reflect changes in limb biomechanics.
A prevailing theory in the cortical control of limb movement posits that premotor cortex initiates a high-level motor plan that is transformed by the primary motor cortex (MI) into a low-level motor command to be executed. This theory implies that the premotor cortex is shielded from the motor periphery, and therefore, its activity should not represent the low-level features of movement. Contrary to this theory, we show that both dorsal (PMd) and ventral premotor (PMv) cortexes exhibit population-level tuning properties that reflect the biomechanical properties of the periphery similar to those observed in M1. We recorded single-unit activity from M1, PMd, and PMv and characterized their tuning properties while six rhesus macaques performed a reaching task in the horizontal plane. Each area exhibited a bimodal distribution of preferred directions during execution consistent with the known biomechanical anisotropies of the muscles and limb segments. Moreover, these distributions varied in orientation or shape from planning to execution. A network model shows that such population dynamics are linked to a change in biomechanics of the limb as the monkey begins to move, specifically to the state-dependent properties of muscles. We suggest that, like M1, neural populations in PMd and PMv are more directly linked with the motor periphery than previously thought.


Attentional demands of continuously monitoring orientation using vestibular information.
The aim of this series of experiments was to determine whether attention is normally required for continuously processing vestibular information concerning orientation, or is required only when orientation is disrupted (eg by vestibular dysfunction or by conflicting visual and vestibular orientation cues). In the first two studies, healthy subjects were passively oscillated, and indicated when they perceived they were passing through their starting position. There was only weak evidence for interference between performance on this 'continuous orientation monitoring task' and on concurrent mental tasks. However, a third study showed that when patients with vestibular imbalance carried out the continuous orientation monitoring task their performance on a concurrent mental arithmetic task was substantially impaired. This dual task interference was correlated with inaccuracy in judging orientation on the continuous orientation monitoring task, which in turn correlated with severity of recent vestibular symptomatology (assessed by questionnaire). In a fourth experiment, disorientation was induced in healthy subjects by rotating the visual field about the line of sight. Bidirectional interference was observed between monitoring orientation (assessed by accuracy in setting a rod to the perceived vertical) and performance of an arithmetic task. Dual task interference was correlated with baseline levels of disorientation induced by the visual field, as indicated by inaccuracy in judging the visual vertical. These findings suggest that monitoring orientation makes significant demands upon cortical processing resources when disorientation is induced, whether the disorientation results from deficient sensory functioning or from ambiguous perceptual information.


Visualizing a monumental past: Archeology, Nasser's Egypt, and the early Cold War.
This article examines geographies of decolonization and the Cold War through a case study in the making of archeological knowledge. The article focuses on an archeological dig that took place in Egypt in the period between the July 1952 Free Officers' coup and the 1956 Suez crisis. Making use of the notion of the 'boundary object', this article demonstrates how the excavation of ancient Egyptian remains at the site of Mit Rahina helped to constitute Nasserist revolutionary modernity and its relationship to wider, post-Second World War political geographies. The dig took place as a result of an Egyptian-American collaboration designed to institute the possibility of archeology taking place along the lines of the Point Four modernization program promoted by the United States. The article discusses how this situation not only engendered contention surrounding the role of the international 'experts' appointed to run this excavation work, but also - and as a result - helped to constitute the monumental visual and material shape that archeological evidence relating to the Egyptian past could now take. Egypt's revolution sat within wider Cold War political struggles, yet the 'ground-up' realities of this relationship helped to constitute the sort of past (and future) monumentality proposed by Nasser's government.


