Structural dynamics of photochemical reactions probed by time-resolved photoelectron spectroscopy using high harmonic pulses.
Femtosecond ring-opening dynamics of 1,3-cyclohexadiene (CHD) in gas phase upon two-photon excitation at 400 nm (=3.1 eV) was investigated by time-resolved photoelectron spectroscopy using 42 nm (=29.5 eV) high harmonic photons probing the dynamics of the lower-lying occupied molecular orbitals (MOs), which are the fingerprints of the molecular structure. After 500 fs, the photoelectron intensity of the MO constituting the C[double bond, length as m-dash]C sigma bond (σC[double bond, length as m-dash]C) of CHD was enhanced, while that of the MO forming the C-C sigma bond (σCC) of CHD was decreased. The changes in the photoelectron spectra suggest that the ring of CHD opens to form a 1,3,5-hexatriene (HT) after 500 fs. The dynamics of the σC[double bond, length as m-dash]C and σCC bands between 200 and 500 fs reflects the ring deformation to a conical intersection between the 21A and 11A potential energy surfaces prior to the ring-opening reaction.


Molecular engineering solutions for therapeutic peptide delivery.
Proteins and their interactions in and out of cells must be well-orchestrated for the healthy functioning and regulation of the body. Even the slightest disharmony can cause diseases. Therapeutic peptides are short amino acid sequences (generally considered <50 amino acids) that can naturally mimic the binding interfaces between proteins and thus, influence protein-protein interactions. Because of their fidelity of binding, peptides are a promising next generation of personalized medicines to reinstate biological harmony. Peptides as a group are highly selective, relatively safe, and biocompatible. However, they are also vulnerable to many in vivo pharmacologic barriers limiting their clinical translation. Current advances in molecular, chemical, and nanoparticle engineering are helping to overcome these previously insurmountable obstacles and improve the future of peptides as active and highly selective therapeutics. In this review, we focus on self-assembled vehicles as nanoparticles to carry and protect therapeutic peptides through this journey, and deliver them to the desired tissue.


MicroRNA-145 targeted therapy reduces atherosclerosis.
MicroRNA are essential posttranscriptional modulators of gene expression implicated in various chronic diseases. Because microRNA-145 is highly expressed in vascular smooth muscle cells (VSMC) and regulates VSMC fate and plasticity, we hypothesized that it may be a novel regulator of atherosclerosis and plaque stability. Apolipoprotein E knockout mice (ApoE(-/-)) mice were treated with either a microRNA-145 lentivirus under the control of the smooth muscle cell (SMC)-specific promoter SM22α or a SM22α control lentivirus before commencing the Western diet for 12 weeks. The SMC-targeted microRNA-145 treatment markedly reduced plaque size in aortic sinuses, ascending aortas, and brachiocephalic arteries. It also significantly increased fibrous cap area, reduced necrotic core area, and increased plaque collagen content. Cellular plaque composition analyses revealed significantly less macrophages in ApoE(-/-) mice treated with the SMC-specific microRNA-145. These mice also demonstrated marked increases in calponin levels and α-smooth muscle actin-positive SMC areas in their atherosclerotic lesions. Furthermore, lentiviral delivery of microRNA-145 resulted in reduced KLF4 and elevated myocardin expression in aortas from ApoE(-/-) mice, consistent with an effect of microRNA-145 to promote a contractile phenotype in VSMC. VSMC-specific overexpression of microRNA-145 is a novel in vivo therapeutic target to limit atherosclerotic plaque morphology and cellular composition, shifting the balance toward plaque stability vs plaque rupture.


Are pit latrines in urban areas of Sub-Saharan Africa performing? A review of usage, filling, insects and odour nuisances.
A pit latrine is the most basic form of improved sanitation which is currently used by a number of people around the globe. In spite of the wide spread use, known successes and advantages associated with pit latrines, they have received little attention in form of research and development. This review focuses on the usage and performance (filling, smell and insect nuisance) of pit latrines in urban areas of sub-Saharan Africa (SSA) and proposes approaches for their improvements and sustainability. Current pit latrine usage within urban SSA was calculated from Joint Monitoring Programme (JMP) water and sanitation country-files. We conducted a literature search and review of documents on pit latrine usage, filling, smell and insect nuisances in urban areas of SSA. Findings of the review are presented and discussed in this paper. Pit latrines are in use by more than half the urban population in SSA and especially among low income earners. An additional 36 million people in urban areas of SSA have adopted the pit latrine since 2007. However, their performance is unsatisfactory. Available literature shows that contributions have been made to address shortfalls related to pit latrine use in terms of science and technological innovations. However, further research is still needed. Any technology and process management innovations to pit latrines should involve scientifically guided approaches. In addition, development, dissemination and enforcement of minimum pit latrine design standards are important while the importance of hygienic latrines should also be emphasized.


The synergistic effect of Escherichia coli inactivation by sequential disinfection with low level chlorine dioxide followed by free chlorine.
To the best of our knowledge, there was little information available on pathogen removal using low level disinfectant followed by free chlorine in sequential disinfection (SD). This study investigated Escherichia coli inactivation by four types of disinfection: single step disinfection (SSD), SD, traditional sequential disinfection (TSD) and mixed disinfectant disinfection (MDD). Results indicated that SD had higher ability to inactivate E. coli than the others, indicating there was a positive synergistic effect on chlorine disinfection by prior dosing with a low level of chlorine dioxide (ClO(2)). The ONPG assay suggested that the permeability of cell wall rather than the viability of E. coli were changed under 0.02 mg/l ClO(2) treatment. The coexistence of residual ClO(2) and free chlorine also plays an active synergistic effect. Additionally, temperature had a positive effect on E. coli inactivation in SD, while inactivation was reduced in alkaline compared to neutral and acidic conditions.


Synergic modulation of the inflammatory state of macrophages utilizing anti-oxidant and phosphatidylserine-containing polymer-lipid hybrid nanoparticles.
Inflammatory activation of macrophages is a key factor in chronic inflammatory diseases such as ulcerative colitis. The excessive production of reactive oxygen species (ROS)/reactive nitrogen species (RNS) by macrophages causes oxidative stress during the inflammatory response and exaggerates inflammatory lesions in ulcerative colitis. Inhibition of the inflammatory activation of macrophages is a promising treatment for chronic inflammatory diseases. Here, we prepared self-filling polymer-lipid hybrid nanoparticles (PST-PLNPs) consisting of poly dl-lactic acid as a hydrophobic biodegradable polymer core encapsulating α-tocopherol (T) and phosphatidylserine (PS) both on the surface and interior of the particle. We confirmed the anti-inflammatory response of these hybrid nanoparticles in activated murine macrophages. PS has anti-inflammatory effects on macrophages by modulating the macrophage phenotype, while α-tocopherol is an antioxidant that neutralizes ROS. We found that PS-containing (PS-PLNPs) and PS plus α-tocopherol-containing (PST-PLNPs) polymer-lipid hybrid nanoparticles significantly increased the viability of lipopolysaccharide (LPS)-treated macrophages compared with phosphatidylcholine-containing PLNPs. PST-PLNPs had a better effect than PS-PLNPs, which was attributed to the synergy between PS and α-tocopherol. This synergic action of PST-PLNPs reduced NO and pro-inflammatory cytokine (IL-6) production and increased anti-inflammatory cytokine (TGF-β1) production when incubated with activated macrophages. Thus, these self-filling biodegradable polymer-lipid hybrid nanoparticles (PST-PLNPs) containing anti-oxidant and anti-inflammatory molecules might be potential alternative drug carriers to liposomes and polymeric nanoparticles for the treatment of chronic inflammatory diseases such as ulcerative colitis.


Dendritic cells and isolevuglandins in immunity, inflammation, and hypertension.
Hypertension is the major risk factor for morbidity and mortality from myocardial infarction, stroke, heart failure, and chronic kidney disease. Despite its importance, the pathogenesis of essential hypertension is poorly understood. During the past several years, it has become evident that T cells contribute to hypertension. Activated T cells accumulate in the perivascular space and the kidney and release cytokines that promote vascular dysfunction and end-organ damage. Although dendritic cells play a pivotal role in initiating adaptive immune responses, T cells have taken center stage in studies implicating the immune system in the genesis of hypertension. The mechanisms by which T cells are activated and the antigens involved are poorly understood. We recently showed that hypertension is associated with increased dendritic cell production of the TH17 polarizing cytokines, IL-6, IL-1β, and IL-23. This occurs in part by increased superoxide production via NADPH oxidase and protein modification by highly reactive isolevuglandins (IsoLGs). IsoLGs are produced via the isoprostane pathway of free radical-mediated lipid peroxidation and, when adducted to proteins, have the potential to act as neoantigens. In this review, we discuss recent advances in our understanding of the role of antigen-presenting dendritic cells in the pathophysiology of hypertension and highlight potential neoantigens that may contribute to this disease.


Substance abuse among native Hawaiian women in the United States: a review of current literature and recommendations for future research.
Information about and understanding of Native Hawaiian substance abuse and utilization of substance abuse treatment services is limited. This article reviews the literature on the prevalence and factors associated with substance abuse and use of health services among Native Hawaiian women in the U.S. The literature review included three review and 13 nonreview articles that were published through December 2006. The majority of the articles reviewed did not present findings by gender-ethnic group. The review of the literature suggested a high prevalence of substance abuse, especially among those who were incarcerated. Risk factors for substance abuse included not being married and young age.Native Hawaiian women also had significantly lower health care utilization rates compared to other groups, and were less likely to have seen a health care provider in the past year. Programs should consider involving Kupunas ("elders") in the design and implementation of culturally appropriate programs in order to better serve the needs of Native Hawaiian women. Further research is needed about the rates of substance abuse and barriers and facilitators to treatment so that effective and culturally competent treatment can be provided for this population.


