Factors associated with self-reported driver sleepiness and incidents in city bus drivers.
Driver fatigue has received increased attention during recent years and is now considered to be a major contributor to approximately 15-30% of all crashes. However, little is known about fatigue in city bus drivers. It is hypothesized that city bus drivers suffer from sleepiness, which is due to a combination of working conditions, lack of health and reduced sleep quantity and quality. The overall aim with the current study is to investigate if severe driver sleepiness, as indicated by subjective reports of having to fight sleep while driving, is a problem for city based bus drivers in Sweden and if so, to identify the determinants related to working conditions, health and sleep which contribute towards this. The results indicate that driver sleepiness is a problem for city bus drivers, with 19% having to fight to stay awake while driving the bus 2-3 times each week or more and nearly half experiencing this at least 2-4 times per month. In conclusion, severe sleepiness, as indicated by having to fight sleep during driving, was common among the city bus drivers. Severe sleepiness correlated with fatigue related safety risks, such as near crashes.


Evidence for repeated independent evolution of migration in the largest family of bats.
How migration evolved represents one of the most poignant questions in evolutionary biology. While studies on the evolution of migration in birds are well represented in the literature, migration in bats has received relatively little attention. Yet, more than 30 species of bats are known to migrate annually from breeding to non-breeding locations. Our study is the first to test hypotheses on the evolutionary history of migration in bats using a phylogenetic framework. In addition to providing a review of bat migration in relation to existing hypotheses on the evolution of migration in birds, we use a previously published supertree to formulate and test hypotheses on the evolutionary history of migration in bats. Our results suggest that migration in bats has evolved independently in several lineages potentially as the need arises to track resources (food, roosting site) but not through a series of steps from short- to long-distance migrants, as has been suggested for birds. Moreover, our analyses do not indicate that migration is an ancestral state but has relatively recently evolved in bats. Our results also show that migration is significantly less likely to evolve in cave roosting bats than in tree roosting species. This is the first study to provide evidence that migration has evolved independently in bat lineages that are not closely related. If migration evolved as a need to track seasonal resources or seek adequate roosting sites, climate change may have a pivotal impact on bat migratory habits. Our study provides a strong framework for future research on the evolution of migration in chiropterans.


Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity.
Intra-tumor heterogeneity is one of the biggest challenges in cancer treatment today. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal prostate cancer using the spatial transcriptomics (ST) technology. Utilizing a novel approach for deconvolution, we analyze the transcriptomes of nearly 6750 tissue regions and extract distinct expression profiles for the different tissue components, such as stroma, normal and PIN glands, immune cells and cancer. We distinguish healthy and diseased areas and thereby provide insight into gene expression changes during the progression of prostate cancer. Compared to pathologist annotations, we delineate the extent of cancer foci more accurately, interestingly without link to histological changes. We identify gene expression gradients in stroma adjacent to tumor regions that allow for re-stratification of the tumor microenvironment. The establishment of these profiles is the first step towards an unbiased view of prostate cancer and can serve as a dictionary for future studies.


Micropatterning of poly(ethylene glycol) diacrylate hydrogels with biomolecules to regulate and guide endothelial morphogenesis.
Angiogenesis, which is morphogenesis undertaken by endothelial cells (ECs) during new blood vessel formation, has been traditionally studied on natural extracellular matrix proteins. In this work, we aimed to regulate and guide angiogenesis on synthetic, bioactive poly(ethylene glycol)-diacrylate (PEGDA) hydrogels. PEGDA hydrogel is intrinsically cell nonadhesive and highly resistant to protein adsorption, allowing a high degree of control over presentation of ligands for cell adhesion and signaling. Since these materials are photopolymerizable, a variety of photolithographic technologies may be applied to spatially control presentation of bioactive ligands. To manipulate EC adhesion, migration, and tubulogenesis, the surface of PEGDA hydrogels was micropatterned with a cell adhesive ligand, Arg-Gly-Asp-Ser (RGDS), in desired concentrations and geometries. ECs cultured on these RGDS patterns reorganized their cell bodies into cord-like structures on 50-microm-wide stripes, but not on wider stripes, suggesting that EC morphogenesis can be regulated by geometrical cues. The cords formed by ECs were reminiscent of capillaries with cells participating in the self-assembly and reorganization into multicellular structures. Further, endothelial cord formation was stimulated on intermediate concentration of RGDS at 20 microg/cm(2), whereas it was inhibited at higher concentrations. This work has shown that angiogenic responses can be tightly regulated and guided by micropatterning of bioactive ligands and also demonstrated great potentials of micropatterned PEGDA hydrogels for various applications in tissue engineering, where vascularization prior to implantation is critical.


Angiotensin II receptor blocker attenuates stress pressor response in young adult African Americans.
African Americans (AAs) are susceptible to hypertension (HTN) and its associated organ damage leading to adverse cardiovascular (CV) outcomes. Psychological stress is proposed to contribute to the development of HTN; however, the potential role of the renin-angiotensin system (RAS) in stress-related HTN in AAs is largely unknown. In this study, we tested the hypothesis that activation of RAS is a potential contributing factor for altered CV responses to stress, and suppression of angiotensin II (Ang II) activity will improve hemodynamic responses to a prolonged mental stressor in healthy young AAs. Utilizing a double-blind, randomized, crossover study design, 132 normotensive AAs (25 ± 7 years) were treated with either a placebo (PLC) or 150 mg/d irbesartan (an Ang II type 1 receptor blocker; ARB) for 1 week. On the final day of each treatment, hemodynamic measures and urinary sodium excretion (UNaV) were collected before, during and after a 45 minute-mental stress. The magnitude of stress-induced increase in blood pressure with ARB was blunted and delayed compared to PLC. Systolic blood pressure at the end of recovery on ARB was significantly lower compared to either PLC (110 ± 13 vs 117 ± 12 mm Hg respectively; P < 0.001) or the prestress level on ARB (P = 0.02). ARB treatment reduced overall vasoconstriction and improved poststress UNaV. ARB attenuated blood pressure responses to mental stress and improved the poststress BP recovery process which were partly linked to reduced overall vasoconstriction and improved stress-induced UNaV in young adult AAs prior to the development of disease conditions. These results suggest that treatment approaches that inhibit RAS action could have significant relevance to potentially lower susceptibility to stress responses and eventually the premature development of HTN in AAs.


Collagen turnover profiles in chronic kidney disease.
Renal fibrosis is a hallmark of chronic kidney disease (CKD) caused by an imbalance between formation and degradation of extracellular matrix proteins. We investigated the collagen turnover profile of 81 non-dialysis CKD stage 2-5 patients by measuring peptides reflecting formation and degradation of collagen type (COL) I, III, IV, and VI. Based on the collagen turnover profile, we identified four clusters of patients. Cluster 1 contained one patient with prostate cancer, who had a distinct collagen turnover. The other clusters generally had severe (Cluster 2), moderate (Cluster 4), or mild CKD (Cluster 3). Cluster 4 patients were characterized by higher levels of COL III, COL IV, and COL VI (all p < 0.001) degradation fragments in plasma, while patients in Clusters 2 and 4 had higher levels of COL VI formation (p < 0.05). COL IV fragments in plasma were lower in Cluster 2 (p < 0.01). Urinary COL III fragments decreased from Cluster 3 to 4, and from Cluster 4 to 2 (both p < 0.001). We show that patients with similar kidney function have a different collagen remodeling profile, suggesting that different phenotypes exist with different disease activity and potentially disease progression. Biomarkers of collagen remodeling could provide additional information to traditional markers of renal function.


Next-generation phenotyping using the parkin example: time to catch up with genetics.
Two decades of intense research have led to important insights into the pathophysiology of neurodegenerative diseases, with limited direct clinical impact. While next-generation sequencing has emerged as a powerful research tool, we hypothesized that systematic exploitation of phenotypic data are lagging behind genetic advances. To use the 15-year experience with parkin-associated Parkinson disease (PD) to evaluate type, quality, and quantity of genetic and phenotypic data and to elucidate clinical or genetic features impacting genetic testing and counseling. We searched MEDLINE: (1998-2012) using the term parkin AND mutation for English publications about proved parkin-associated PD and at least minimal, individual clinical information excluding digenic cases, and redundant articles. This approach identified 877 articles, of which 196 described patients with PD with confirmed parkin mutations and 127 articles fulfilled our inclusion criteria. Information was extracted using predefined criteria and a consensus approach for questionable details. To evaluate study method differences, we devised a quality score representing the completeness of clinical, demographic, and genetic information. In the data about 1184 patients, the quality score increased steadily and was driven exclusively by improvements in genetic analyses. By contrast, demographic and clinical content stagnated. The mean age at onset was 9 years lower in index patients with 2 mutant parkin alleles than in heterozygotes. Genotype-phenotype correlation was observed for the number of mutated alleles and dystonia. By contrast, dementia was rare in all parkin-mutation carriers (<3%), despite long disease duration. Notwithstanding large gaps in phenotypic information content, we identified dystonia and the absence of dementia as "red flags" to be incorporated in counseling guidelines. We propose mandatory minimal criteria for genotype-phenotype studies to facilitate the next breakthrough-following genetics-toward more personalized medicine for genetic conditions, extending well beyond the parkin example.


A link between LRRK2, autophagy and NAADP-mediated endolysosomal calcium signalling.
Mutations in LRRK2 (leucine-rich repeat kinase 2) represent a significant component of both sporadic and familial PD (Parkinson's disease). Pathogenic mutations cluster in the enzymatic domains of LRRK2, and kinase activity seems to correlate with cytotoxicity, suggesting the possibility of kinase-based therapeutic strategies for LRRK2-associated PD. Apart from cytotoxicity, changes in autophagy have consistently been observed upon overexpression of mutant, or knockdown of endogenous, LRRK2. However, delineating the precise mechanism(s) by which LRRK2 regulates autophagy has been difficult. Recent data suggest a mechanism involving late steps in autophagic-lysosomal clearance in a manner dependent on NAADP (nicotinic acid-adenine dinucleotide phosphate)-sensitive lysosomal Ca2+ channels. In the present paper, we review our current knowledge of the link between LRRK2 and autophagic-lysosomal clearance, including regulation of Ca2+-dependent events involving NAADP.