Does Intravenous Contrast Improve the Diagnostic Yield of Fluorodeoxyglucose Positron-emission Tomography/Computed Tomography in Patients with Head-and-neck Malignancy.
In the present time, iodinated contrast agents are increasingly being used in the computed tomography (CT) component of positron-emission tomography (PET) study with the assumption that contrast-enhanced CT (CECT) will provide better diagnostic yield, although the utility of this procedure is still being debated. The aim of the study was to evaluate the effect of contrast CT on the diagnostic yield of PET-CT scan in patients with head-and-neck malignancies. In a prospective study, 204 patients (140 males and 64 females) of head-and-neck malignancies underwent contrast-enhanced and nonenhanced fluorodeoxyglucose (FDG)-PET-CT for various clinical indications following informed consent. After a plain CT scan, CECT was done using iodinated contrast iopromide-370 at a dose of 1 ml/kg intravenously. After CECT acquisition, FDG-PET acquisition was done and images were reconstructed to obtain whole-body PET/CT and PET-CECT images. Both the modalities could detect similar number of primary lesions (n = 127), lymph nodal lesions (n = 118), and metastatic involvement (n = 55) with no significant difference between SUVmax. However, conspicuity of primary tumors and lymph nodal architecture was significantly better delineated with CECT, leading to better interpreter confidence. CECT data as part of the combined PET-CT examination provide precise anatomic localization and delineation of the primary tumor in comparison to nonenhanced PET-CT. However, no significant diagnostic changes are noted in the nodal and metastatic staging.


Role of the alpha-chemokine stromal cell-derived factor (SDF-1) in the developing and mature central nervous system.
alpha-chemokines, which control the activation and directed migration of leukocytes, participate in the inflammatory processes in host defense response. One of the alpha-chemokines, CXCL12 or stromal cell-derived factor 1 (SDF-1), not only regulates cell growth and migration of hematopoietic stem cells but may also play a central role in brain development as we discuss here. SDF-1 indeed activates the CXCR4 receptor expressed in a variety of neural cells, and this signaling results in diverse biological effects. It enhances migration and proliferation of cerebellar granule cells, chemoattracts microglia, and stimulates cytokine production and glutamate release by astrocytes. Moreover, it elicits postsynaptic currents in Purkinje cells, triggers migration of cortical neuron progenitors, and produces pain by directly exciting nociceptive neurons. By modulating cell signaling and survival during neuroinflammation, SDF-1 may also play a role in the pathogenesis of brain tumors, experimental allergic encephalitis, and the nervous system dysfunction associated with acquired immunodeficiency syndrome.


DNA display I. Sequence-encoded routing of DNA populations.
Recently reported technologies for DNA-directed organic synthesis and for DNA computing rely on routing DNA populations through complex networks. The reduction of these ideas to practice has been limited by a lack of practical experimental tools. Here we describe a modular design for DNA routing genes, and routing machinery made from oligonucleotides and commercially available chromatography resins. The routing machinery partitions nanomole quantities of DNA into physically distinct subpools based on sequence. Partitioning steps can be iterated indefinitely, with worst-case yields of 85% per step. These techniques facilitate DNA-programmed chemical synthesis, and thus enable a materials biology that could revolutionize drug discovery.


Choosing which ear to implant in adult candidates with functional residual hearing.
This study examined whether audiologists consider the potential benefits of contralateral hearing aid use following cochlear implantation when recommending which ear to implant in UK adult candidates with residual hearing. Thirty-four audiologists from providers of adult implantation services completed a decision-choice experiment. Clinicians were willing to consider recommending that the poorer ear be implanted, provided it had been aided continuously, suggesting that their decision making seeks to preserve access to residual hearing in the non-implanted ear where possible. Future approaches to determining candidacy should therefore consider that a sub-set of patients may obtain additional benefit from this residual hearing following implantation.


Methods for Estimating the Global Burden of Cerebrovascular Diseases.
The Global Burden of Disease (GBD) study is a long-standing effort to report consistent and comprehensive measures of disease burden for the world. In this paper, we describe the methods used to estimate the global burden of stroke for the GBD 2013 study. Pathologic subtypes of stroke are modeled separately for two mutually exclusive and exhaustive categories: (1) ischemic stroke and (2) hemorrhagic and other non-ischemic strokes. Acute and chronic strokes are estimated separately. The GBD 2013 study has incorporated large amounts of new data on stroke death rates, incidence and case fatality. Disease modeling methods have been updated to better integrate mortality and incidence data. Future efforts will focus on incorporating data on the regional variation in severity of disability. Stroke remains a new area for disease modeling. A better understanding of stroke incidence, mortality and severity, and how it varies among countries, can help guide priority setting and improve health policy related to this important condition.