Interpretable Cognitive Ability Prediction: A Comprehensive Gated Graph Transformer Framework for Analyzing Functional Brain Networks.
Graph convolutional deep learning has emerged as a promising method to explore the functional organization of the human brain in neuroscience research. This paper presents a novel framework that utilizes the gated graph transformer (GGT) model to predict individuals' cognitive ability based on functional connectivity (FC) derived from fMRI. Our framework incorporates prior spatial knowledge and uses a random-walk diffusion strategy that captures the intricate structural and functional relationships between different brain regions. Specifically, our approach employs learnable structural and positional encodings (LSPE) in conjunction with a gating mechanism to efficiently disentangle the learning of positional encoding (PE) and graph embeddings. Additionally, we utilize the attention mechanism to derive multi-view node feature embeddings and dynamically distribute propagation weights between each node and its neighbors, which facilitates the identification of significant biomarkers from functional brain networks and thus enhances the interpretability of the findings. To evaluate our proposed model in cognitive ability prediction, we conduct experiments on two large-scale brain imaging datasets: the Philadelphia Neurodevelopmental Cohort (PNC) and the Human Connectome Project (HCP). The results show that our approach not only outperforms existing methods in prediction accuracy but also provides superior explainability, which can be used to identify important FCs underlying cognitive behaviors.


Longitudinal growth of hospitalized very low birth weight infants.
The interpretation of growth rates for very low birth weight infants is obscured by limited data, recent changes in perinatal care, and the uncertain effects of multiple therapies. To develop contemporary postnatal growth curves for very low birth weight preterm infants and to relate growth velocity to birth weight, nutritional practices, fetal growth status (small- or appropriate-for-gestational-age), and major neonatal morbidities (chronic lung disease, nosocomial infection or late-onset infection, severe intraventricular hemorrhage, and necrotizing enterocolitis). Large, multicenter, prospective cohort study. Growth was prospectively assessed for 1660 infants with birth weights between 501 to 1500 g admitted by 24 hours of age to 1 of the 12 National Institute of Child Health and Human Development Neonatal Research Network centers between August 31, 1994 and August 9, 1995. Infants were included if they survived >7 days (168 hours) and were free of major congenital anomalies. Anthropometric measures (body weight, length, head circumference, and midarm circumference) were performed from birth until discharge, transfer, death, age 120 days, or a body weight of 2000 g. To obtain representative data, nutritional practices were not altered by the study protocol. Postnatal growth curves suitable for clinical and research use were constructed for body weight, length, head circumference, and midarm circumference. Once birth weight was regained, weight gain (14.4-16.1 g/kg/d) approximated intrauterine rates. However, at hospital discharge, most infants born between 24 and 29 weeks of gestation had not achieved the median birth weight of the reference fetus at the same postmenstrual age. Gestational age, race, and gender had no effect on growth within 100-g birth weight strata. Appropriate-for-gestational age infants who survived to hospital discharge without developing chronic lung disease, severe intraventricular hemorrhage, necrotizing enterocolitis, or late onset-sepsis gained weight faster than comparable infants with those morbidities. More rapid weight gain was also associated with a shorter duration of parenteral nutrition providing at least 75% of the total daily fluid volume, an earlier age at the initiation of enteral feedings, and an earlier age at achievement of full enteral feedings. These growth curves may be used to better understand postnatal growth, to help identify infants developing illnesses affecting growth, and to aid in the design of future research. They should not be taken as optimal. Randomized clinical trials should be performed to evaluate whether different nutritional management practices will permit birth weight to be regained earlier and result in more rapid growth, more appropriate body composition, and improved short- and long-term outcomes.


HIV-1 subtype C envelope characteristics associated with divergent rates of chronic disease progression.
HIV-1 envelope diversity remains a significant challenge for the development of an efficacious vaccine. The evolutionary forces that shape the diversity of envelope are incompletely understood. HIV-1 subtype C envelope in particular shows significant differences and unique characteristics compared to its subtype B counterpart. Here we applied the single genome sequencing strategy of plasma derived virus from a cohort of therapy naïve chronically infected individuals in order to study diversity, divergence patterns and envelope characteristics across the entire HIV-1 subtype C gp160 in 4 slow progressors and 4 progressors over an average of 19.5 months. Sequence analysis indicated that intra-patient nucleotide diversity within the entire envelope was higher in slow progressors, but did not reach statistical significance (p = 0.07). However, intra-patient nucleotide diversity was significantly higher in slow progressors compared to progressors in the C2 (p = 0.0006), V3 (p = 0.01) and C3 (p = 0.005) regions. Increased amino acid length and fewer potential N-linked glycosylation sites (PNGs) were observed in the V1-V4 in slow progressors compared to progressors (p = 0.009 and p = 0.02 respectively). Similarly, gp41 in the progressors was significantly longer and had fewer PNGs compared to slow progressors (p = 0.02 and p = 0.02 respectively). Positive selection hotspots mapped mainly to V1, C3, V4, C4 and gp41 in slow progressors, whereas hotspots mapped mainly to gp41 in progressors. Signature consensus sequence differences between the groups occurred mainly in gp41. These data suggest that separate regions of envelope are under differential selective forces, and that envelope evolution differs based on disease course. Differences between slow progressors and progressors may reflect differences in immunological pressure and immune evasion mechanisms. These data also indicate that the pattern of envelope evolution is an important correlate of disease progression in chronic HIV-1 subtype C infection.


Muscle Synergies During Walking in Children With Cerebral Palsy: A Systematic Review.
Background: Walking problems in children with cerebral palsy (CP) can in part be explained by limited selective motor control. Muscle synergy analysis is increasingly used to quantify altered neuromuscular control during walking. The early brain injury in children with CP may lead to a different development of muscle synergies compared to typically developing (TD) children, which might characterize the abnormal walking patterns. Objective: The overarching aim of this review is to give an overview of the existing studies investigating muscle synergies during walking in children with CP compared to TD children. The main focus is on how muscle synergies differ between children with CP and TD children, and we examine the potential of muscle synergies as a measure to quantify and predict treatment outcomes. Methods: Bibliographic databases were searched by two independent reviewers up to 22 April 2019. Studies were included if the focus was on muscle synergies of the lower limbs during walking, obtained by a matrix factorization algorithm, in children with CP. Results: The majority (n = 12) of the 16 included studies found that children with CP recruited fewer muscle synergies during walking compared to TD children, and several studies (n = 8) showed that either the spatial or temporal structure of the muscle synergies differed between children with CP and TD children. Variability within and between subjects was larger in children with CP than in TD children, especially in more involved children. Muscle synergy characteristics before treatments to improve walking function could predict treatment outcomes (n = 3). Only minimal changes in synergies were found after treatment. Conclusions: The findings in this systematic review support the idea that children with CP use a simpler motor control strategy compared to TD children. The use of muscle synergy analysis as a clinical tool to quantify altered neuromuscular control and predict clinical outcomes seems promising. Further investigation on this topic is necessary, and the use of muscle synergies as a target for development of novel therapies in children with CP could be explored.


Direct and specific activation of human inward rectifier K+ channels by membrane phosphatidylinositol 4,5-bisphosphate.
Many ion channels are modulated by phosphatidylinositol 4,5-bisphosphate (PIP(2)), but studies examining the PIP(2) dependence of channel activity have been limited to cell expression systems, which present difficulties for controlling membrane composition. We have characterized the PIP(2) dependence of purified human Kir2.1 and Kir2.2 activity using (86)Rb(+) flux and patch clamp assays in liposomes of defined composition. We definitively show that these channels are directly activated by PIP(2) and that PIP(2) is absolutely required in the membrane for channel activity. The results provide the first quantitative description of the dependence of eukaryotic Kir channel function on PIP(2) levels in the membrane; Kir2.1 shows measureable activity in as little as 0.01% PIP(2), and open probability increases to ∼0.4 at 1% PIP(2). Activation of Kir2.1 by phosphatidylinositol phosphates is also highly selective for PIP(2); PI, PI(4)P, and PI(5)P do not activate channels, and PI(3,4,5)P(3) causes minimal activity. The PIP(2) dependence of eukaryotic Kir activity is almost exactly opposite that of KirBac1.1, which shows marked inhibition by PIP(2). This raises the interesting hypothesis that PIP(2) activation of eukaryotic channels reflects an evolutionary adaptation of the channel to the appearance of PIP(2) in the eukaryotic cell membrane.


What is the feasibility and observed effect of two implementation packages for stroke rehabilitation therapists implementing upper limb guidelines? A cluster controlled feasibility study.
Hand and arm activity after stroke improves with evidence-based rehabilitation. Therapists face known barriers when providing evidence-based rehabilitation and require support to implement guidelines. The aim of this study was to investigate the feasibility of two implementation packages on guideline adherence by occupational therapists and physiotherapists, and explore effect on patient upper limb outcomes. This was a non-randomised clustered feasibility study of occupational and physiotherapy rehabilitation services (n=3 inpatient and n=3 outpatient services). Services were allocated to one of three groups: (group A) facilitator-mediated implementation package, (group B) self-directed implementation package or (group C) usual care (control); we recruited n=1 inpatient and n=1 outpatient service per group. Outcomes of feasibility, adherence to guidelines (medical file audits) and patient upper limb impairment (Fugl-Meyer Upper Extremity Assessment), activity (Box and Block Test) and practice (minutes/week) were collected at baseline and after 3 months of intervention. 29 therapists (8 in group A, 13 in groups B and 8 in group C) and 55 patients participated. Both the facilitator-mediated and the self-directed implementation packages were feasible to deliver in the rehabilitation setting. Therapists in group A improved with respect to guideline adherence (medical file audits; median within-group proportion difference of 0.29 (95% CI 0.22 to 0.36, p<0.0001) preintervention to postintervention). No significant within-group differences from baseline to postintervention were found in group B or group C, and no between-group differences were found for upper limb outcomes. A facilitator-mediated package was acceptable to therapists working in stroke rehabilitation, and feasibility data suggest increased guideline uptake following implementation. An adequately powered study is planned to understand how to support therapists to provide evidence-based upper limb rehabilitation after stroke. Australian New Zealand Clinical Trials Registry (ACTRN12619000596101).


Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs.
Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40-60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor-SNP interactions. By perturbing NFκB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFκB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases.


Proteomic Analysis of Quercetin-Treated K562 Cells.
Among natural products under investigation for their additive potential in cancer prevention and treatment, the flavonoid quercetin has received attention for its effects on the cell cycle arrest and apoptosis. In the past, we addressed this issue in K562 cells, a cellular model of the human chronic myeloid leukemia. Here, we applied stable isotope labeling by amino acids in cell culture (SILAC) proteomics with the aim to increase knowledge on the regulative and metabolic pathways modulated by quercetin in these cells. After 24 h of quercetin treatment, we observed that apoptosis was not completely established, thus we selected this time range to capture quantitative data. As a result, we were able to achieve a robust identification of 1703 proteins, and to measure fold changes between quercetin-treated and untreated cells for 1206 proteins. Through a bioinformatics functional analysis on a subset of 112 proteins, we propose that the apoptotic phenotype of K562 cells entails a significant modulation of the translational machinery, RNA metabolism, antioxidant defense systems, and enzymes involved in lipid metabolism. Finally, we selected eight differentially expressed proteins, validated their modulated expression in quercetin-treated K562 cells, and discussed their possible role in flavonoid cytotoxicity. This quantitative profiling, performed for the first time on this type of tumor cells upon treatment with a flavonoid, will contribute to revealing the molecular basis of the multiplicity of the effects selectively exerted by quercetin on K562 cells.


Longitudinal smoking patterns and adult cardiometabolic risk among African Americans.
To better understand mechanisms influencing health in African Americans (AAs), the aims of this study were (a) to identify longitudinal cigarette smoking classes among AAs across adolescence and into young adulthood; (b) to identify risk factors for smoking and how cardiometabolic health in adulthood differs by smoking class; and (c) to investigate whether smoking mediates the relation between adolescent risk factors and adult cardiometabolic health. This study used 4 waves of nationally representative data, restricted to an AA subsample (N = 2,009). Participants self-reported on multilevel risk factors in adolescence and smoking across adolescence and young adulthood; cardiometabolic risk was assessed in adulthood. Growth mixture modeling and structural equation modeling were conducted. Five classes emerged: nonsmoker; early onset, heavier smoking; later onset; early onset, light smoking; and maturing out or declining smoking. Predictors of class membership included living with individuals who smoke, having friends who smoke, and limited access to medical care. The early onset, light smoking class had the greatest cardiometabolic risk. Smoking class mediated the relation between living with people who smoke in adolescence and adult cardiometabolic risk. Nuanced smoking patterns among AAs were identified, and 23% fell into classes characterized by an early onset and persistent smoking trajectory. The early onset, light smoking class had the greatest cardiometabolic risk in adulthood. The results suggest unique protective factors may be present for youth who remain nonsmokers even when their family smokes. Results have implications for health promotion and tobacco prevention efforts among AA families. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Outcrossed cottonseed and adventitious Bt plants in Arizona refuges.
Outcrossing of non-Bt cotton (Gossypium hirsutum (L.)) in refuges by transgenic Bt cultivars could reduce the efficacy of refuges for delaying resistance in seed-feeding pests. Based on reports that outcrossing decreased as distance from Bt cotton increased in small-scale studies, we hypothesized that increasing refuge width or distance from Bt fields would reduce outcrossing. In a large-scale study in Arizona, we quantified Bt seed in refuges of experimental and commercial fields, comparing outcrossing between in-field (narrow) and external (wide) refuges and among rows of refuges at various distances from Bt fields. Some refuges, including those in tightly controlled experimental plots, contained up to 8% adventitious Bt plants. Some, but not all, Bt plants likely resulted from Bt seed in the non-Bt seed bags. We did not detect a difference in outcrossing between in-field and external refuges. However, statistical power was low because outcrossing was low (< 0.4% of seeds) in both treatments. Higher outcrossing levels (< or = 4.6% of seeds) were observed in the studies measuring outcrossing at various distances from Bt fields, yet outcrossing did not decrease as the distance from Bt fields increased. We hypothesize that Bt plants in refuges cross-pollinated surrounding non-Bt plants, overshadowing the expected association between distance from Bt fields and outcrossing.


A new non-pterodactyloid pterosaur from the Late Jurassic of southern Germany.
The 'Solnhofen Limestone' beds of the Southern Franconian Alb, Bavaria, southern Germany, have for centuries yielded important pterosaur specimens, most notably of the genera Pterodactylus and Rhamphorhynchus. Here we describe a new genus of non-pterodactyloid pterosaur based on an extremely well preserved fossil of a young juvenile: Bellubrunnus rothgaengeri (gen. et sp. nov.). The specimen was examined firsthand by all authors. Additional investigation and photography under UV light to reveal details of the bones not easily seen under normal lighting regimes was completed. This taxon heralds from a newly explored locality that is older than the classic Solnhofen beds. While similar to Rhamphorhynchus, the new taxon differs in the number of teeth, shape of the humerus and femur, and limb proportions. Unlike other derived non-pterodacytyloids, Bellubrunnus lacks elongate chevrons and zygapophyses in the tail, and unlike all other known pterosaurs, the wingtips are curved anteriorly, potentially giving it a unique flight profile.


The microenvironment of visceral adipose tissue and liver alter natural killer cell viability and function.
The role of NK cells in visceral adipose tissue (VAT) and liver inflammation in obesity is not fully understood. This study investigated the frequency, cytokine expression, chemokine receptor, and cytotoxicity receptor profile of NK cells in the blood, omentum, and liver of patients with the obesity-associated cancer, oesophageal adenocarcinoma (OAC). The effect of chronically inflamed tissue microenvironments on NK cell viability and function was also examined. We identified significantly lower NK cell frequencies in the liver of OAC patients compared with healthy controls and within the omentum and liver of OAC patients compared with blood, whereas IL-10-producing populations were significantly higher. Interestingly, our data suggest that reduced frequencies of NK cells in omentum and liver of OAC patients are not a result of impaired NK cell chemotaxis to these tissues. In fact, our functional data revealed that secreted factors from omentum and liver of OAC patients induce significant levels of NK cell death and lead to reduced percentages of TNF-α+ and NKP46+ NK cells and higher frequencies of IL-10-producing NK cells. Together, these data suggest that the omental and hepatic microenvironments of OAC patients alter the NK cell phenotype to a more anti-inflammatory homeostatic role.


Diagnosis and management of somatosensory tinnitus: review article.
Tinnitus is the perception of sound in the absence of an acoustic external stimulus. It affects 10-17% of the world's population and it a complex symptom with multiple causes, which is influenced by pathways other than the auditory one. Recently, it has been observed that tinnitus may be provoked or modulated by stimulation arising from the somatosensorial system, as well as from the somatomotor and visual-motor systems. This specific subgroup -somatosensory tinnitus - is present in 65% of cases, even though it tends to be underdiagnosed. As a consequence, it is necessary to establish evaluation protocols and specific treatments focusing on both the auditory pathway and the musculoskeletal system.


Treatment of device thrombus in the HeartWare HVAD: Success and outcomes depend significantly on the initial treatment strategy.
Pump thrombosis is a major adverse event in patients supported with a left ventricular assist device (LVAD). Treatment approaches include device exchange, lytic therapy, or augmentation of anticoagulation or antiplatelet therapy. The optimal strategy in the HeartWare HVAD Ventricular Assist System (HeartWare, Framingham, MA) is uncertain, and because few large studies have examined differing treatment outcomes, we have reviewed findings from the Mechanical Circulatory Support Research Network registry. Between March 2009 and August 2014, 175 patients (133 male) underwent implantation of the HeartWare HVAD at institutions that comprise the Mechanical Circulatory Support Research Network. Median age at implant was 59 years (range, 18-76 years). Follow-up was available in all patients for a median of 6 months (maximum, 61 months) and for a total of 163 patient-years of support. There were 36 pump thromboses (using Interagency Registry for Mechanically Assisted Circulatory Support criteria) in 21 patients for a total event rate of 0.22 events/patient-year of support; 13 patients had 1 event, 4 had 2, 2 had 3, 1 had 4, and 1 had 5. The median time to the first thrombosis was 6.4 months, and to each subsequent thrombosis was 4, 3, 2, and 2 months, respectively. Primary treatment success was defined as the patient remaining alive and within the first 30 days of the initial treatment be free from stroke, recurrence of pump thrombosis, device exchange, or urgent transplantation (United Network of Organ Sharing Status 1A). Medical treatment was defined as tissue plasminogen activator, heparin plus glycoprotein IIb/IIIa inhibitor, or heparin alone, not followed by surgical treatment within 72 hours. Initial medical treatment was used in 29 episodes (tissue plasminogen activator in 24, heparin alone in 4, and heparin plus glycoprotein IIb/IIIa in 1) and surgical (device exchange) in 7. Medical treatment was successful in 14 of 29 episodes (48%). Complications of medical treatment included hemorrhagic stroke in 6 patients (21%), need for urgent device exchange/transplant in 6 (21%), and death in 3 (10%). Surgical treatment was successful in all 7 patients (100%). No significant early complications or early deaths occurred after device exchange. In this large multicenter analysis, we observed that medical therapy, as the initial treatment strategy for HeartWare HVAD thrombosis, is associated with low success (48%) and a significant risk of hemorrhagic stroke (21%) and death (10%). However, initial treatment with device exchange was uniformly successful and not associated with significant early morbidity or death. Although the optimal treatment approach for HeartWare HVAD pump thrombosis remains undecided, these data do not support the routine use of medical therapy as an initial treatment strategy.