Pain relief following vertebroplasty in patients with and without localizing tenderness on palpation.
Focal point tenderness over the fractured level is believed to be a necessary criterion for performing vertebroplasty. The purpose of this study was to explore whether the presence of focal-point tenderness over a fracture treated with vertebroplasty predicts superior clinical outcome as compared with outcomes in patients without such tenderness. In this retrospective study, we divided patients into 3 groups on the basis of pain patterns noted during history and physical examination before an initial vertebroplasty in 534 consecutive patients. Group 1 comprised 373 (70%) of 534 patients with focal-point tenderness over the treated fractures. Group 2 comprised 119 (22%) patients with focal-point tenderness over the treated fractures as well as subjective off-midline pain or focal tenderness to palpation over nontreated vertebrae. Group 3 comprised 42 (8%) patients without focal-point tenderness over the treated fractures but with subjective off-midline pain or tenderness to palpation over nontreated vertebrae. Outcomes included pain at rest and with activity as well as the Roland-Morris Disability Questionnaire score. Statistical tools included the 2-tailed t test with a Bonferroni adjustment. Baseline pain at rest and with activity was not different among groups, but the proportion of group 3 patients maintained on a narcotic anesthesia preprocedure was less than that of groups 1 and 2 (P = .02 compared with both groups). Group 3 achieved significantly lower pain scores at rest at 1 month (P < .0001 compared with group 1 and P < .001 compared with group 2). The presence of focal-point tenderness does not predict superior clinical response following vertebroplasty compared with the absence of focal tenderness. Even patients without focal tenderness may benefit from vertebroplasty.


Whose perceptions matter more: mine or my group's? An actor-partner interdependence analysis disaggregating between-person and between-session effects of group climate perceptions on intimate behaviors.
Group climate refers to the atmosphere that is both created and experienced by a group of people. Theoretically, the "climate" of a group should therefore be related to the behaviors of its members during group sessions; however, this has not been empirically tested. A longitudinal design was used to examine the relationship between group member perceptions of engagement and conflict and group member intimate behaviors during the group session. Data came from 73 incarcerated women participating in 6 manualized (Trauma Recovery and Empowerment Model) therapy groups. At each session, group members completed measures of their perceptions of the group's engagement and conflict (the Group Climate Questionnaire), and the group leader completed a behavioral count of each member's intimate behaviors. Group climate was examined both for the group member (actor) and aggregated across the other group members, excluding the actor (partner). In addition, these actor and partner scores were decomposed into between-member and within-member components. None of the between-member differences in engaged or conflict perceptions were significantly related to intimate behaviors. There was a significant positive relationship between actor's and partner's engagement ratings and partner's conflict ratings in a session and the actor's intimate behaviors in that session. Study results highlight the importance of examining changes that may be occurring from session to session in group climate perceptions and the need to examine partner's perceptions in order to best understand how an individual group member will behave.


Long-range regulation of alpha globin gene expression during erythropoiesis.
The analysis of globin gene expression during erythropoiesis has established many principles underlying normal mammalian gene expression. New aspects of gene regulation have been revealed by natural mutations that downregulate globin gene expression and cause thalassemia. Deletions involving sequences upstream of the alpha and beta clusters suggested that the globin genes might be controlled by remote regulatory elements. This was demonstrated experimentally and suggested that many mammalian genes may be controlled in a similar manner. Completion of the Human Genome Project and the associated encyclopaedia of DNA elements (ENCODE) project confirmed that human gene expression is commonly controlled by long-range, cis-acting elements. The development of chromatin immunoprecipitation has allowed us to identify binding of transcription factors and chromatin modifications at the key cis-acting sequences in vivo. In addition, chromosome conformation capture has enabled us to address the topological models proposed to mediate long-range interactions. Together, these methods have given us some insight into how long-range elements may influence gene expression and how this process may be subverted in thalassemia. The review asks how remote elements regulate alpha globin expression and how natural mutations interfere with this mechanism to cause alpha thalassemia. We also speculate as to why long-range control of gene expression may have evolved in higher organisms.


Changes in terms of risks/benefits of shifting diets towards healthier and more sustainable dietary models.
Food production and therefore human diet are identified as important sources of environmental impact. Unhealthy and unsustainable diets with high intake of meat and low intake of plant-based products are predominant worldwide. On the other hand, a balance between health and sustainability is necessary, since diets that are environmentally sustainable could lack essential macro- and micronutrients and result in nutrient deficiencies, non-communicable diseases and malnutrition. The aim of this project was to investigate the nutritional adequacy and environmental impact of adults' diet by comparing current dietary habits and new alternative dietary scenarios. First, a systematic review was conducted following PRISMA guidelines to assess the environmental impact of current diets and sustainable dietary scenarios such as vegan, vegetarian, pescatarian, omnivorous and optimised dietary patterns worldwide. In the second part of the project, an optimisation study was conducted, based on a multi-objective optimisation approach, with the purpose of creating the optimal diet based on nutritional and environmental constraints for the adult Italian population. The dietary scenarios of the optimised models were developed in accordance with the Italian food-based dietary guidelines. Food consumption data was extracted from the INHES study and used as baseline diet. A clear evaluation of the current environmental impact because of diet and potential sustainable dietary scenarios globally is challenging. Finally, national food-based guidelines should be adjusted by suggesting healthy and sustainable dietary recommendations in line with traditional eating habits and local food availability in order the desirable dietary shifts towards sustainability to be feasible.


Action potential propagation in a thick strand of cardiac muscle.
A theoretical model of action potential propagation in a thick strand of cardiac muscle is presented. The calculation takes into account the anisotropic and syncytial properties of the tissue, the presence of the interstitial space, the effect of the surrounding tissue bath, and the variation of the potential both along the strand length and across the strand cross section. The bidomain model is used to represent the electrical properties of the tissue, and the Ebihara-Johnson model is used to represent the properties of the active sodium channels. The calculated wave front is curved, with the action potential at the surface of the strand leading that at the center. The rate of rise of the action potential and the time constant of the action potential foot vary with depth into the tissue. The velocity of the wave front is nearly independent of strand radius for radii greater than 0.5 mm. The conduction velocity decreases as the volume fraction of the interstitial space decreases. In the limit of tightly packed cells, an action potential propagates quickly over the surface of the strand; the bulk of the tissue is then excited by a slow inward wave front initiated on the surface. This model does not predict an increase in conduction velocity when cells are tightly packed, a hypothesis that has been proposed previously to explain the fast conduction velocity in Purkinje fibers of some species.


Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury.
Hypocretin-1 is involved in the regulation of the sleep-wake cycle. The authors prospectively assessed CSF hypocretin-1 levels in 44 consecutive patients with acute traumatic brain injury (TBI). Compared with controls, hypocretin-1 levels were abnormally lower in 95% of patients with moderate to severe TBI and in 97% of patients with posttraumatic brain CT changes. Hypocretin-1 deficiency after TBI may reflect hypothalamic damage and be linked with the frequent development of posttraumatic sleep-wake disorders.


Exercise, caloric restriction, and systemic oxidative stress.
In humans, the main sources of reactive oxygen species (ROS), the molecules causing oxidative stress, are mitochondrial superoxide ions and neutrophil-derived oxidative radicals. Circulating antioxidants contribute to the protection against oxidative stress. Although the formation of ROS and secretion of antioxidants are independently regulated by exercise and diet, little is known about their combined effect. We hypothesized that relatively brief, intense exercise training may reduce systemic oxidation via an intrinsic mechanism, independent of changes in circulating antioxidants and of neutrophil-derived enzymes (as may be caused by concomitant caloric restriction). Nineteen volunteers exercised for 7 days, 3 hours/day at 75% of oxygen uptake. Caloric intake was either 110% of caloric expenditure (high calorie, n=10) or 75% of caloric expenditure (low calorie, n=9). Blood samples for F2-isoprostanes, catalase, myeloperoxidase (MPO), interleukin-x (IL-x), white blood cells (WBCs), and other metabolic variables were taken at baseline, at the end of training, and 1 week after completion of the study. Serum F2-isoprostanes (microg/mL), markers of lipid peroxidation, were similarly reduced after 7 days of exercise in the high-calorie (from 35+/-4 to 27+/-2) and low-calorie (from 35+/-3 to 24+/-2) groups. Similar reductions were observed in IL-x concentrations. Conversely, no change was observed in circulating concentrations of the antioxidant catalase. Whereas total WBCs and neutrophil counts were significantly reduced in the low-calorie group only, no difference in neutrophil-derived MPO was measured between groups. A significant reduction in systemic oxidation may occur relatively early during intense exercise training in healthy young men, independent of caloric intake. The potential contribution to these effects of circulating antioxidants and neutrophil-derived oxidative enzymes will require further investigation.


Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression.
Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. Some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with SSRIs attenuates amygdala responses (Ma, 2015). We hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. In this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. Psychological support was provided before, during and after these sessions and 19 completed fMRI scans one week prior to the first session and one day after the second and last. Neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. Group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. Increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. Psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with SSRIs. This suggests fundamental differences in these treatments' therapeutic actions, with SSRIs mitigating negative emotions and psilocybin allowing patients to confront and work through them. Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions. TRIAL REGISTRATION: ISRCTN, number ISRCTN14426797. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.