Antidepressant use and risk of adverse outcomes in older people: population based cohort study.
To investigate the association between antidepressant treatment and risk of several potential adverse outcomes in older people with depression and to examine risks by class of antidepressant, duration of use, and dose. Cohort study of people aged 65 and over diagnosed as having depression. 570 general practices in the United Kingdom supplying data to the QResearch primary care database. 60,746 patients diagnosed as having a new episode of depression between the ages of 65 and 100 years from 1 January 1996 to 31 December 2007 and followed up until 31 December 2008. Hazard ratios associated with antidepressant use for all cause mortality, attempted suicide/self harm, myocardial infarction, stroke/transient ischaemic attack, falls, fractures, upper gastrointestinal bleeding, epilepsy/seizures, road traffic accidents, adverse drug reactions, and hyponatraemia, adjusted for a range of potential confounding variables. Hazard ratios were calculated for antidepressant class (tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants), dose, and duration of use and for commonly prescribed individual drugs. 54,038 (89.0%) patients received at least one prescription for an antidepressant during follow-up. A total of 1,398,359 antidepressant prescriptions were issued: 764,659 (54.7%) for selective serotonin reuptake inhibitors, 442,192 (31.6%) for tricyclic antidepressants, 2203 (0.2%) for monoamine oxidase inhibitors, and 189,305 (13.5%) for the group of other antidepressants. The associations with the adverse outcomes differed significantly between the antidepressant classes for seven outcomes. Selective serotonin reuptake inhibitors were associated with the highest adjusted hazard ratios for falls (1.66, 95% confidence interval 1.58 to 1.73) and hyponatraemia (1.52, 1.33 to 1.75) compared with when antidepressants were not being used. The group of other antidepressants was associated with the highest adjusted hazard ratios for all cause mortality (1.66, 1.56 to 1.77), attempted suicide/self harm (5.16, 3.90 to 6.83), stroke/transient ischaemic attack (1.37, 1.22 to 1.55), fracture (1.64, 1.46 to 1.84), and epilepsy/seizures (2.24, 1.60 to 3.15), compared with when antidepressants were not being used. Tricyclic antidepressants did not have the highest hazard ratio for any of the outcomes. Significantly different associations also existed between the individual drugs for the same seven outcomes; trazodone (tricyclic antidepressant), mirtazapine, and venlafaxine (both in the group of other antidepressants) were associated with the highest rates for some of these outcomes. Absolute risks over 1 year for all cause mortality were 7.04% for patients while not taking antidepressants, 8.12% for those taking tricyclic antidepressants, 10.61% for selective serotonin reuptake inhibitors, and 11.43% for other antidepressants. Selective serotonin reuptake inhibitors and drugs in the group of other antidepressants were associated with an increased risk of several adverse outcomes compared with tricyclic antidepressants. Among individual drugs, trazodone, mirtazapine, and venlafaxine were associated with the highest risks for some outcomes. As this is an observational study, it is susceptible to confounding by indication, channelling bias, and residual confounding, so differences in characteristics between patients prescribed different antidepressant drugs that could account for some of the associations between the drugs and the adverse outcomes may remain. Further research is needed to confirm these findings, but the risks and benefits of different antidepressants should be carefully evaluated when these drugs are prescribed to older people.


Endosymbiotic bacteria living inside the poultry red mite (Dermanyssus gallinae).
This study investigated the endosymbiotic bacteria living inside the poultry red mite collected from five samples of one commercial farm from the UK and 16 farms from France using genus-specific PCR, PCR-TTGE and DNA sequencing. Endosymbiotic bacteria are intracellular obligate organisms that can cause several phenotypic and reproductive anomalies to their host and they are found widespread living inside arthropods. The farm sampled from the UK was positive for bacteria of the genera Cardinium sp. and Spiroplasma sp. From France, 7 farms were positive for Cardinium sp., 1 farm was positive for Spiroplasma sp., 1 farm was positive for Rickettsiella sp. and 2 farms were positive for Schineria sp. However, it was not possible to detect the presence of the genus Wolbachia sp. which has been observed in other ectoparasites. This study is the first report of the presence of endosymbionts living inside the poultry red mite. The results obtained suggest that it may be possible that these bacterial endosymbionts cause biological modifications to the poultry red mite.