Comparative genome and methylome analysis reveals restriction/modification system diversity in the gut commensal Bifidobacterium breve.
Bifidobacterium breve represents one of the most abundant bifidobacterial species in the gastro-intestinal tract of breast-fed infants, where their presence is believed to exert beneficial effects. In the present study whole genome sequencing, employing the PacBio Single Molecule, Real-Time (SMRT) sequencing platform, combined with comparative genome analysis allowed the most extensive genetic investigation of this taxon. Our findings demonstrate that genes encoding Restriction/Modification (R/M) systems constitute a substantial part of the B. breve variable gene content (or variome). Using the methylome data generated by SMRT sequencing, combined with targeted Illumina bisulfite sequencing (BS-seq) and comparative genome analysis, we were able to detect methylation recognition motifs and assign these to identified B. breve R/M systems, where in several cases such assignments were confirmed by restriction analysis. Furthermore, we show that R/M systems typically impose a very significant barrier to genetic accessibility of B. breve strains, and that cloning of a methyltransferase-encoding gene may overcome such a barrier, thus allowing future functional investigations of members of this species.


Sociality influences cultural complexity.
Archaeological and ethnohistorical evidence suggests a link between a population's size and structure, and the diversity or sophistication of its toolkits or technologies. Addressing these patterns, several evolutionary models predict that both the size and social interconnectedness of populations can contribute to the complexity of its cultural repertoire. Some models also predict that a sudden loss of sociality or of population will result in subsequent losses of useful skills/technologies. Here, we test these predictions with two experiments that permit learners to access either one or five models (teachers). Experiment 1 demonstrates that naive participants who could observe five models, integrate this information and generate increasingly effective skills (using an image editing tool) over 10 laboratory generations, whereas those with access to only one model show no improvement. Experiment 2, which began with a generation of trained experts, shows how learners with access to only one model lose skills (in knot-tying) more rapidly than those with access to five models. In the final generation of both experiments, all participants with access to five models demonstrate superior skills to those with access to only one model. These results support theoretical predictions linking sociality to cumulative cultural evolution.


Injury-prevention practices as depicted in G- and PG-rated movies, 2003-2007.
Our goal was to determine if the depiction of injury-prevention practices in children's movies is different from what was reported from 2 earlier studies, which showed infrequent depiction of characters practicing recommended safety behaviors. The top-grossing 25 domestic G-rated (general audience) and PG-rated (parental guidance suggested) movies per year for 2003-2007 were included in this study. Movies or scenes were excluded if they were animated, not set in the present day, fantasy, documentary, or not in English. Injury-prevention practices involving motor vehicles, pedestrians, boaters, and bicyclists were recorded for characters with speaking roles. Sixty-seven (54%) of 125 movies met the inclusion criteria for this study. A total of 958 person-scenes were examined: 524 (55%) depicted children and 434 (45%) adults. Twenty-two person-scenes involved crashes or falls, resulting in 3 injuries and no deaths. Overall, 311 (56%) of 555 motor-vehicle passengers were belted; 73 (35%) of 211 pedestrians used crosswalks; 60 (75%) of 80 boaters wore personal flotation devices; and 8 (25%) of 32 bicyclists wore helmets. In comparison with previous studies, usage of safety belts, crosswalks, personal flotation devices, and bicycle helmets increased significantly. The entertainment industry has improved the depiction of selected safety practices in G- and PG-rated movies. However, approximately one half of scenes still depict unsafe practices, and the consequences of these behaviors are rarely shown. The industry should continue to improve how it depicts safety practices in children's movies. Parents should highlight the depiction of unsafe behaviors and educate children in following safe practices.


Prevalence and fluid management of dehydration in children without diarrhoea admitted to Kenyan hospitals: a multisite observational study.
To examine the prevalence of dehydration without diarrhoea among admitted children aged 1-59 months and to describe fluid management practices in such cases. A multisite observational study that used routine in-patient data collected prospectively between October 2013 and December 2018. Study conducted in 13 county referral hospitals in Kenya. Children aged 1-59 months with admission or discharge diagnosis of dehydration but had no diarrhoea as a symptom or diagnosis. Children aged <28 days and those with severe acute malnutrition were excluded. The prevalence of dehydration in children without diarrhoea was 3.0% (2019/68 204) and comprised 15.9% (2019/12 702) of all dehydration cases. Only 55.8% (1127/2019) of affected children received either oral or intravenous fluid therapy. Where fluid treatment was given, the volumes, type of fluid, duration of fluid therapy and route of administration were similar to those used in the treatment of dehydration secondary to diarrhoea. Pneumonia (1021/2019, 50.6%) and malaria (715/2019, 35.4%) were the two most common comorbid diagnoses. Overall case fatality in the study population was 12.9% (260/2019). Sixteen per cent of children hospitalised with dehydration do not have diarrhoea but other common illnesses. Two-fifths do not receive fluid therapy; a regimen similar to that used in diarrhoeal cases is used in cases where fluid is administered. Efforts to promote compliance with guidance in routine clinical settings should recognise special circumstances where guidelines do not apply, and further studies on appropriate management for dehydration in the absence of diarrhoea are required.


Alzheimer's disease therapeutic trials: EU/US Task Force report on recruitment, retention, and methodology.
While we may not be able to find a cure for Alzheimer's disease (AD) in the near future, several drugs presently in trials have shown promise as possible modifiers of disease progression. However, we may not be able to demonstrate efficacy due to issues of recruitment, retention, site-to-site variability, and other methodological issues. It is thus incumbent on the scientific community to find solutions to these problems, particularly as the field moves toward preventing illness or treating the disease in its prodromal stages, where these methodological issues will become even more critical. We need to better understand why participants agree or refuse to enter drug trials, and why both primary care physicians and Alzheimer's specialists agree or refuse to involve their patients. We also need to quantify the impact of requiring imaging studies, extensive questionnaires, cognitive testing, and lumbar punctures on recruitment and retention. With these concerns in mind, an international task force meeting of experts from academia and industry in the United States, European Union, and Japan in San Diego, California on November 2, 2011 to focus on recruitment, retention and other methodological issues related to clinical trials for AD. Based on the recommendations of this Task force meeting, this Perspectives article critically reflects on the most critical and timely methodological issues related to recruitment and retention in prevention and therapeutic trials in AD, which are paralleled by a paradigm shift in the diagnostic conceptualization of this disease, as reflected by recently new proposed diagnostic criteria involving preclinical stages of the disease.


Nanobioprobe mediated DNA aptamers for explosive detection.
Specific nucleic acid aptamers using the microtiter plate based modified SELEX method against explosive trinitrotoluene are reported. Efficient partitioning of dsDNA was carried out using streptavidin labeled gold nanoprobes for the selection of specific aptamers. The selected binders having an affinity of ~10(-7) M were used in the newly developed electrochemical aptasensor, exhibiting a detection limit of around 1 ppb for trinitrotoluene.


Supernumerary isochromosome 1, idic(1)(p12), leading to tetrasomy 1q in Burkitt lymphoma.
Burkitt lymphoma (BL) is an aggressive mature B-cell neoplasm. The cytogenetic hallmark are MYC-involving translocations, most frequently as t(8;14)(q24;q32). Additional cytogenetic abnormalities are seen in the majority of cases. The most frequent additional aberration involves the long arm of chromosome 1, either as partial or complete trisomy 1q. A very rare additional aberration is a supernumerary isochromosome 1q, i(1)(q10), resulting in tetrasomy 1q. The biological significance of this aberration is unclear. We present a highly aggressive case of BL in a child with immature B-cell immunophenotype (IP) and supernumerary i(1)(q10). Diagnostic karyotyping showed 47,XY,+i(1)(q10),t(8;14)(q24;q32)[2]/47,idem,del(15)(q24)[21]/46,XY[2]. aCGH analysis detected a gain of 1p12qter and a loss of 15q22q25. FISH analysis confirmed the isodicentric chromosome 1, which has not previously been reported in BL. In the literature, supernumerary i(1)(q10) was found in 11 cases of which >80% presented with immature B-cell IP and >60% relapsed or died. Tetrasomy 1q resulting from supernumerary idic(1)(p12) or i(1)(q10) is a rare genetic event in BL and probably associated with immature B-cell IP. We propose that high amplification of genes on chromosome 1p12qter may contribute to the BL IP and disease progression.


Study of the effects of oral zinc supplementation on peroxynitrite levels, arginase activity and NO synthase activity in seminal plasma of Iraqi asthenospermic patients.
Low concentrations of nitric oxide (NO) are necessary for the biology and physiology of spermatozoa, but high levels of NO are toxic and have negative effects on sperm functions. Although several studies have considered the relationship between infertility and semen NO concentrations, no study on the effects of asthenospermia treatments such as oral zinc supplementation on concentrations of NO, which are important in fertility, has been reported. Studies have shown that oral zinc supplementation develops sperm count, motility and the physical characteristics of sperm in animals and in some groups of infertile men. The present study was conducted to study the effect of zinc supplementation on the quantitative and qualitative characteristics of semen, along with enzymes of the NO pathway in the seminal plasma of asthenospermic patients. Semen samples were obtained from 60 fertile and 60 asthenozoospermic infertile men of matched age. The subfertile group was treated with zinc sulfate; each participant took two capsules (220 mg per capsule) per day for 3 months. Semen samples were obtained (before and after zinc sulfate supplementation). After liquefaction of the seminal fluid at room temperature, routine semen analyses were performed. The stable metabolites of NO (nitrite) in seminal plasma were measured by nitrophenol assay. Arginase activity and NO synthase activity were measured spectrophotometrically. Peroxynitrite levels, arginase activity, NO synthase activity and various sperm parameters were compared among fertile controls and infertile patients (before and after treatment with zinc sulfate). Peroxynitrite levels and NO synthase activity were significantly higher in the infertile patients compared to the fertile group. Conversely, arginase activity was significantly higher in the fertile group than the infertile patients. Peroxynitrite levels, arginase activity and NO synthase activity of the infertile patient were restored to normal values after treatment with zinc sulfate. Volume of semen, progressive sperm motility percentage and total normal sperm count were increased after zinc supplementation. Treatment of asthenospermic patients with zinc supplementation leads to restored peroxynitrite levels, arginase activity and NO synthase activity to normal values and gives a statistically significant improvement of semen parameters compared with controls.


Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity.
Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of the uracil catabolic pathway, being critically important for inactivation of the commonly prescribed anti-cancer drug 5-fluorouracil (5-FU). DPD impairment leads to increased exposure to 5-FU and, in turn, increased anabolism of 5-FU to cytotoxic nucleotides, resulting in more severe clinical adverse effects. Numerous variants within the gene coding for DPD, DPYD, have been described, although only a few have been demonstrated to reduce DPD enzyme activity. To identify DPYD variants that alter enzyme function, we expressed 80 protein-coding variants in an isogenic mammalian system and measured their capacities to convert 5-FU to dihydro-fluorouracil, the product of DPD catabolism. The M166V, E828K, K861R, and P1023T variants exhibited significantly higher enzyme activity than wild-type DPD (120%, P = 0.025; 116%, P = 0.049; 130%, P = 0.0077; 138%, P = 0.048, respectively). Consistent with clinical association studies of 5-FU toxicity, the D949V substitution reduced enzyme activity by 41% (P = 0.0031). Enzyme activity was also significantly reduced for 30 additional variants, 19 of which had <25% activity. None of those 30 variants have been previously reported to associate with 5-FU toxicity in clinical association studies, which have been conducted primarily in populations of European ancestry. Using publicly available genotype databases, we confirmed the rarity of these variants in European populations but showed that they are detected at appreciable frequencies in other populations. These data strongly suggest that testing for the reported deficient DPYD variations could dramatically improve predictive genetic tests for 5-FU sensitivity, especially in individuals of non-European descent.


Online social networking sites-a novel setting for health promotion?
Among adolescents, online social networking sites (SNS) such as Facebook are popular platforms for social interaction and may therefore be considered as 'novel settings' that could be exploited for health promotion. In this article, we examine the relevant definitions in health promotion and literature in order to analyze whether key characteristics of 'settings for health promotion' and the socio-ecological settings approach can be transferred to SNS. As many of our daily activities have shifted to cyberspace, we argue that online social interaction may gain more importance than geographic closeness for defining a 'setting'. While exposition to positive references to risk behavior by peers may render the SNS environment detrimental to health, SNS may allow people to create their own content and therefore foster participation. However, those health promotion projects delivered on SNS up until today solely relied on health education directed at end users. It remains unclear how health promotion on SNS can meet other requirements of the settings approach (e.g. building partnerships, changing the environment). As yet, one should be cautious in terming SNS a 'setting'.


Major facilitator superfamily domain-containing protein 2a (MFSD2A) has roles in body growth, motor function, and lipid metabolism.
The metabolic adaptations to fasting in the liver are largely controlled by the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARα), where PPARα upregulates genes encoding the biochemical pathway for β-oxidation of fatty acids and ketogenesis. As part of an effort to identify and characterize nutritionally regulated genes that play physiological roles in the adaptation to fasting, we identified Major facilitator superfamily domain-containing protein 2a (Mfsd2a) as a fasting-induced gene regulated by both PPARα and glucagon signaling in the liver. MFSD2A is a cell-surface protein homologous to bacterial sodium-melibiose transporters. Hepatic expression and turnover of MFSD2A is acutely regulated by fasting/refeeding, but expression in the brain is constitutive. Relative to wildtype mice, gene-targeted Mfsd2a knockout mice are smaller, leaner, and have decreased serum, liver and brown adipose triglycerides. Mfsd2a knockout mice have normal liver lipid metabolism but increased whole body energy expenditure, likely due to increased β-oxidation in brown adipose tissue and significantly increased voluntary movement, but surprisingly exhibited a form of ataxia. Together, these results indicate that MFSD2A is a nutritionally regulated gene that plays myriad roles in body growth and development, motor function, and lipid metabolism. Moreover, these data suggest that the ligand(s) that are transported by MFSD2A play important roles in these physiological processes and await future identification.


Implementation of an expanded-scope-of-practice physiotherapist role in a regional hospital emergency department.
The aim of the present study was to describe the implementation of an expanded-scope physiotherapy service in a regional hospital emergency department (ED) in Australia and discuss the lessons learnt in terms of long-term sustainability of these roles in regional areas. The existing ED advanced physiotherapist was trained in extended scope of practice skills. For sustainability, a senior physiotherapist was recruited to develop further ED practice skills through a locally developed professional development package and ultimately be eligible to complete extended-scope training. Mixed methods data collection included document review, patient and staff satisfaction surveys and data mining of routine clinical data sets. The extended-hours service operated for 12 months. The advanced physiotherapist completed postgraduate course requirements and was able to work to an expanded scope of practice including increased autonomy in management and discharge of patients treated in the ED and independent ordering and interpreting of plain film X-rays. The professional development package was not completed and the senior physiotherapist role was filled for only part of the study period. It is feasible to implement an expanded scope of physiotherapy service in a regional hospital ED. For sustainability in regional areas, a larger advanced-level physiotherapy workforce and easier access to expanded-scope training are required.


Localized irradiation of mouse legs using an image-guided robotic linear accelerator.
To investigate the potential of human satellite cells in muscle regeneration small animal models are useful to evaluate muscle regeneration. To suppress the inherent regeneration ability of the tibialis muscle of mice before transplantation of human muscle fibers, a localized irradiation of the mouse leg should be conducted. We analyzed the feasibility of an image-guided robotic irradiation procedure, a routine treatment method in radiation oncology, for the focal irradiation of mouse legs. After conducting a planning computed tomography (CT) scan of one mouse in its customized mold a three-dimensional dose plan was calculated using a dedicated planning workstation. 18 Gy have been applied to the right anterior tibial muscle of 4 healthy and 12 mice with immune defect in general anesthesia using an image-guided robotic linear accelerator (LINAC). The mice were fixed in a customized acrylic mold with attached fiducial markers for image guided tracking. All 16 mice could be irradiated as prevised without signs of acute radiation toxicity or anesthesiological side effects. The animals survived until scarification after 8, 21 and 49 days as planned. The procedure was straight forward and the irradiation process took 5 minutes to apply the dose of 18 Gy. Localized irradiation of mice legs using a robotic LINAC could be conducted as planned. It is a feasible procedure without recognizable side effects. Image guidance offers precise dose delivery and preserves adjacent body parts and tissues.


Serum Phthalate and Triclosan Levels Have Opposing Associations With Risk Factors for Gestational Diabetes Mellitus.
Certain phthalates and bisphenol A (BPA) have been associated with insulin resistance and type 2 diabetes in non-pregnant adults, but studies of gestational diabetes mellitus (GDM) have reported conflicting results for phthalates and no associations with BPA. Our aim was to investigate the relationship between maternal serum levels of phthalate metabolites and phenols at 10-17 weeks of gestation and glucose homeostasis at 28 weeks of gestation. 232 women aged ≥16 years without type 1 or 2 diabetes with singleton male pregnancies were recruited from a single UK maternity centre between 2001 and 2009 as part of a prospective observational study (Cambridge Baby Growth Study). Serum levels of 16 phthalate metabolites and 9 phenols (including BPA) were measured using liquid chromatography/tandem mass spectrometry. Oral glucose tolerance tests were performed at 28 weeks. 47/232 (20.3%) women had GDM. First-trimester triclosan (TCS) was inversely associated with incident GDM (adjusted odds ratio per log increase in concentration 0.54, 95% confidence interval 0.34-0.86, p = 0.010). Amongst women without GDM, first-trimester mono-(2-ethylhexyl) phthalate and mono(carboxyisooctyl) phthalate levels were positively associated with 120-min plasma glucose (adjusted β 0.268 and 0.183, p = 0.0002 and 0.010, respectively) in mid-pregnancy. No other monotonic associations were detected between phthalate or phenol levels and fasting or stimulated plasma glucose, β-cell function, insulin resistance, or 60-min disposition index. Our results support a glycaemia-raising effect of phthalates during pregnancy, consistent with findings in non-pregnant populations and suggest a possible protective effect of exposure to TCS against GDM.


Overexpression of ATP-binding cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF(V600E) mutant cancer cells.
Melanoma is the most serious type of skin cancer with a high potential for metastasis and very low survival rates. The discovery of constitutive activation of the BRAF kinase caused by activating BRAF(V600E) kinase mutation in most melanoma patients led to the discovery of the first potent BRAF(V600E) signaling inhibitor, vemurafenib. Vemurafenib was effective in treating advanced melanoma patients and was proposed for the treatment of other BRAF(V600E) mutant cancers as well. Unfortunately, the success of vemurafenib was hampered by the rapid development of acquired resistance in different types of BRAF(V600E) mutant cancer cells. It becomes important to identify and evaluate all of the potential mechanisms of cellular resistance to vemurafenib. In this study, we characterized the interactions of vemurafenib with three major ATP-binding cassette (ABC) transporters, ABCB1, ABCC1 and ABCG2. We found that vemurafenib stimulated the ATPase activity and potently inhibited drug efflux mediated by ABCB1 and ABCG2. Vemurafenib also restored drug sensitivity in ABCG2-overexpressing cells. Moreover, we revealed that in the presence of functional ABCG2, BRAF kinase inhibition by vemurafenib is reduced in BRAF(V600E) mutant A375 cells. Taken together, our findings indicate that ABCG2 confers resistance to vemurafenib in A375 cells, suggesting involvement of this transporter in acquired resistance to vemurafenib. Thus, combination chemotherapy targeting multiple pathways could be an effective therapeutic strategy to overcome acquired resistance to vemurafenib for cancers harboring the BRAF(V600E) mutation.