A Randomized Controlled Trial Protocol to Evaluate the Effectiveness of an Integrated Care Management Approach to Improve Adherence Among HIV-Infected Patients in Routine Clinical Care: Rationale and Design.
Adherence to antiretroviral medications is a key determinant of clinical outcomes. Many adherence intervention trials investigated the effects of time-intensive or costly interventions that are not feasible in most clinical care settings. We set out to evaluate a collaborative care approach as a feasible intervention applicable to patients in clinical care including those with mental illness and/or substance use issues. We developed a randomized controlled trial (RCT) investigating an integrated, clinic-based care management approach to improve clinical outcomes that could be integrated into the clinical care setting. This is based on the routine integration and systematic follow-up of a clinical assessment of patient-reported outcomes targeting adherence, depression, and substance use, and adapts previously developed and tested care management approaches. The primary health coach or care management role is provided by clinic case managers allowing the intervention to be generalized to other human immunodeficiency virus (HIV) clinics that have case managers. We used a stepped-care approach to target interventions to those at greatest need who are most likely to benefit rather than to everyone to maintain feasibility in a busy clinical care setting. The National Institutes of Health funded this study and had no role in study design, data collection, or decisions regarding whether or not to submit manuscripts for publication. This trial is currently underway, enrollment was completed in 2015, and follow-up time still accruing. First results are expected to be ready for publication in early 2017. This paper describes the protocol for an ongoing clinical trial including the design and the rationale for key methodological decisions. There is a need to identify best practices for implementing evidence-based collaborative care models that are effective and feasible in clinical care. Adherence efficacy trials have not led to sufficient improvements, and there remains little guidance regarding how adherence interventions should be implemented into clinical care. By focusing on improving adherence within care settings using existing staff, routine assessment of key domains, such as depression, adherence, and substance use, and feasible interventions, we propose to evaluate this innovative way to improve clinical outcomes. Clinicaltrials.gov NCT01505660; http://clinicaltrials.gov/ct2/show/NCT01505660 (Archived by WebCite at http://www.webcitation/ 6ktOq6Xj7).


Saccades and pursuit: two outcomes of a single sensorimotor process.
Saccades and smooth pursuit eye movements are two different modes of oculomotor control. Saccades are primarily directed toward stationary targets whereas smooth pursuit is elicited to track moving targets. In recent years, behavioural and neurophysiological data demonstrated that both types of eye movements work in synergy for visual tracking. This suggests that saccades and pursuit are two outcomes of a single sensorimotor process that aims at orienting the visual axis.


Glucocorticoids in pregnancy.
The physiological changes that occur during pregnancy include altered regulation of the hypothalamo-pituitary-adrenal axis. The fetoplacental unit plays a major role in this, together with alteration of circulating cortisol-binding globulin levels, with a net effect to increase both total and free cortisol levels. Importantly, there are several pathological conditions that require steroid treatment or replacement during pregnancy, and optimizing therapy is clearly crucial. The potential for acute and chronic adverse effects that can impact upon both the mother and the fetus makes the decision of how and when to instigate steroid therapy particularly challenging. In this review, we describe the physio-pathological changes to the hypothalamo-pituitary-adrenal axis that occur during pregnancy, tools to assess endogenous glucocorticoid reserve as well as discuss treatment strategies and the potential for the development of adverse events.


Managing diabetes with integrated teams: maximizing your efforts with limited time.
The importance of glycemic control has been well established. In response, the American Diabetes Association has established goals for glycemic control and other cardiovascular parameters, including blood pressure and low-density and high-density lipoprotein cholesterol. However, the National Health and Nutrition Examination Survey has shown that only about half (57%) of patients with diabetes meet a glycated hemoglobin A(1c) (HbA(1c)) goal of < 7%, approximately 45% meet blood pressure and total cholesterol goals, and only 12% achieve all 3 treatment goals. While treating hyperglycemia remains the primary treatment goal, careful selection of pharmacotherapies that do not adversely affect cardiovascular risk factors or long-term glycemic control is an important consideration for patients with type 2 diabetes mellitus. During the past 5 years, the number of treatment options and the complexity of treatment guidelines for diabetes have increased markedly, which makes treatment decisions more complicated and time-consuming, and greatly impacts the workload of the primary care physicians who deliver care to the majority of this population. To provide optimal diabetes care when time and resources are limited, primary care physicians may want to enlist the support of other providers, such as nurse practitioners, physician assistants, diabetes educators, dietitians, and social and case workers. The use of team care, coupled with appropriately chosen pharmacologic therapy and patient education that fosters the development of critical thinking skills and the ability to make self-management decisions, have been shown to improve glycemic control and cardiovascular outcomes.


Population differentiation and genetic variation in performance on eight hosts in the pea aphid complex.
Phytophagous insects frequently use multiple host-plant species leading to the evolution of specialized host-adapted populations and sometimes eventually to speciation. Some insects are confronted with a large number of host-plant species, which may provide complex routes of gene flow between host-adapted populations. The pea aphid (Acyrthosiphon pisum) attacks a broad range of plants in the Fabaceae and it is known that populations on Trifolium pratense and Medicago sativa can be highly specialized at exploiting these species. To find out whether adaptation to a broad range of co-occurring hosts has occurred, we tested the performance of pea aphid clones collected from eight host-plant genera on all of these plants in a reciprocal transfer experiment. We provide evidence for pervasive host-plant specialization. The high performance of all aphid clones on Vicia faba suggests that this host plant could be a site of gene flow between different populations that could limit further host-associated divergence. The genetic variance in host-plant usage was partitioned into within- and among-population components, which represent different levels of host adaptation. Little evidence of within-population trade-offs in performance on different plant species was found.


The role of maternal affect attunement in dyadic and triadic communication.
The influence of maternal affect attunement on the relationship between gaze monitoring during dyadic communication at 3 months and coordinated attention during triadic communication at 5, 7 and 10 months was examined in a longitudinal study. Although most infants engaged in gaze monitoring at 3 months and in coordinated attention at 5, 7 and 10 months, a regression analysis revealed that gaze monitoring at 3 months significantly predicted coordinated attention at 10 months only when maternal affect attunement was high. These findings are discussed in terms of theories that emphasize the role of social interaction in the development of meaningful communication and continuity in mental state awareness during the first year of life.


Cancer mortality following radium treatment for uterine bleeding.
Cancer mortality in relation to radiation dose was evaluated among 4153 women treated with intrauterine radium (226Ra) capsules for benign gynecologic bleeding disorders between 1925 and 1965. Average follow up was 26.5 years (maximum = 59.9 years). Overall, 2763 deaths were observed versus 2687 expected based on U.S. mortality rates [standardized mortality ratio (SMR) = 1.03]. Deaths due to cancer, however, were increased (SMR = 1.30), especially cancers of organs close to the radiation source. For organs receiving greater than 5 Gy, excess mortality of 100 to 110% was noted for cancers of the uterus and bladder 10 or more years following irradiation, while a deficit was seen for cancer of the cervix, one of the few malignancies not previously shown to be caused by ionizing radiation. Part of the excess of uterine cancer, however, may have been due to the underlying gynecologic disorders being treated. Among cancers of organs receiving average or local doses of 1 to 4 Gy, excesses of 30 to 100% were found for leukemia and cancers of the colon and genital organs other than uterus; no excess was seen for rectal or bone cancer. Among organs typically receiving 0.1 to 0.3 Gy, a deficit was recorded for cancers of the liver, gall bladder, and bile ducts combined, death due to stomach cancer occurred at close to the expected rate, a 30% excess was noted for kidney cancer (based on eight deaths), and there was a 60% excess of pancreatic cancer among 10-year survivors, but little evidence of dose-response. Estimates of the excess relative risk per Gray were 0.006 for uterus, 0.4 for other genital organs, 0.5 for colon, 0.2 for bladder, and 1.9 for leukemia. Contrary to findings for other populations treated by pelvic irradiation, a deficit of breast cancer was not observed (SMR = 1.0). Dose to the ovaries (median, 2.3 Gy) may have been insufficient to protect against breast cancer. For organs receiving greater than 1 Gy, cancer mortality remained elevated for more than 30 years, supporting the notion that radiation damage persists for many years after exposure.


Food deprivation and restriction during late gestation affects the sexual behavior of postpartum female meadow voles, Microtus pennsylvanicus.
In many species of small mammals, including meadow voles, Microtus pennsylvanicus, females come into postpartum estrus (PPE) within 12-24 h of giving birth, allowing them to mate and become pregnant while raising the current litter. PPE females show increases in attractivity, proceptivity, and receptivity, the three components of sexual behavior, relative to females not in PPE. Several studies have shown that food deprivation and restriction reduce attractivity, proceptivity, and receptivity of females not in PPE. We tested the hypothesis that food deprivation and restriction during late gestation causes deficits and decreases the attractivity, proceptivity, and receptivity of females when they enter PPE. Our data support the hypothesis. On day 1 of lactation, females that were food deprived and food restricted produced scent marks that were significantly less attractive as those produced by control PPE females. Food deprivation but not food restriction caused females to no longer display significant preferences for the scent marks of males over those of females (proceptivity). Food deprivation and food restriction were sufficient to induce females to become significantly less sexually receptive than control females. Eleven of 12 control PPE females mated, 4 of 12 food-restricted females mated, and 3 of 12 food-deprived females mated. Dams facing food deprivation or restriction during late gestation may have to balance the benefits of mating during PPE with the increased costs associated with getting pregnant while they are lactating.