Amphibian pathogens at northern latitudes: presence of chytrid fungus and ranavirus in northeastern Canada.
Infections by the fungal pathogen Batrachochytrium dendrobatidis (Bd) and members of the genus Ranavirus (Rv) are increasingly reported as significant determinants of amphibian population die-offs. The complexity associated with their transmission and spatial distribution leads to an increase in demand for comprehensive reporting systems and global mapping of their distribution. Here, we document the distribution of these 2 pathogens in a remote northern temperate lowland where environmental sensitivity is high, providing important insight into the pathogens' natural history and infection patterns. Wood frog Lithobates sylvaticus tissues were collected from the James Bay area in northeastern Canada and were screened for the presence of Bd and Rv using conventional and real-time PCR. Both pathogens were present in the study area, which is the northernmost record in eastern North America. Interestingly, different patterns of distribution were observed between the eastern and western coasts of James Bay, suggesting differences in the spatial and transmission dynamics for each pathogen. Anthropogenic introduction may still influence the distribution patterns observed, even at these latitudes. The presence of infections in this remote area also raises further questions on the risk these pathogens pose to northern amphibian communities. We encourage further research in remote locations for a better understanding of these pathogens, their transmission dynamics, and especially their respective impacts on amphibian populations worldwide.


Sensory acceptable equivalent doses of β-phenylethyl isothiocyanate (PEITC) induce cell cycle arrest and retard the growth of p53 mutated oral cancer in vitro and in vivo.
High doses of β-phenylethyl isothiocyanate (PEITC), a phytochemical in cruciferous vegetables, are not feasible for consumption due to a strong mouth-tingling effect. This study investigated the anti-cancer effect of PEITC at sensory acceptable doses. In vitro, PEITC was selectively toxic to oral cancer cells (CAL-27, FaDu, SCC4, SCC 9, SCC15, SCC25 and TU138), compared to oral keratinocytes (OKF6/TERT2 and NOK/Si). In vivo, 5 and 10 mg kg-1 PEITC, equivalent to human organoleptically acceptable doses, retarded tumor growth and prolonged the survival of mice bearing p53-mutated oral cancer cells - TU138 xenograft. Mechanistically, PEITC induced ROS accumulation, nuclear translocation of p53 and p21 and G1/S cell cycle arrest in vitro; increased p53 and 8-oxo-dG levels; and decreased Ki-67 intense/mild staining ratios without TUNEL changes in vivo. These findings suggested that the sensory acceptable doses of PEITC selectively induced ROS-mediated cell cycle arrest leading to delayed tumor progression and extended survival. PEITC could be a functional ingredient for oral cancer prevention.


Rheology of red blood cells under flow in highly confined microchannels. II. Effect of focusing and confinement.
We study the focusing of red blood cells and vesicles in pressure-driven flows in highly confined microchannels (10-30 μm), identifying the control parameters that dictate the cell distribution along the channel. Our results show that an increase in the flow velocity leads to a sharper cell distribution in a lateral position of the channel. This position depends on the channel width, with cells flowing at outer (closer to the walls) positions in thicker channels. We also study the relevance of the object shape, exploring the different behaviour of red blood cells and different vesicles. We also analyze the implications of these phenomena in the cell suspension rheology, highlighting the crucial role of the wall confinement in the rheological properties of the suspension.