Thrombocytopenia in chronic hepatitis C.
Thrombocytopenia in patients with chronic hepatitis C may be the result of several factors: bone marrow inhibition, the decrease of liver thrombopoietin production and an autoimmune mechanism. Clinical variables such as age, gender, severity of liver disease and degree of viremia could influence the severity of platelet reduction. The goal of this study is to determine the prevalent mechanism of thrombocytopenia in patients with chronic hepatitis C and the clinical predictors of its severity. Eighty-one patients with chronic hepatitis C and thrombocytopenia were included. The viral inhibition on the bone marrow (central mechanism) was studied by performing bone marrow biopsy from the iliac crest. The presence of antiplatelet antibodies by ELISA assessed the peripheral mechanism. The clinical predictors included in the analysis were: age, gender, ALT level, liver fibrosis stage and HCV RNA. Coexistence of a central and peripheral mechanism was found in the vast majority (93.3%) of patients with severe thrombocytopenia (< 100,000/microL) and in most patients (61.53%) with moderate thrombocytopenia (100,000- 125,000/microL). In patients with less severe thrombocytopenia (126,000-149,000/microL), autoimmune destruction was the sole mechanism (85%). Thrombocytopenia was significantly associated with ALT values, viral load and stage of fibrosis. Our data demonstrates that chronic hepatitis C is associated with a variable degree of thrombocytopenia. As the disease advances, the platelet count decreases and, in most cases, both mechanisms are involved. The stage of fibrosis is one of the major determinants of thrombocytopenia.


The capacity of mitogen-responsive T cells to "home" to their tissue of origin, analyzed by means of chromosome markers.
Lance and Taub (1) showed that when radioactively labeled lymphocytes were injected into a syngeneic mouse and the lymph node cells of this animal transferred to a second syngeneic recipient, the proportion of radioactivity found in the lymph node relative to the amount present in the spleen of the secondary recipient had increased markedly. The interpretation of this result was that some lymphocytes have the capacity to "home" to their organ of origin. The purpose of the experiments described here was to test the "homing" copacity of T cells by a method that did not involve radioactive labeling. It has been shown elsewhere that some or all mouse T cells are stimulated to divide in culture by the mitogens phytohemagglutinin (PHA) and concanavalin A (Con A) (2). We therefore elected to inject karyotypically distinct lymphocytes into syngeneic recipients and to follow their subsequent distribution by culture of lymph node and spleen cells of the recipient with PHA or Con A. In this manner the homing capacities of spleen and lymph node T cells could be determined, and furthermore, the effects of labeling with chromium-51 ((51)Cr) could be assayed with respect to the persistence of mitogen responsiveness in the injected cells.


Are there social correlates to suicide?
A structural-sociological approach to suicide research holds that an aggregate-level cause of suicide should correlate with the suicide rates in a population. In 1980, Sainsbury, Jenkins, and Levey published the article "The Social Correlates of Suicide in Europe" which related the suicide rates in 1961-63 and the changes in them in the following 11 years to 15 social variables in 18 European countries. Its main findings were that the changes in suicide rates could be attributed to specific changes in the social environment. Complementary discriminant analyses showed that it was possible accurately to divide the countries into low- and high-change suicide rate groups on the basis of a combination of the social variables. Although criticized for its method, the study has been widely quoted and sometimes presented as the most definitive current study on the subject. In order to see whether its results held for similar data 16 years later it was replicated for 1977-79 and the ensuing 11 years, with data and method as similar as possible to the original. The results agreed with those of the original study on only one point: the correlations between the levels of the social variables and those of the suicide rates were similar in both periods. However, changes in the suicide rates were unrelated to either the levels of the social variables or the changes in them: correlations found in the original study tended to change profoundly or disappear. Moreover, the results of the original discriminant analyses were a property of the method employed and thus independent of the data. Statistical artefacts or social processes such as changing expectations are unlikely to explain the suddenly changing or vanishing correlations. The original correlations seem to have been largely spurious and dependent on the fact that the more modern countries in Europe experienced a "suicide boom" in the 1960s. As the boom waned in these, it was beginning in the less modern countries: the correlations between the processes indicated by the social variables and the suicide rates were reversed or disappeared. The results call the existence of clear relations between these "suicidogenic" social circumstances and the suicide rates into question. Since many of the variables used are traditional "Durkheimian" indicators of the integration of society, a critique of this still-dominant view of the relationship between society and suicide mortality, or its common operationalization, is implied.


Fluid flow regulates E-selectin protein levels in human endothelial cells by inhibiting translation.
The purpose of this study was to determine the mechanism with which fluid flow inhibits endothelial E-selectin expression. Cultured human umbilical vein endothelial cells were stimulated with inflammatory agonists (tumor necrosis factor-alpha [TNF-alpha], interleukin-1beta, oncostatin M, or phorbol ester) in the presence or absence of fluid flow (peak shear stress, approximately 12 dynes/cm(2)) imposed with an orbital shaker. E-selectin expression was assessed with ribonuclease protection assay, immunoblotting, enzyme-linked immunosorbent assay, or metabolic labeling as appropriate. All agonists caused human umbilical vein endothelial cells to express E-selectin protein. Fluid flow inhibited E-selectin protein levels by about 50% in response to TNF-alpha but had no effect on total E-selectin messenger RNA (mRNA) expression. Flow inhibited E-selectin protein production even after initiation of E-selectin transcription. Flow did not cause E-selectin to be shed from the cell surface nor was E-selectin degradation accelerated. Although fluid flow did not reduce total cellular E-selectin mRNA levels in response to TNF-alpha, the amount of E-selectin mRNA present in the actively translated polysome fraction was markedly attenuated. These findings indicate that E-selectin expression is subject to translational and transcriptional control. Fluid mechanical forces can regulate endothelial phenotype by targeting translational control points.


The homeodomain protein IDX-1 increases after an early burst of proliferation during pancreatic regeneration.
Islet duodenal homeobox 1 (IDX-1/PF-1/STF-1/PDX-1), a homeodomain protein that transactivates the insulin promoter, has been shown by targeted gene ablation to be required for pancreatic development. After 90% pancreatectomy (Px), the adult pancreas regenerates in a process recapitulating embryonic development, starting with a burst of proliferation in the epithelium of the common pancreatic duct. In this model, IDX-1 mRNA was detected by semiquantitative reverse transcription-polymerase chain reaction in total RNA from isolated common pancreatic ducts at levels 10% of those of isolated islets. The IDX-1 mRNA levels were not significantly different for common pancreatic ducts of Px, sham Px, and unoperated rats and did not change with time after surgery. By immunoblot analysis, IDX-1 protein was only faintly detected in these ducts 1 and 7 days after Px or sham Px but was easily detected at 2 and 3 days after Px. Similarly, IDX-1 immunostaining was barely detectable in sham or unoperated ducts but was strong in ducts at 2-3 days after Px. The increase of IDX-1 immunostaining followed that of BrdU incorporation (proliferation). These results indicate a posttranscriptional regulation of the IDX-1 expression in ducts. In addition, islets isolated 3-7 d after Px showed higher IDX-1 protein expression than control islets. Thus, in pancreatic regeneration IDX-1 is upregulated in newly divided ductal cells as well as in islets. The timing of enhanced expression of IDX-1 implies that IDX-1 is not important in the initiation of regeneration but may be involved in the differentiation of ductal cells to beta-cells.


HCV-related burden of disease in Europe: a systematic assessment of incidence, prevalence, morbidity, and mortality.
Hepatitis C virus (HCV) is a leading cause of chronic liver disease, end-stage cirrhosis, and liver cancer, but little is known about the burden of disease caused by the virus. We summarised burden of disease data presently available for Europe, compared the data to current expert estimates, and identified areas in which better data are needed. Literature and international health databases were systematically searched for HCV-specific burden of disease data, including incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and liver transplantation. Data were collected for the WHO European region with emphasis on 22 countries. If HCV-specific data were unavailable, these were calculated via HCV-attributable fractions. HCV-specific burden of disease data for Europe are scarce. Incidence data provided by national surveillance are not fully comparable and need to be standardised. HCV prevalence data are often inconclusive. According to available data, an estimated 7.3-8.8 million people (1.1-1.3%) are infected in our 22 focus countries. HCV-specific mortality, DALY, and transplantation data are unavailable. Estimations via HCV-attributable fractions indicate that HCV caused more than 86000 deaths and 1.2 million DALYs in the WHO European region in 2002. Most of the DALYs (95%) were accumulated by patients in preventable disease stages. About one-quarter of the liver transplants performed in 25 European countries in 2004 were attributable to HCV. Our results indicate that hepatitis C is a major health problem and highlight the importance of timely antiviral treatment. However, data on the burden of disease of hepatitis C in Europe are scarce, outdated or inconclusive, which indicates that hepatitis C is still a neglected disease in many countries. What is needed are public awareness, co-ordinated action plans, and better data. European physicians should be aware that many infections are still undetected, provide timely testing and antiviral treatment, and avoid iatrogenic transmission.


Diencephalic-mesencephalic junction dysplasia: a novel recessive brain malformation.
We describe six cases from three unrelated consanguineous Egyptian families with a novel characteristic brain malformation at the level of the diencephalic-mesencephalic junction. Brain magnetic resonance imaging demonstrated a dysplasia of the diencephalic-mesencephalic junction with a characteristic 'butterfly'-like contour of the midbrain on axial sections. Additional imaging features included variable degrees of supratentorial ventricular dilatation and hypoplasia to complete agenesis of the corpus callosum. Diffusion tensor imaging showed diffuse hypomyelination and lack of an identifiable corticospinal tract. All patients displayed severe cognitive impairment, post-natal progressive microcephaly, axial hypotonia, spastic quadriparesis and seizures. Autistic features were noted in older cases. Talipes equinovarus, non-obstructive cardiomyopathy and persistent hyperplastic primary vitreous were additional findings in two families. One of the patients required shunting for hydrocephalus; however, this yielded no change in ventricular size suggestive of dysplasia rather than obstruction. We propose the term 'diencephalic-mesencephalic junction dysplasia' to characterize this autosomal recessive malformation.