The population genetics of sperm displacement.
This article reports the results of some sperm displacement experiments, as well as the results of a theoretical study of selection arising from genetic differences in displacing ability. The experimental work involved the use of three genetic marker stocks in double and triple matings. The speed of displacement following the matings was determined by scoring the progeny of each female daily. There were clear differences between strains in their displacing ability. It is shown how new information concerning the displacement process results when three markers are used; however, no new light is shed by these experiments on the mechanism of displacement. The theoretical study of selection resulting from displacement uses a one-locus, two-allele model in which three diploid male genotypes confer different displacing abilities. The results indicate stable equilibria if (1) there is heterosis, and (2) there are certain nontransitive relationships in displacing ability among the different kinds of double matings. Some evolutionary consequences are discussed in which sperm displacement is regarded as a form of sexual selection.


Global warming, elevational range shifts, and lowland biotic attrition in the wet tropics.
Many studies suggest that global warming is driving species ranges poleward and toward higher elevations at temperate latitudes, but evidence for range shifts is scarce for the tropics, where the shallow latitudinal temperature gradient makes upslope shifts more likely than poleward shifts. Based on new data for plants and insects on an elevational transect in Costa Rica, we assess the potential for lowland biotic attrition, range-shift gaps, and mountaintop extinctions under projected warming. We conclude that tropical lowland biotas may face a level of net lowland biotic attrition without parallel at higher latitudes (where range shifts may be compensated for by species from lower latitudes) and that a high proportion of tropical species soon faces gaps between current and projected elevational ranges.


Varicocele percutaneous embolization outcomes in a pediatric group: 7-year retrospective study.
Percutaneous embolization and surgical repair are the current treatment options for varicocele, but determining method superiority remains controversial. In this retrospective study, we evaluate the technical success, complication and recurrence rates following percutaneous embolization in a pediatric group, which were compared to reported outcomes for surgical repairs. Thirty children treated for percutaneous varicocele embolization were recruited. The side and grade of varicocele, symptoms, testicular asymmetry, mean recurrence time, total radiation dose and complications were evaluated. Recurrence and follow-up complications due to embolization were also reviewed. The venography showed retrograde filling of the internal spermatic vein with the identification of aberrantly fed vessels in 23 % of patients. None of the patients suffered from procedure complications except one who had venous injury which was treated with a sclerosing agent. The technical success rate was 93 % (28 patients) with a recurrence rate of 13 % (4 patients). Interestingly, the mean radiation dose used was 862.5 µGy m(2), 3 times lower than abdominal CT. Considering the intravascular nature of embolization, which aims to avoid testicular artery and spermatic cord damage (difficult to avoid with the surgical method), and consequently a lower complication rate, along with the same success rate and recurrence rate, our study supports that embolization is a superior method to surgical interventions.


Cell size regulation, a mechanism that controls cellular RNA accumulation: consequences on regulation of the ubiquitous transcription factors Oct1 and NF-Y and the liver-enriched transcription factor DBP.
Cell sizes can differ vastly between cell types in individual metazoan organisms. In rat liver, spleen, and thymus, differences in average cell size roughly reflect differences in RNA:DNA ratios. For example, hepatocytes were found to have a cytoplasmic:nuclear volume ratio and an RNA:DNA ratio which were 34- and 21-fold higher, respectively, than those in thymocytes. RNA synthesis per DNA-equivalent in the hepatocytes was 25-fold greater than that in thymocytes, suggesting that differences in overall transcriptional activity, not differences in overall RNA stability, were primarily responsible for determining cellular RNA:DNA ratios. The mechanisms determining the capacity of large cells to synthesize and accumulate more ubiquitous cytoplasmic macromolecules, such as ribosomes, than smaller cells is entitled "cell size regulation." Cell size regulation may have important consequences on the tissue distribution of transcription factors. Thus, in liver, lung, kidney, spleen, and brain, cellular levels of the mRNA encoding the leucine zipper protein DBP correlate closely to cellular RNA:DNA ratios. Our results suggest that DBP mRNA levels, like rRNA levels, are transcriptionally determined. Thus the dbp gene, like the ribosomal genes, may be subject to cell size regulation. As a consequence, nuclei from liver, a tissue with a very large average cell size, accumulated higher levels of DBP protein than nuclei from small-celled tissues, such as spleen or lung. In contrast to DBP, the ubiquitous transcription factors Oct1 and NF-Y escaped cell size control. Nuclei from most tissues contained similar amounts of these factors irrespective of cell size. Likewise, tissues with large or small average cell sizes contained similar levels of the mRNAs encoding Oct1 or NF-Ya, one of the subunits of the heteromeric CCAAT-binding factor NF-Y, per DNA-equivalent. Interestingly, mRNA encoding NF-Yb, another subunit of NF-Y, was subject to cell size regulation. Our results suggest that NF-Yb protein escapes cell size regulation at a posttranslational level.


Reliability, validity and minimal detectable change of 2-minute walk test, 6-minute walk test and 10-meter walk test in frail older adults with dementia.
Walk tests are commonly used to evaluate walking ability in frail older adults with dementia but their psychometric evidence in this population is lacking. 1) To examine test-retest and inter-rater reliability, construct and known-group validity, and minimal detectable change at 95% level of confidence (MDC95) of walk tests in frail older adults with dementia, and 2) to examine the feasibility and consistency of a cueing system in facilitating participants in completing walk tests. Psychometric study with repeated measures. Day care and residential care facilities. Thirty-nine frail older adults with a mean age 87.1 and a diagnosis of dementia or Alzheimer's disease who were able to walk independently for at least 15 m. The participants underwent a 2-minute walk test (2MWT), 6-minute walk test (6MWT) and 10-meter walk test (10MeWT) on 6 separate occasions under 2 independent assessors using a cueing system. Functional status was measured using the Elderly Mobility Scale (EMS), Berg Balance Scale (BBS) and Modified Barthel Index (MBI). Excellent test-retest (ICC = 0.91-0.98) and inter-rater reliability (ICC = 0.86-0.96) were shown in the 2MWT, 6MWT and 10MeWT. The walk tests were strongly correlated with each other (ρ = 0.85-0.94). The correlations between the walk tests and the functional measures were moderate in general (ρ = 0.34-0.55). All the walk tests were able to distinguish between those who could walk outdoor and indoor only (p ≤ .036). The MDC95 were 9.1 m in the 2MWT, 28.1 m in the 6MWT, and.16 m/s in the 10MeWT. The cues provided by the assessors in the walk tests were generally consistent (ICC = 0.62-0.89). The 2MWT, 6MWT and 10MeWT are reliable and valid measures in evaluating walking ability in frail older adults with dementia. The MDC95 of the walk tests has been established. The cueing system is feasible and reliable to facilitate the administration of the walk tests in this population group.


Changes in sexual risk behavior among MSM participating in a research cohort in coastal Kenya.
To describe changes in sexual risk behavior among Kenyan MSM who received regular risk reduction counseling (RRC). Data were derived from two cohorts of HIV-1-negative and HIV-1-positive MSM in Kenya. Behavioral data were collected at enrollment and at monthly or quarterly scheduled follow-up visits. At each visit, RRC was provided to all men and HIV-1 testing to seronegative men. Random effects logistic and Poisson regression models with time since study entry as main variable of interest were used to evaluate changes in number of sex partners and unprotected sex in the past week, and insertive, receptive, and unprotected anal intercourse in the past 3 months. Analyses were adjusted for HIV-1-status, calendar year of follow-up, and several baseline characteristics. Trends over follow-up time were allowed to differ by HIV-1-status. Men were censored when they seroconverted for HIV. Number of regular and casual sex partners and unprotected anal intercourse decreased in both HIV-1-negative and HIV-1-positive men. Unprotected sex with both regular and casual sex partners decreased more strongly early in follow-up in HIV-1-positive men than in HIV-1-negative men. Decreases in insertive anal intercourse were found for HIV-1-positive men only, whereas decreases in receptive anal intercourse were found for HIV-1-negative men only. MSM who were regularly exposed to RRC showed some reductions in sexual risk behavior, but it is uncertain if these reductions are sustained over time. As HIV-1 incidences in Kenyan MSM are very high, RRC should be supported by comprehensive biomedical interventions.


[The classification of coronary lesion from Society for Cardiac Angiography and Intervention predicts better results of coronary angioplasty than the one from American College of Cardiology/American Heart Association Coronary Disease].
The classification of coronary lesion complexity, using the American College of Cardiology/American Heart Association (ACC/AHA) is a predictor of balloon angioplasty success. Stents have improved results even in complex lesions. To compare the ACC/AHA and the new Society for Cardiac Angiography (SCA&I) coronary lesion scores as predictors of angioplasty success. Ali consecutive angioplasty procedures (n = 346, 456 lesions, 47% stents) were prospectively analyzed from August 1996 to March 1999. Coronary lesions were classified using the ACC/AHA and SCA&I scores. Angiographic success was assessed and its multivariate predictors determined with logistic regression analysis. According to the ACC/AHA score, angiographic success was 97, 92.7, 93.3, and 82.3% in A, Bl, B2 and C lesions respectively (p = 0.013). There only were significant differences in success between C and A, Bl or B2 lesions. According to the SCA&I score success was achieved in 97.3, 97.9, 75.8 and 33.3% in nonCP, CP, nonCO and CO lesions respectively (P < 0.001). With the SCA&I score statistically significant differences in angiographic success were found for all lesion score comparisons, except between nonCP and CP lesions. No other variables had predictive value for angiographic success. Coronary angioplasty angiographic success is better predicted by the new SCA&l lesion score than with the ACC/AHA lesion classification in a group of patients with frequent use of stents.


Physical activity in relation to energy intake and body fat in 8- and 13-year-old children in Sweden.
A random sample of 682 8- and 13-year-old children resident in Sweden was studied with regard to physical activity, energy intake, height, weight and skinfold thickness. A reduction of physical activity over the years was indicated by a tendency towards a higher body fat content in spite of a lower mean energy intake as compared with such values obtained 10-15 years ago in Swedish children of equal ages. Children characterized by high habitual physical activity tended to have a lower body fat content, despite a higher energy intake, than less active children. Children, especially girls, of parents with a low educational level showed a tendency towards higher body fat content as compared with those of parents with higher education.