In vitro reconstitution of discrete stages of dynamin-dependent endocytosis.
Many proteins involved in vesicle budding are able to interact with lipids and to deform membranes. In this review we present three in vitro assays that can be used to study the roles of these types of proteins and to reconstitute distinct stages of vesicle budding and tubule formation. In the first assay, the dynamic effect of peripheral membrane proteins on liposome morphology is studied, providing insight into the roles of proteins (e.g., the endocytic proteins; dynamins, epsins, amphiphysins, and endophilins) in deforming membranes and in recognizing membrane curvature. In the second assay, preformed lipid nanotubes are used to mimic the neck of a coated vesicle. These nanotubes form a suitable template to study molecules of the dynamin family, allowing visualization of the different conformations of dynamin that occur during vesicle scission. Finally, lipid monolayers have been used as mimics of the internal leaflet of the plasma membrane to investigate early stages of clathrin-coated pit formation. In principle this can equally be used to study budding mechanisms of other coated vesicle types. A combination of these three assays has given considerable insight into the roles of endocytic proteins and is allowing reconstitution and dissection of the different stages of vesicle formation.


A study of temperament and personality in anorexia and bulimia nervosa.
Although temperament and personality traits could influence the development and course of eating disorders, only a few studies examined the similarities and differences in personality between anorexia and bulimia nervosa. We compared 72 patients with DSM-IV eating disorders and 30 healthy controls. Dimensions of personality and personality disorders were evaluated with the Eysenck's EPQ, Cloninger's TCI, and the SCID-II questionnaires. The rates of impulsivity and clinical features were evaluated using specific rating scales. A comorbid personality disorder was found in 61.8% of patients with eating disorder. Avoidant personality disorder appeared was relatively common in anorexia nervosa restricting type; borderline personality disorder was most frequent in bulimia nervosa and the binge eating-purging type of anorexia nervosa. From a dimensional perspective, anorexic patients presented high scores in the dimension of persistence. Higher harm avoidance and impulsivity was found in bulimic patients. The overall eating disorders group presented high scores in neuroticism and low scores in self-directedness. Eating disorder patients have heterogeneous features of temperament and personality traits. Cluster C personality disorders seem more common in anorexia nervosa restricting type and impulsive personality features are associated with bulimic symptoms. Impulsivity seems to be a key aspect of temperament of bulimic patients, whereas anorexic symptoms are linked to persistent temperament traits.


Kidney and kidney/pancreas transplantation at Stanford University Medical Center.
The disparity between the supply of cadaveric donors and the demand for renal allografts continues to grow. We have taken a multifaceted approach to increase the allograft pool: 1. Spiral computed tomography to evaluate potential living kidney donors is safer, less invasive, less expensive and more time efficient and thus should encourage living organ donation. 2. Use of selected expanded criteria cadaveric donor kidneys (aged 60 or over, hypertensive) in size- and age-matched recipients have short-term function at 3 and 6 months comparable to standard cadaveric renal allografts. 3. Kidneys from expanded criteria donors over age 59 and with an adjusted creatinine clearance less than 90 ml/min should be used as a dual kidney transplant into an appropriate sized- and aged-matched recipient. 4. Kidneys from pediatric donors < 5 years of age should be utilized as en-bloc grafts, when transplanted into adult recipients. Pediatric renal transplantation poses numerous challenges given the different and problematic etiologies of ESRD, the surgical considerations in small children and infants and the enhanced immune response witnessed in children. Nevertheless, renal transplantation is clearly the therapy of choice for children with ESRD and excellent results can be obtained through strict adherence to surgical detail, tight immunosuppressive management, and aggressive fluid management in infants and small children. We feel it is also critically important that transplantation and follow-up care be carried out by an integrated and experienced surgical and medical team. Managed healthcare has had profound effects on the practice and management of transplantation centers. The one area of greatest impact has been the pressure upon programs to reduce their cost of transplantation. We have initiated a number of new outpatient treatment protocols as part of an effort to contain costs. Most patients with acute rejection are evaluated (including transplant kidney biopsy) and treated in an ambulatory setting. Completion of OKT3 therapy in selected patients is also performed at home through visiting nurses or at our ambulatory care center. Additionally, treatment of CMV disease is now performed almost exclusively on an outpatient basis.