Locally-adaptive and memetic evolutionary pattern search algorithms.
Recent convergence analyses of evolutionary pattern search algorithms (EPSAs) have shown that these methods have a weak stationary point convergence theory for a broad class of unconstrained and linearly constrained problems. This paper describes how the convergence theory for EPSAs can be adapted to allow each individual in a population to have its own mutation step length (similar to the design of evolutionary programing and evolution strategies algorithms). These are called locally-adaptive EPSAs (LA-EPSAs) since each individual's mutation step length is independently adapted in different local neighborhoods. The paper also describes a variety of standard formulations of evolutionary algorithms that can be used for LA-EPSAs. Further, it is shown how this convergence theory can be applied to memetic EPSAs, which use local search to refine points within each iteration.


Involvement of endoplasmic reticulum stress-mediated CHOP (GADD153) induction in the cytotoxicity of 2-aminophenoxazine-3-one in cancer cells.
In this study, 2-aminophenoxazine-3-one (Phx-3) exhibited a potent cell growth inhibitory effect with apoptotic features in a dose-dependent manner in various cancer cell lines tested. Comparison of the expression profiles of endoplasmic reticulum (ER) stress-related genes in U266 multiple myeloma cells after treatment with Phx-3 and the ER stress inducers tunicamycin (TNM) and thapsigargin (TPG) indicated that although TNM and TPG potently induced pro-apoptotic transcription factor CHOP (GADD153) within 8 h of treatment, Phx-3 induced almost no CHOP within 48 h of treatment in U266 cells. However, murine embryonic fibroblast (MEF) cells and other cancer cell lines (e.g. A549 lung cancer cells and HL-60 acute leukemia cells) exhibited up-regulation of CHOP after treatment with Phx-3. The potency of CHOP induction in response to Phx-3 appeared to be partially correlated with the cytotoxic sensitivity of Phx-3 among various cell lines tested. MEF cells derived from CHOP knockout mice were more resistant to Phx-3 than wild-type MEF cells. Since Phx-3 has been shown to induce activation of NF-κB, a transcription factor functioning as a repressor of CHOP, we further treated U266 cells with a combination of Phx-3 and NF-κB inhibitors (e.g. BAY11-7082 or parthenolide). This enhanced cytotoxicity along with up-modulation of CHOP in U266 cells. These data suggest that ER stress-mediated CHOP induction by Phx-3 is involved in the cytotoxic effect. Regulation of CHOP expression appears to be a potent therapeutic target for cancer treatment.


Identification of diarrheagenic Escherichia coli isolated from infants and children in Dar es Salaam, Tanzania.
Relatively few studies have been done in Tanzania to detect and classify diarrheagenic Escherichia coli (DEC) strains among children with diarrhea. This study aimed at investigating DEC among children in Dar es Salaam aged less than five years hospitalized due to acute/persistent diarrhea. DEC were isolated from stool samples collected from two hundred and eighty children with acute/persistent diarrhea at Muhimbili National Hospital and Ilala and Mwananyamala Municipal Hospitals in Dar es Salaam. A multiplex PCR system method was used to detect a species specific gene for E.coli and ten different virulence genes for detection of five pathogroups of DEC namely enteroaggregative- (EAEC), enteropathogenic- (EPEC), enterotoxigenic- (ETEC), enteroinvasive- (EIEC) and enterohemorghagic- Escherichia coli (EHEC). Sixty-four patients (22.9%) harbored DEC. Forty-one of them (14.6%) were categorized as EAEC. Most of the EAEC (82.9%) were classified as typical EAEC possessing the aggR gene, and 92.6% carried the aat gene. Isolates from thirteen patients were EPEC (4.6%) and most of these (92.3%) were typical EPEC with both eae and bfpA genes. Ten isolates were identified as ETEC (3.6%) with only the heat stable toxin; either st1a or st1b but not both. Age wise, EAEC and EPEC were significantly more prevalent among the age group 0-6 months (p < 0.05). Genes for EHEC (stx1 and stx2) and EIEC (ial) were not detected in this study group. The results show a high proportion of DEC among Tanzanian children with diarrhea, with typical EAEC and typical EPEC predominating. The use of primers for both variants of ST1 (st1a and st1b) increased the sensitivity for detection of ETEC strains.


Abnormal gray matter aging in chronic pain patients.
Widespread brain gray matter (GM) atrophy is a normal part of the aging process. However, recent studies indicate that age-related GM changes are not uniform across the brain and may vary according to health status. Therefore the aims of this study were to determine whether chronic pain in temporomandibular disorder (TMD) is associated with abnormal GM aging in focal cortical regions associated with nociceptive processes, and the degree to which the cumulative effects of pain contributes to age effects. We found that patients have accelerated whole brain GM atrophy, compared to pain-free controls. We also identified three aberrant patterns of GM aging in five focal brain regions: 1) in the thalamus, GM volume correlated with age in the TMD patients but not in the control group; 2) in the anterior mid- and pregenual cingulate cortex (aMCC/pgACC), the TMD patients showed age-related cortical thinning, whereas the controls had age-related cortical thickening; and 3) in the dorsal striatum and the premotor cortex (PMC). Interestingly, the controls but not the patients showed age-related GM reductions. Finally, a result of particular note is that after accounting for the effects of TMD duration, age remained as a significant predictor of GM in the PMC and dorsal striatum. Thus, abnormal GM aging in TMD may be due to the progressive impact of TMD-related factors in pain-related regions, as well as inherent factors in motor regions, in patients with TMD. This study is the first to show that chronic pain is associated with abnormal GM aging in focal cortical regions associated with pain and motor processes.


Effects of aliphatic diamines on rat liver ornithine decarboxylase activity.
Rat liver ornithine decarboxylase activity was decreased by administration of putrescine (1,4-diaminobutane) or other diamines, including 1,3-diaminopropane, 1,5-diaminopentane and 1,6-diaminohexane. This effect was seen in control rats and in rats in which hepatic ornithine decarboxylase activity had been increased by administration of growth hormone (somatotropin) or thioacetamide. Loss of activity was not dependent on the conversion of putrescine into polyamines and was short-lived. Within 6h after intraperitoneal administration of 0.8 mmol/kg body wt., ornithine decarboxylase activity had returned to normal values. This return correlated with the rapid loss of the diamines from the liver, and the decrease in activity could be slightly prolonged by treatment with aminoguanidine, a diamine oxidase inhibitor. A decrease in ornithine decarboxylase activity by these diamines was accompanied by the accumulation in the liver of a nondiffusible inhibitor that decreased the activity of a purified ornithine decarboxylase preparation. The possibility that administration of non-physiological diamines that are not converted into polyamines might be useful for the inhibition of polyamine synthesis is discussed.


Mammalian linker-histone subtypes differentially affect gene expression in vivo.
Posttranslational modifications and remodeling of nucleosomes are critical factors in the regulation of transcription. Higher-order folding of chromatin also is likely to contribute to the control of gene expression, but the absence of a detailed description of the structure of the chromatin fiber has impaired progress in this area. Mammalian somatic cells contain a set of H1 linker-histone subtypes, H1 (0) and H1a to H1e, that bind to nucleosome core particles and to the linker DNA between nucleosomes. To determine whether the H1 histone subtypes play differential roles in the regulation of gene expression, we combined mice lacking specific H1 histone subtypes with mice carrying transgenes subject to position effects. Because position effects result from the unique chromatin structure created by the juxtaposition of regulatory elements in the transgene and at the site of integration, transgenes can serve as exquisitely sensitive indicators of chromatin structure. We report that some, but not all, linker histones can attenuate or accentuate position effects. The results suggest that the linker-histone subtypes play differential roles in the control of gene expression and that the sequential arrangement of the linker histones on the chromatin fiber might regulate higher-order chromatin structure and fine-tune expression levels.


Suitability of simple human immunodeficiency virus rapid tests in clinical trials in community-based clinic settings.
The suitability and accuracy of using simple human immunodeficiency virus (HIV) rapid (SR) tests in community-based clinics in northwest Tanzania were determined to assess eligibility for participation in clinical trials. The HIV rapid and ELISA test results for 789 women aged 16 to 54 who were screened for two clinical trials of HIV prevention were compared. Women were offered voluntary HIV counseling and testing (VCT) at screening; those who accepted were tested with the Abbott Determine and Trinity Biotech Capillus SR tests in parallel. The results were confirmed by two parallel HIV enzyme-linked immunosorbent assay (ELISA) tests (Abbott Murex HIV Ag/Ab combination and Vironostika Uniform II HIV Ag/Ab) to determine eligibility. Positive samples for any of the four assays were confirmed by a line immunoassay and p24 testing. The parallel SR tests had high concordance (96.2%) with the parallel ELISA algorithm. The sensitivities of the SR tests were 98.6% for Capillus (95% confidence interval [CI], 95.1 to 99.8%), 99.3% for Determine (95% CI, 96.2 to 100%), and 98.6% for the parallel SR (95% CI, 95.1 to 99.8%). The specificities were 99.7% for Capillus (95% CI, 98.9 to 100%), 99.7% for Determine (95% CI, 98.9 to 100%), and 100% for the parallel SR (95% CI, 99.4 to 100%). SR tests are suitable for use in community-based clinical research settings to assess eligibility both for trial participation and for the provision of on-site VCT services.