Perceptions of general practitioners towards the use of a new system for treating back pain: a qualitative interview study.
Changing clinicians' behaviour is recognised as a major challenge. It is clear that behaviour change not only depends on demonstrating the proven effectiveness of clinical interventions; contextual and occupational factors, such as 'change readiness', may be central to their implementation. This paper highlights the context of behaviour change in relation to a healthcare innovation introduced within primary care, highlighting the importance of organisational and interpersonal factors that may help explain the dynamics of implementation. Qualitative interviews were conducted with general practitioners (GPs) before (n = 32) and after (n = 9) the introduction of a subgrouping for targeted treatment system. GPs were offered an electronic six-item subgrouping tool, to identify patients according to their risk of poor outcome ('high', 'low') in order to help inform their decision making about treatment approaches. Recruitment was based on a 'maximum diversification sample', to obtain a wide representation of views across all five practices. A coding scheme was developed based on the emergent findings, and the data were analysed using 'constant comparison', drawing upon insights and developing connections between themes. We adopted the normalisation process theory (NPT) to explain the uptake of the new system and to examine the relevance of coherence for the implementation of innovations in organisations. GPs perceived back pain as a low clinical priority, and highlighted the importance of 'practical' and 'relational' coherence in decisions to adopt and engage with the new subgrouping for targeted treatment system. Health professionals often engage in 'sense making' about new innovations to 'road test' their applicability or relevance to daily clinical routines. Low back pain was generally perceived as an 'uninteresting' and clinically unchallenging health problem by GPs, which may partly explain their lack of engagement with the new subgrouping for targeted treatment system. The adoption of this new way of working by GPs was determined by the meaning that they ascribed to it in the context of their daily clinical routines. We conclude that the key obstacle to implementation of the new subgrouping for targeted treatment system for low back pain in primary care was an initial failure to achieve 'coherence' of the desired practice change with GPs. Despite this, GPs used the tool to different degrees, though this signified a general commitment to participating in the study rather than a deeper attitude change towards the new system.


Efficient reverse-engineering of a developmental gene regulatory network.
Understanding the complex regulatory networks underlying development and evolution of multi-cellular organisms is a major problem in biology. Computational models can be used as tools to extract the regulatory structure and dynamics of such networks from gene expression data. This approach is called reverse engineering. It has been successfully applied to many gene networks in various biological systems. However, to reconstitute the structure and non-linear dynamics of a developmental gene network in its spatial context remains a considerable challenge. Here, we address this challenge using a case study: the gap gene network involved in segment determination during early development of Drosophila melanogaster. A major problem for reverse-engineering pattern-forming networks is the significant amount of time and effort required to acquire and quantify spatial gene expression data. We have developed a simplified data processing pipeline that considerably increases the throughput of the method, but results in data of reduced accuracy compared to those previously used for gap gene network inference. We demonstrate that we can infer the correct network structure using our reduced data set, and investigate minimal data requirements for successful reverse engineering. Our results show that timing and position of expression domain boundaries are the crucial features for determining regulatory network structure from data, while it is less important to precisely measure expression levels. Based on this, we define minimal data requirements for gap gene network inference. Our results demonstrate the feasibility of reverse-engineering with much reduced experimental effort. This enables more widespread use of the method in different developmental contexts and organisms. Such systematic application of data-driven models to real-world networks has enormous potential. Only the quantitative investigation of a large number of developmental gene regulatory networks will allow us to discover whether there are rules or regularities governing development and evolution of complex multi-cellular organisms.


Improved dual-luciferase reporter assays for nuclear receptors.
Nuclear receptors play important roles in many cellular functions through control of gene transcription. It is also a large target class for drug discovery. Luciferase reporter assays are frequently used to study nuclear receptor function because of their wide dynamic range, low endogenous activity, and ease of use. Recent improvements of luciferase genes and vectors have further enhanced their utilities. Here we applied these improvements to two reporter formats for studying nuclear receptors. The first assay contains a Murine Mammary Tumor Virus promoter upstream of a destabilized luciferase. The presence of response elements for nuclear hormone receptor in this promoter allows the studies of endogenous and/or exogenous full length receptors. The second assay contains a ligand binding domain (LBD) of a nuclear receptor fused to the GAL4 DNA binding domain (DBD) on one vector and multiple Gal4 Upstream Activator Sequences (UAS) upstream of luciferase reporter on another vector. We showed that codon optimization of luciferase reporter genes increased expression levels in conjunction with the incorporation of protein destabilizing sequences into luciferase led to a larger assay dynamic range in both formats. The optimum number of UAS to generate the best response was determined. The expression vector for nuclear receptor LBD/GAL4 DBD fusion also constitutively expresses a Renilla luciferase-neo(R) fusion protein, which provides selection capability (G418 resistance, neo(R)) as well as an internal control (Renilla luciferase). This dual-luciferase format allowed detecting compound cytotoxicity or off-target change in expression during drug screening, therefore improved data quality. These luciferase reporter assays provided better research and drug discovery tools for studying the functions of full length nuclear receptors and ligand binding domains.


Outpatient parenteral antimicrobial therapy for orthopedic infections - a successful public healthcare experience in Brazil.
Treatment of orthopedic infections usually requires prolonged antimicrobial therapy, ranging from 14 days up to 6 months. Nowadays, rising levels of antimicrobial resistance demands parenteral therapy for many patients. Outpatient parenteral antimicrobial therapy (OPAT) is a modality that allows treatment out of hospital in these situations. In Brazil, where a public universal healthcare system allows full coverage for all citizens, implantation and dissemination of OPAT programs would be beneficial for patients and for the system, because it would allow a better allocation of health resources. The Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Faculdade de Medicina da USP (IOT) started, in July 2013, a partnership with municipal health authorities in Sao Paulo, Brazil, in order to initiate an OPAT program in which patients discharged from that hospital would be able to continue antimicrobial therapy at primary care facilities. When necessary, patients could also receive their therapy at the day-hospital located at IOT. Primary care nursing and physician staff were trained about antimicrobial infusion and peripherally inserted central catheter manipulation. An OPAT specific antimicrobial protocol was designed and a special reference and counter-reference organized. As a result, 450 primary healthcare professionals were trained. In the first year of this program, 116 patients were discharged for OPAT. Chronic and acute osteomyelitis were most frequent diagnosis. Teicoplanin, ertapenem and tigecycline were the most used drugs. Duration of treatment varied from 10 to 180 days (average 101, median 42). Total sum of days in OPAT regimen was 11,698. Only 3 patients presented adverse effects. Partnership between services of different levels of complexity allowed implantation of a safe and effective public healthcare OPAT program for treatment of orthopedic infections. This program can serve as a model for developing similar strategies in other regions of Brazil and Latin America.


Obesity in children and adolescents with chronic pain: associations with pain and activity limitations.
Obesity is associated with functional disability in adults with chronic pain, but less is known about obesity among youth with chronic pain. The purpose of this study was to (1) identify the prevalence of overweight and obesity in children and adolescents receiving treatment for chronic pain, and (2) examine associations between Body Mass Index (BMI), pain intensity, and activity limitations in this population. Data were obtained from records of 118 patients, ages 8 to 18, seen in a multidisciplinary pediatric pain clinic. Information about age, sex, pain problem, duration and severity, medical diagnoses, medications, height, and weight were collected from medical records and intake questionnaires. The CDC's pediatric BMI calculator was used to obtain percentile and category (underweight, healthy weight, overweight, obese). Children and parents completed the Child Activity Limitations Interview-21 (CALI-21), a self-report measure of activity limitations. A significantly higher rate of overweight and obesity was observed among youth with chronic pain compared with a normative sample. BMI percentile was predictive of concurrent limitations in vigorous activities, according to parent report. BMI percentile and weight status may contribute to activity limitations among children and adolescents with chronic pain. Weight status is an important factor to consider in the context of treatment of chronic pain and disability in children and adolescents.


Top-Down Modulation on the Perception and Categorization of Identical Pitch Contours in Speech and Music.
Whether pitch in language and music is governed by domain-specific or domain-general cognitive mechanisms is contentiously debated. The aim of the present study was to investigate whether mechanisms governing pitch contour perception operate differently when pitch information is interpreted as either speech or music. By modulating listening mode, this study aspired to demonstrate that pitch contour perception relies on domain-specific cognitive mechanisms, which are regulated by top-down influences from language and music. Three groups of participants (Mandarin speakers, Dutch speaking non-musicians, and Dutch musicians) were exposed to identical pitch contours, and tested on their ability to identify these contours in a language and musical context. Stimuli consisted of disyllabic words spoken in Mandarin, and melodic tonal analogs, embedded in a linguistic and melodic carrier phrase, respectively. Participants classified identical pitch contours as significantly different depending on listening mode. Top-down influences from language appeared to alter the perception of pitch contour in speakers of Mandarin. This was not the case for non-musician speakers of Dutch. Moreover, this effect was lacking in Dutch speaking musicians. The classification patterns of pitch contours in language and music seem to suggest that domain-specific categorization is modulated by top-down influences from language and music.


Circulating Fibroblast Growth Factor 21 (Fgf21) as Diagnostic and Prognostic Biomarker in Renal Cancer.
The finding of new biomarkers is needed to have a better sub-classification of primary renal tumors (RCC) as well as more reliable predictors of outcome and therapy response. In this study, we evaluated the role of circulating FGF21, an endocrine factor, as a diagnostic and prognostic biomarker for ccRCC. Serum samples from healthy controls (HC), clear cell and chromophobe RCC cancer patients were obtained from the serum biobank "Biobanco Público de Muestras Séricas Oncológicas" (BPMSO) of the "Instituto de Oncología "Ángel H. Roffo". Serum FGF21 and leptin were measured by ELISA while other metabolic markers were measured following routinely clinical procedures. One of our major findings was that FGF21 levels were significantly increased in ccRCC patients compared with HC. Moreover, we showed an association between the increased serum FGF21 levels and the shorter disease free survival in a cohort of 98 ccRCC patients, after adjustment for other predictors of outcome. Our results suggest that higher FGF21 serum level is an independent prognostic biomarker, associated with worse free-disease survival.


Crustal dilatation observed by GRACE after the 2004 Sumatra-Andaman earthquake.
We report the detection of an earthquake by a space-based measurement. The Gravity Recovery and Climate Experiment (GRACE) satellites observed a +/-15-microgalileo gravity change induced by the great December 2004 Sumatra-Andaman earthquake. Coseismic deformation produces sudden changes in the gravity field by vertical displacement of Earth's layered density structure and by changing the densities of the crust and mantle. GRACE's sensitivity to the long spatial wavelength of gravity changes resulted in roughly equal contributions of vertical displacement and dilatation effects in the gravity measurements. The GRACE observations provide evidence of crustal dilatation resulting from an undersea earthquake.


Primary Hepatic Lymphoma: A Retrospective, Multicenter Rare Cancer Network Study.
Primary hepatic lymphoma (PHL) is a rare malignancy. We aimed to assess the clinical profile, outcome and prognostic factors in PHL through the Rare Cancer Network (RCN). A retrospective analysis of 41 patients was performed. Median age was 62 years (range, 23-86 years) with a male-to-female ratio of 1.9:1.0. Abdominal pain or discomfort was the most common presenting symptom. Regarding B-symptoms, 19.5% of patients had fever, 17.1% weight loss, and 9.8% night sweats. The most common radiological presentation was multiple lesions. Liver function tests were elevated in 56.1% of patients. The most common histopathological diagnosis was diffuse large B-cell lymphoma (65.9%). Most of the patients received Chop-like (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimens; 4 patients received radiotherapy (dose range, 30.6-40.0 Gy). Median survival was 163 months, and 5- and 10-year overall survival rates were 77 and 59%, respectively. The 5- and 10-year disease-free and lymphoma-specific survival rates were 69, 56, 87 and 70%, respectively. Multivariate analysis revealed that fever, weight loss, and normal hemoglobin level were the independent factors influencing the outcome. In this retrospective multicenter RCN study, patients with PHL had a relatively better prognosis than that reported elsewhere. Multicenter prospective studies are still warranted to establish treatment guidelines, outcome, and prognostic factors.


TRIM21/Ro52 - Roles in Innate Immunity and Autoimmune Disease.
TRIM21 (Ro52/SSA1) is an E3 ubiquitin ligase with key roles in immune host defence, signal transduction, and possibly cell cycle regulation. It is also an autoantibody target in Sjögren's syndrome, systemic lupus erythematosus, and other rheumatic autoimmune diseases. Here, we summarise the structure and function of this enzyme, its roles in innate immunity, adaptive immunity and cellular homeostasis, the pathogenesis of autoimmunity against TRIM21, and the potential impacts of autoantibodies to this intracellular protein.


Perspectives on Phytochemicals as Antibacterial Agents: An Outstanding Contribution to Modern Therapeutics.
Despite the considerable advancements in the development of antimicrobial agents, incidents of epidemics due to multi drug resistance in microorganisms have created a massive hazard to mankind. Due to increased resistance against conventional antibiotics, researchers and pharmaceutical industries are more concerned about novel therapeutic agents for the prevention of bacterial infections. Enormous wealth of traditional system of medicine gains importance in health therapies over again. With ancient credentials of potent medicinal plants, various herbal remedies came forward for the management of bacterial infections. The Ayurvedic approach facilitates the development of new therapeutic agents due to structural and functional diversity among phytochemicals. The abundance and diversity is responsible for the characterization of new lead structures from medicinal plants. Industrial interest has increased due to recent research advancements viz. synergistic and high-throughput screening approach for the evaluation of vast variety of phytochemicals. The review certainly emphasizes on the traditional medicines as alternatives to conventional chemotherapeutic drugs. The review briefly describes mode of action of various antibiotics and resistance mechanisms. This review focuses on the chemical diversity and various mechanisms of action of phytochemicals against bacterial pathogens.


Analysis of correlation between white matter changes and functional responses in thalamic stroke: a DTI & EEG study.
Diffusion tensor imaging (DTI) allows in vivo structural brain mapping and detection of microstructural disruption of white matter (WM). One of the commonly used parameters for grading the anisotropic diffusivity in WM is fractional anisotropy (FA). FA value helps to quantify the directionality of the local tract bundle. Therefore, FA images are being used in voxelwise statistical analyses (VSA). The present study used Tract-Based Spatial Statistics (TBSS) of FA images across subjects, and computes the mean skeleton map to detect voxelwise knowledge of the tracts yielding to groupwise comparison. The skeleton image illustrates WM structure and shows any changes caused by brain damage. The microstructure of WM in thalamic stroke is investigated, and the VSA results of healthy control and thalamic stroke patients are reported. It has been shown that several skeleton regions were affected subject to the presence of thalamic stroke (FWE, p < 0.05). Furthermore the correlation of quantitative EEG (qEEG) scores and neurophysiological tests with the FA skeleton for the entire test group is also investigated. We compared measurements that are related to the same fibers across subjects, and discussed implications for VSA of WM in thalamic stroke cases, for the relationship between behavioral tests and FA skeletons, and for the correlation between the FA maps and qEEG scores.Results obtained through the regression analyses did not exceed the corrected statistical threshold values for multiple comparisons (uncorrected, p < 0.05). However, in the regression analysis of FA values and the theta band activity of EEG, cingulum bundle and corpus callosum were found to be related. These areas are parts of the Default Mode Network (DMN) where DMN is known to be involved in resting state EEG theta activity. The relation between the EEG alpha band power values and FA values of the skeleton was found to support the cortico-thalamocortical cycles for both subject groups. Further, the neurophysiological tests including Benton Face Recognition (BFR), Digit Span test (DST), Warrington Topographic Memory test (WTMT), California Verbal Learning test (CVLT) has been regressed with the FA skeleton maps for both subject groups. Our results corresponding to DST task were found to be similar with previously reported findings for working memory and episodic memory tasks. For the WTMT, FA values of the cingulum (right) that plays a role in memory process was found to be related with the behavioral responses. Splenium of corpus callosum was found to be correlated for both subject groups for the BFR.


The experience of 'feeling fat' in women with anorexia nervosa, dieting and non-dieting women: an exploratory study.
To provide a preliminary, systematic exploration of some features associated with the experience of 'feeling fat'. Women with anorexia nervosa (N = 16), women who were dieting (N = 15) and non-dieting women (N = 17) took part in a semi-structured interview. Feeling fat was common in all three groups of women. It was associated with distress, negative emotions, internal and external body sensations, images in a range of modalities, negative self beliefs and a first memory of feeling fat. Differences specifically characteristic of those with anorexia nervosa were identified, including feeling fatter, greater associated distress, more negative emotions, greater 'emotional' belief in cognitions, a richer experience, an earlier first memory, greater strength of negative self beliefs and a link to restricting behaviour. Some qualitative data are reported. The experience of feeling fat can be 'unpacked' in a way that may be useful in cognitive therapy for those with anorexia nervosa.


Protocol for a prospective, randomized study on neurophysiological assessment of lower urinary tract function in a healthy cohort.
Lower urinary tract symptoms are highly prevalent and a large proportion of these symptoms are known to be associated with a dysfunction of the afferent pathways. Diagnostic tools for an objective and reproducible assessment of afferent nerve function of the lower urinary tract are missing. Previous studies showed first feasibility results of sensory evoked potential recordings following electrical stimulation of the lower urinary tract in healthy subjects and patients. Nevertheless, a refinement of the methodology is necessary. This study is a prospective, randomized trial conducted at Balgrist University Hospital, Zürich, Switzerland. Ninety healthy subjects (forty females and fifty males) without lower urinary tract symptoms are planned to be included in the study. All subjects will undergo a screening visit (including standardized questionnaires, 3-day bladder diary, urinalysis, medical history taking, vital signs, physical examination, neuro-urological examination) followed by two measurement visits separated by an interval of 3 to 4 weeks. Electrical stimulations (0.5Hz-5Hz, bipolar, square wave, pulse width 1 ms) will be applied using a custom-made transurethral catheter at different locations of the lower urinary tract including bladder dome, trigone, proximal urethra, membranous urethra and distal urethra. Every subject will be randomly stimulated at one specific site of the lower urinary tract. Sensory evoked potentials (SEP) will be recorded using a 64-channel EEG cap. For an SEP segmental work-up we will place additional electrodes on the scalp (Cpz) and above the spine (C2 and L1). Visit two and three will be conducted identically for reliability assessment. The measurement of lower urinary tract SEPs elicited by electrical stimulation at different locations of the lower urinary tract has the potential to serve as a neurophysiological biomarker for lower urinary tract afferent nerve function in patients with lower urinary tract symptoms or disorders. For implementation of such a diagnostic tool into clinical practice, an optimized setup with efficient and reliable measurements and data acquisition is crucial. In addition, normative data from a larger cohort of healthy subjects would provide information on variability, potential confounding factors and cut-off values for investigations in patients with lower urinary tract dysfunction/symptoms. Clinicaltrials.gov; Identifier: NCT02272309 .


Incidence, impact, and predictors of cranial nerve palsy and haematoma following carotid endarterectomy in the international carotid stenting study.
Cranial nerve palsy (CNP) and neck haematoma are complications of carotid endarterectomy (CEA). The effects of patient factors and surgical technique were analysed on the risk, and impact on disability, of CNP or haematoma in the surgical arm of the International Carotid Stenting Study (ICSS), a randomized controlled clinical trial of stenting versus CEA in patients with symptomatic carotid stenosis. A per-protocol analysis of early outcome in patients receiving CEA in ICSS is reported. Haematoma was defined by the surgeon. CNP was confirmed by an independent neurologist. Factors associated with the risk of CNP and haematoma were investigated in a binomial regression analysis. Of the patients undergoing CEA, 45/821 (5.5%) developed CNP, one of which was disabling (modified Rankin score = 3 at 1 month). Twenty-eight (3.4%) developed severe haematoma. Twelve patients with haematoma also had CNP, a significant association (p < .01). Independent risk factors modifying the risk of CNP were cardiac failure (risk ratio [RR] 2.66, 95% CI 1.11 to 6.40), female sex (RR 1.80, 95% CI 1.02 to 3.20), the degree of contralateral carotid stenosis, and time from randomization to treatment >14 days (RR 3.33, 95% CI 1.05 to 10.57). The risk of haematoma was increased in women, by the prescription of anticoagulant drugs pre-procedure and in patients with atrial fibrillation, and was decreased in patients in whom a shunt was used and in those with a higher baseline cholesterol level. CNP remains relatively common after CEA, but is rarely disabling. Women should be warned about an increased risk. Attention to haemostasis might reduce the incidence of CNP. ICSS is a registered clinical trial: ISRCTN 25337470.


Using cytochrome P-450 gene knock-out mice to study chemical metabolism, toxicity, and carcinogenicity.
Cytochrome P-450 (CYP) enzymes are heme-containing proteins that carry out oxidative metabolism of a wide range of structurally diverse exogenous chemicals and therapeutic agents as well as endogenous compounds. For some of these xenobiotics, oxidative metabolism results in the formation of toxic, mutagenic, or carcinogenic metabolites. In the past, the role of CYP enzymes in metabolism and chemical-induced toxicity was studied indirectly through use of specific antibodies or inducers and inhibitors of these enzymes. Progress in molecular biology and the ability to bioengineer animal models that do not express CYP1A2, CYP1A1, CYP1B1, CYP2E1, or both CYP1A2 and CYP2E1 isozymes has allowed for direct investigations of the in vivo role of these enzymes in the metabolism, toxicity, and carcinogenicity of xenobiotics. This article reviews research conducted to date that utilizes these genetically bioengineered mice in metabolism, toxicity, or carcinogenicity studies of chemicals. Some studies showed a positive correlation between in vivo results and in vitro predictions for the role of a specific CYP in chemical-induced effects, whereas other studies did not support in vitro predictions. Work reviewed herein demonstrates the importance of using animal models for investigating the role of specific CYP enzymes in metabolism and chemical-induced toxicity or carcinogenicity rather than relying solely on in vitro techniques. Eventually, studies of this nature will facilitate a more accurate assessment of human risks with regard to chemicals by helping us to understand the relationships between chemical metabolism, carcinogenicity, and polymorphisms in CYP enzymes.


Time-to-treatment of mental disorders in a community sample of Dutch adolescents. A TRAILS study.
Timely recognition and treatment of mental disorders with an onset in childhood and adolescence is paramount, as these are characterized by greater severity and longer persistence than disorders with an onset in adulthood. Studies examining time-to-treatment, also referred to as treatment delay, duration of untreated illness or latency to treatment, and defined as the time between disorder onset and initial treatment contact, are sparse and all based on adult samples. The aim of this study was to describe time-to-treatment and its correlates for any health care professional (any care) and secondary mental health care (secondary care), for a broad range of mental disorders, in adolescents. Data from the Dutch community-based cohort study TRacking Adolescents' Individual Lives Survey (TRAILS; N = 2230) were used. The Composite International Diagnostic Interview (CIDI) was administered to assess DSM-IV disorders, the age of onset, and the age of initial treatment contact with any health care professional in 1584 adolescents of 18-20 years old. In total 43% of the adolescents (n = 675) were diagnosed with a lifetime DSM-IV disorder. The age of initial treatment contact with secondary care was based on administrative records from 321 adolescents without a disorder onset before the age of 10. Descriptive statistics, cumulative lifetime probability plots, and Cox regression analyses were used analyze time-to-treatment. The proportion of adolescents who reported lifetime treatment contact with any care varied from 15% for alcohol dependence to 82% for dysthymia. Regarding secondary care, proportions of lifetime treatment contact were lower for mood disorders and higher for substance dependence. Time-to-treatment for any care varied considerably between and within diagnostic classes. The probability of lifetime treatment contact for mood disorders was above 90%, whereas for other mental disorders this was substantially lower. An earlier age of onset predicted a longer, and the presence of a co-morbid mood disorder predicted a shorter time-to-treatment in general. Disorder severity predicted a shorter time-to-treatment for any care, but not for secondary care. Time-to-treatment for secondary care was shorter for adolescents from low and middle socioeconomic background than for adolescents from a high socioeconomic background. Although the time-to-treatment was shorter for adolescents than for adults, it was still substantial, and the overall patterns were remarkably similar to those found in adults. Efforts to reduce time-to-treatment should therefore be aimed at children and adolescents. Future research should address mechanisms underlying time-to-treatment and its consequences for early-onset disorders in particular.


Toward the establishment of a forensic nursing specialty in Brazil: an integrative literature review.
Over the past two decades, Brazil has made progress in bringing political and community attention to issues related to violence. The recognition of links between violence and health has intensified calls to accelerate the development of a forensic nursing specialty in Brazil. The aim of this study was to systematically examine and synthesize the literature on the development of the forensic nursing specialty around the globe and to extract important lessons for the establishment of a forensic nursing specialty in Brazil. An integrative review was conducted according to the method described by Whittmore and Knafl (2005). Electronic searches of the following databases were conducted between December 2012 and March 2013: CINAHL Plus with Full Text, Criminal Justice, Index to Legal periodicals, MEDLINE, Soc Index with Full Text, Social Work Abstracts, SCOPUS, and PsycINFO. The search terms used were: [(TI nurs* or SU nurs*) and [TI (forensic* or penal or prison*) or SU (forensic* or penal or prison*)] and (sexual assault nurse examiner*). Preestablished inclusion/exclusion criteria were used to select published articles for review. Twenty-three articles met inclusion criteria and were included in the full review. Important lessons for Brazil are discussed in terms of education and curricular issues and forensic psychiatric nursing. In Brazil, there is a window of opportunity to contribute the theoretical foundations of forensic nursing science and to advance nursing specialty practice in the areas of Sexual Assault Nurse Examiners and forensic psychiatric nurses.


Introduction: The specter of opiate addiction in reproductive medicine.
The alarming trend in opiate misuse in developed countries is prompting an increasingly strident public call for action. Although many in our field have assumed that this building crisis does not really affect us or our patients, data show that the emerging demographic at highest risk for misusing opiates clearly includes patients who seek care in our practices. The goals of this Views and Reviews are to provide a clear understanding of emerging trends in opiate misuse, to review the impact of opiates on the reproductive axis, and to suggest practical recommendations aimed at both mitigating iatrogenic influences on promoting misuse and developing treatment frameworks when misuse is suspected or identified. Regrettably, there is little if any information on treatment of opiate misuse in the infertility population; we are perhaps best served by learning from successful approaches used in pregnant patients. It is hoped that this Views and Reviews will stimulate focused research and, ultimately, evidence-based guidelines and pathways that will address this widespread clinical problem.


How Equity-Oriented Health Care Affects Health: Key Mechanisms and Implications for Primary Health Care Practice and Policy.
Policy Points A consensus regarding the need to orient health systems to address inequities is emerging, with much of this discussion targeting population health interventions and indicators. We know less about applying these approaches to primary health care. This study empirically demonstrates that providing more equity-oriented health care (EOHC) in primary health care, including trauma- and violence-informed, culturally safe, and contextually tailored care, predicts improved health outcomes across time for people living in marginalizing conditions. This is achieved by enhancing patients' comfort and confidence in their care and their own confidence in preventing and managing health problems. This promising new evidence suggests that equity-oriented interventions at the point of care can begin to shift inequities in health outcomes for those with the greatest need. Significant attention has been directed toward addressing health inequities at the population health and systems levels, yet little progress has been made in identifying approaches to reduce health inequities through clinical care, particularly in a primary health care context. Although the provision of equity-oriented health care (EOHC) is widely assumed to lead to improvements in patients' health outcomes, little empirical evidence supports this claim. To remedy this, we tested whether more EOHC predicts more positive patient health outcomes and identified selected mediators of this relationship. Our analysis uses longitudinal data from 395 patients recruited from 4 primary health care clinics serving people living in marginalizing conditions. The participants completed 4 structured interviews composed of self-report measures and survey questions over a 2-year period. Using path analysis techniques, we tested a hypothesized model of the process through which patients' perceptions of EOHC led to improvements in self-reported health outcomes (quality of life, chronic pain disability, and posttraumatic stress [PTSD] and depressive symptoms), including particular covariates of health outcomes (age, gender, financial strain, experiences of discrimination). Over a 24-month period, higher levels of EOHC predicted greater patient comfort and confidence in the health care patients received, leading to increased confidence to prevent and manage their health problems, which, in turn, improved health outcomes (depressive symptoms, PTSD symptoms, chronic pain, and quality of life). In addition, financial strain and experiences of discrimination had significant negative effects on all health outcomes. This study is among the first to demonstrate empirically that providing more EOHC predicts better patient health outcomes over time. At a policy level, this research supports investments in equity-focused organizational and provider-level processes in primary health care as a means of improving patients' health, particularly for those living in marginalizing conditions. Whether these results are robust in different patient groups and across a broader range of health care contexts requires further study.


[Epidemiology of Internet Use by an Adolescent Population and its Relation with Sleep Habits].
In the last decades, the great technological development increased Internet popularity, emerging the concern about its overuse. The objectives of this study were to assess and characterize Internet use in adolescence, determine Internet addiction and clarify its association with sleep disorders and excessive daytime sleepiness. It was performed an observational, cross sectional and community-based study. The target were students attending 7th and 8th grades, to whom was applied an online self-report questionnaire to assess sociodemographic features, Internet use, Internet dependence, sleep characteristics and excessive daytime sleepiness. A total of 727 adolescents were included with a mean age 13 ± 0.9 years. Three-quarters of teenagers use Internet daily and 41% do it for three or more hours/day, mainly at home. The phone and laptop were the main devices used. Online games and social networks use were the main activities performed. Internet dependence was observed in 19% of adolescents, and it was associated with male gender, social networks use, mainly Twitter and Instagram use, self-perceived sleep problems, initial and middle insomnia and excessive daytime sleepiness (p < 0.05). The results confirm the highlight that Internet has in adolescents routine, who prioritize in their use access to social networks and online games, using single devices, less subject to parental control. The Internet addiction rate observed and its association with sleep alterations and daytime sleepiness emphasizes the importance of this issue.


Development and growth of a large multispecialty certification examination: sleep medicine certification--results of the first three examinations.
This paper summarizes the results of the first three examinations (2007, 2009, and 2011) of the Sleep Medicine Certification Examination, administered by its six sponsoring American Board of Medical Specialty Boards. There were 2,913 candidates who took the 2011 examination through one of three pathways-self-attested practice experience, previous certification by the American Board of Sleep Medicine, or formal Sleep Medicine fellowship training. The 2011 exam was the last administration in which candidates who had not previously been admitted could take it without completion of formal Sleep Medicine fellowship training. As expected, the number of candidates admitted to the 2011 examination through the practice experience pathway increased, and the overall scores of these candidates were on average lower than the other candidates. Consequently, the pass rate for all first takers of the 2011 examination (65%) was lower than that observed from the 2009 examination (78%) and the 2007 examination (73%). For each administration, candidates admitted through the fellowship training pathway scored the highest; over 90% of them passed the 2011 and 2009 examinations.


Effects of age and amyloid deposition on Aβ dynamics in the human central nervous system.
The amyloid hypothesis predicts that increased production or decreased clearance of β-amyloid (Aβ) leads to amyloidosis, which ultimately culminates in Alzheimer disease (AD). To investigate whether dynamic changes in Aβ levels in the human central nervous system may be altered by aging or by the pathology of AD and thus contribute to the risk of AD. Repeated-measures case-control study. Washington University School of Medicine in St Louis, Missouri. Participants with amyloid deposition, participants without amyloid deposition, and younger normal control participants. In this study, hourly cerebrospinal fluid (CSF) Aβ concentrations were compared with age, status of amyloid deposition, electroencephalography, and video recording data. Linear increases were observed over time in the Aβ levels in CSF samples obtained from the younger normal control participants and the older participants without amyloid deposition, but not from the older participants with amyloid deposition. Significant circadian patterns were observed in the Aβ levels in CSF samples obtained from the younger control participants; however, circadian amplitudes decreased in both older participants without amyloid deposition and older participants with amyloid deposition. Aβ diurnal concentrations were correlated with the amount of sleep but not with the various activities that the participants participated in while awake. A reduction in the linear increase in the Aβ levels in CSF samples that is associated with amyloid deposition and a decreased CSF Aβ diurnal pattern associated with increasing age disrupt the normal physiology of Aβ dynamics and may contribute to AD.


Methodological limitations of economic evaluations of antenatal screening.
A review of recent economic studies of antenatal screening reveals widespread violation of accepted economic evaluation methodology. In particular, the costs and benefits of antenatal screening are often misclassified and conflated, and the non-resource effects of averted costs are often excluded from the evaluation process. The result is a widespread violation of the explicit and systematic approaches taken by economic analysts more generally, and conclusions that may be described as misleading. This letter calls for economic analysts to be consistent in their application of economic evaluation methodology to antenatal screening programmes.


Patient-Reported Satisfaction and Quality of Life in Obese Patients: A Comparison between Microsurgical and Prosthetic Implant Recipients.
Patients undergoing autologous breast reconstruction have higher rates of patient-reported satisfaction compared to patients undergoing prosthetic reconstruction. Obesity has been shown to increase postoperative complications in both microsurgical and implant reconstructions. The authors evaluated the effects of microsurgical breast reconstruction and prosthetic breast reconstruction on patient-reported outcomes and quality of life in obese patients. A retrospective review of obese patients who underwent breast reconstruction from January of 2009 to December of 2017 was conducted. Patients were divided into two cohorts: microsurgical and two-stage tissue expander/implant-based reconstruction. BREAST-Q survey response, demographic information, complications, and need for revision procedures were analyzed. One hundred fifty-five patients met the inclusion criteria: 75 (48.4 percent) underwent microsurgical breast reconstruction and 80 (51.6 percent) underwent implant-based reconstruction. Cohorts were similar in body mass index, mean mastectomy specimen weight, laterality, indication for surgery, smoking status, and postoperative complications. Microsurgical reconstruction patients were younger (49.0 years versus 53.0 years; p = 0.02) and more likely to have delayed reconstruction [n = 70 (64.2 percent) versus n = 0 (0.0 percent); p = 0.0001]. BREAST-Q responses showed that microsurgery patients were more satisfied with their breasts (Q-Score of 63.4 ± 6.9 versus 50.8 ± 12.8; p = 0.0001), overall outcome (Q-Score 70.5 ± 13.0 versus 60.3 ± 10.8; p = 0.0001), and chest physical well-being (Q-Score of 69.1 ± 10.9 versus 63.8 ± 8.2; p = 0.01). Microsurgical breast reconstruction in obese patients yields higher satisfaction with breasts, overall outcomes, and chest physical well-being than implant-based reconstruction. Despite increased postoperative complications associated with obesity, microsurgical breast reconstruction appears to be a good choice for women who understand its risks and benefits and choose to proceed with it.


Diagnosis of pancreas rejection: cystoscopic transduodenal versus percutaneous computed tomography scan-guided biopsy.
The most common cause of graft failure after technically successful pancreas transplants is rejection. Laboratory parameters for detecting pancreas graft rejection are not consistently reliable and can lead to unnecessary antirejection treatment. Histopathologic evaluation is the gold standard in the differential diagnosis of pancreas graft dysfunction. Four biopsy techniques have been described: cystoscopic transduodenal (CB), percutaneous computed tomography scan-guided (PB), open, and laparoscopic biopsy. We studied the two most common techniques, CB and PB, in pancreas transplant recipients with presumed rejection. Group 1 comprised 103 attempts at CB in 82 recipients (53 men, 29 women) with bladder-drained (BD) pancreas transplants, at 1 to 80 (median, 14) months after transplant. Group 2 comprised 93 attempts at PB in 68 recipients (41 men, 27 women), at 0.5 to 64 (median, 14) months after transplant. In group 1, of 103 attempts at CB, adequate tissue was obtained in 90 (87%): pancreas alone in 23 (22%), pancreas + duodenum in 35 (34%), duodenum alone in 32 (31%). Of the 58 pancreas biopsies, 23 (40%) showed acute rejection. Of the 67 duodenal biopsies, 16 (24%) showed acute rejection. Complications of CB included macrohematuria in 4 recipients (4%) and microhematuria in 32 (31%). We noted no biopsy-related pancreatitis. The mean cost of CB was $2561+/-246. In group 2, of 93 attempts at PB, adequate tissue (all pancreas) was obtained in 67 (72%); of these, 29 (43%) showed acute rejection. Of 23 inaccessible pancreases, 9 (39%) underwent CB; pancreatic tissue was obtained in four (45%), and results were consistent with rejection in all four. Complications of PB included biopsy-related pancreatitis (serum amylase > or = 25%) in five (7%) recipients, macrohematuria in one (1%), and abdominal hemorrhage in two (3%). The mean cost of PB was $1038+/-78. (1) CB and PB prevented unnecessary antirejection treatment in 44% of our recipients with successful biopsies; (2) CB had a higher success rate for obtaining tissue (including duodenal specimens) and a lower rate of major complications; (3) PB was easier and cheaper, did not require general anesthesia, and was performed as an outpatient procedure. We conclude that PB should become the biopsy technique of choice in recipients with presumed pancreas graft rejection. If PB fails, recipients with bladder-drained pancreas transplants should undergo CB. If CB fails, or in recipients with enteric-drained or duct-injected pancreas transplants, a laparoscopic or open biopsy should be considered.


In vivo observation of lactate methyl proton magnetization transfer in rat C6 glioma.
Magnetic resonance spectroscopy (MRS) measurements of the lactate methyl proton in rat brain C6 glioma tissue acquired in the presence of an off-resonance irradiation field, analyzed using coupled Bloch equation formalism assuming two spin pools, demonstrated the occurrence of magnetization transfer. Quantitative analysis revealed that a very small fraction of lactate (f = 0.0012) is rotationally immobilized despite a large magnetization transfer effect. Off-resonance rotating frame spin-lattice relaxation studies demonstrated that deuterated lactate binds to bovine serum albumin and the proteins present in human plasma, thereby providing a possible physical basis for the observed magnetization transfer effect. These results demonstrate that partial or complete saturation of the motionally restricted lactate pool (as well as other metabolites) by the application of an off-resonance irradiation field, such as that used for water presaturation, can lead to a substantial decrease in resonance intensity by way of magnetization transfer effects, resulting in quantitation errors.