Neural cell adhesion molecule: structure, immunoglobulin-like domains, cell surface modulation, and alternative RNA splicing.
The neural cell adhesion molecule, N-CAM, appears on early embryonic cells and is important in the formation of cell collectives and their boundaries at sites of morphogenesis. Later in development it is found on various differentiated tissues and is a major CAM mediating adhesion among neurons and between neurons and muscle. To provide a molecular basis for understanding N-CAM function, the complete amino acid sequences of the three major polypeptides of N-CAM and most of the noncoding sequences of their messenger RNA's were determined from the analysis of complementary DNA clones and were verified by amino acid sequences of selected CNBr fragments and proteolytic fragments. The extracellular region of each N-CAM polypeptide includes five contiguous segments that are homologous in sequence to each other and to members of the immunoglobulin superfamily, suggesting that interactions among immunoglobulin-like domains form the basis for N-CAM homophilic binding. Although different in their membrane-associated and cytoplasmic domains, the amino acid sequences of the three polypeptides appear to be identical throughout this extracellular region (682 amino acids) where the binding site is located. Variations in N-CAM activity thus do not occur by changes in the amino acid sequence that alter the specificity of binding. Instead, regulation is achieved by cell surface modulation events that alter N-CAM affinity, prevalence, mobility, and distribution on the surface. A major mechanism for modulation is alternative RNA splicing resulting in N-CAM's with different cytoplasmic domains that differentially interact with the cell membrane. Such regulatory mechanisms may link N-CAM binding function with other primary cellular processes during the embryonic development of pattern.


Impact of Enzymatic and Microbial Bioprocessing on Protein Modification and Nutritional Properties of Wheat Bran.
Besides providing dietary fiber, wheat bran is a recognized source of protein and is considered a very valuable substitute for other protein-rich sources in the food and feed industry. Nonetheless, several factors affect protein bioavailability, including bran's layered structure. This study showed the influence on the release and protein modification of wheat bran of different bioprocessing methods involving the activation of endogenous enzymes of bran, the addition of an enzyme mixture having carbohydrase activity, and microbial fermentation. Bioprocessing in acidic conditions significantly enhanced the solubilization of protein from wheat bran, reaching the highest value in the treatment where the sole endogenous protease activity was activated. Bioprocessing through controlled fermentation allowed a more intense proteolysis and strongly impacted the in vitro digestibility of proteins. The combined use of starter cultures and cell-wall-degrading enzymes was characterized by the highest increase of phytase activity and total phenols.


High Burden of Subclinical and Cardiovascular Disease Risk in Adults With Metabolically Healthy Obesity: The Atherosclerosis Risk in Communities (ARIC) Study.
It is controversial whether adults who are obese but "metabolically healthy" have cardiovascular disease (CVD) risk comparable with that of normal-weight adults. High-sensitivity cardiac troponin T (hs-cTnT), a biomarker of myocardial damage, is useful in characterizing subclinical CVD. We categorized obesity phenotypes and studied their associations with subclinical and clinical CVD and CVD subtypes, including heart failure (HF). We conducted cross-sectional and prospective analyses of 9,477 adults in the Atherosclerosis Risk in Communities (ARIC) study. We used the Adult Treatment Panel III criteria and BMI to define obesity phenotypes as follows: metabolically healthy normal weight, metabolically healthy overweight, metabolically healthy obese, metabolically unhealthy normal weight, metabolically unhealthy overweight, and metabolically unhealthy obese. At baseline (1990-1992), mean age was 56 years, 56% were female, 23% were Black, and 25% had detectable hs-cTnT (≥6 ng/L). Over a median of 17 years of follow-up, there were 2,603 clinical CVD events. Those with the metabolically healthy obese (hazard ratio [HR] 1.38, 95% CI 1.15-1.67), metabolically unhealthy normal weight (HR 1.51, 95% CI 1.30-1.76), metabolically unhealthy overweight (HR 1.60, 95% CI 1.41-1.82), and metabolically unhealthy obese (HR 2.14, 95% CI 1.88-2.44) phenotypes had higher CVD risks in comparison with metabolically healthy normal weight. Detectable hs-cTnT (≥6 ng/L) was associated with higher CVD risk, even among metabolically healthy normal-weight adults. Metabolically healthy obese adults had higher HF risk (HR 1.65, 95% CI 1.30-2.09) in comparison with metabolically healthy normal weight. The metabolically healthy obese phenotype was associated with excess burden of clinical CVD, primarily driven by an excess risk of HF. hs-cTnT was useful in stratifying CVD risk across all obesity phenotypes, even among obese individuals who appear otherwise metabolically healthy.


Clinical outcome of arthrodesis of the ankle using rigid internal fixation with cancellous screws.
Thirty consecutive patients underwent arthrodesis of the ankle using rigid internal fixation with cancellous screws between 1992 and 1996. One patient died of causes unrelated to the surgery before bony union. Primary fusion occurred in 27 of the remaining 29 patients (93%). The average time to primary union was 9 weeks. Two patients developed a delayed union and were treated with an additional bone-grafting procedure. Ultimately, each of the 29 patients went on to fusion. Use of tobacco during the postoperative period had no apparent effect on the rate of fusion or time to fusion. Twenty-five patients were available for clinical evaluation at an average of 24 months after surgery. Subjective evaluation using questionnaires revealed a high level of satisfaction. All patients stated that they would undergo the procedure again. The mean postoperative score on the American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale was 81 points, compared with 48 points preoperatively (of a possible 100). Constant pain was the reason given by all patients for seeking treatment. After the arthrodesis, pain was reported as absent in 13 and occasional in 12 patients. All patients noted less pain in the hindfoot after fusion of the ankle. Active litigation and Workers' Compensation claims during the perioperative period had a significant negative effect on scores on the American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale and seemed to decrease patients' perceived ability to return to work.


Angiotensin II: enhanced renal responsiveness in young genetically hypertensive rats.
Renovascular and renal excretory responses to intrarenally infused angiotensin II (Ang II) (1 and 3 ng/min, one dose per rat) were assessed in young (approximately 6 weeks of age) anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats acutely treated with captopril. Urinary excretion of cyclic adenosine monophosphate (cAMP) was also measured in these rats to examine whether Ang II has an enhanced ability to inhibit adenylate cyclase activity in SHR. Ang II (1 ng/min i.r.a.) significantly reduced renal blood flow (RBF) and increased renal vascular resistance (RVR) in SHR but not in WKY rats. At this dose, Ang II produced significant decreases in glomerular filtration rate (GFR), filtration fraction (FF), urine volume (UV) and urinary excretion of sodium (UNaV) and potassium (UkV) in SHR without altering any of these parameters in WKY rats. Ang II at either dose did not cause any increase in systemic blood pressure in either SHR or WKY rats. Ang II (3 ng/min i.r.a.) decreased RBF in both SHR and WKY rats to a similar extent. However, the higher dose of Ang II produced significant decrements in GFR, FF, UV, UNaV and fractional excretion of sodium in SHR but not in WKY rats. Also, Ang II at both the doses significantly decreased urinary cAMP excretion rate in SHR without affecting the same in WKY rats. These data demonstrate that, even during the developmental phase of hypertension, the SHR kidney is more responsive to Ang II as compared with the WKY rat kidney. Also, these results suggest that the ability of Ang II to inhibit renal adenylate cyclase activity in young SHR may be enhanced. The exaggerated renal reactivity to Ang II may be an important determinant of the development of hypertension in SHR.


Use of capsule endoscopy in inflammatory bowel disease in clinical practice in Spain. Results from a national survey.
Small bowel capsule endoscopy (SBCE) is a non-invasive diagnostic technique whose use in inflammatory bowel disease (IBD) has spread. A panenteric capsule, PillCam Crohn's (PCC), has recently been developed. We lack information on the availability and use of the CEID and PCC in our environment. We conducted an electronic and anonymous survey among the members of the Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) [Spanish Working Group on Crohn's Disease and Ulcerative Colitis] and the Asociación Española de Gastroenterología (AEG) [Spanish Association of Gastroenterology], consisting of 37 multiple-choice questions. One hundred and fifty members participated, the majority dedicated to IBD (69.3%). 72.8% worked at centres with an IBD unit. 79% had SBCE available at their hospital, 14% referred patients to another centre; 22% had a PCC available, 9% referred patients to another centre. 79.3% of respondents with available SBCE used it in a small percentage of patients with IBD and 15.6% in the majority. The most frequent scenarios were suspicion of Crohn's disease (76.3%), assessment of inflammatory activity (54.7%) and assessment of the extent of the disease (54.7%). More than half (59.7%) preferentially used the Patency capsule to assess intestinal patency. Almost all respondents (99.3%) considered that training resources should be implemented in this technique. SBCE is widely available in Spanish hospitals for the management of IBD, although its use is still limited. There is an opportunity to increase training in this technique, and consequently its use.


Molecular abnormalities in chronic myeloid leukemia: deregulation of cell growth and apoptosis.
Chronic myeloid leukemia (CML) is a disease of the hematopoietic system, characterized by the presence of the Bcr-Abl oncoprotein. The main characteristics of this disease include adhesion independence, growth factor independence, and resistance to apoptosis. Loss or mutation of the tumor suppressor gene, p53, is one of the most frequent secondary mutations in CML blast crisis. The transition between chronic phase and blast crisis is associated with increased resistance to apoptosis correlating with poor prognosis. This review focuses on the involvement of these two oncoproteins in the development and progression of the apoptotic-resistant phenotype in CML.


A body image scale for evaluating transsexuals.
Body image has come to mean not only the way one perceives his body but also how one feels about these perceptions. It is an important part of one's total self-concept. As such, it can present a significant problem for many individuals. For individuals with gender identity problems, such as transsexuals, body image dissatisfaction and distortion are a fundamental aspect of their condition. It is possible to more fully understand this condition by appreciating the distinction between the reality of the transsexual's body and his preferred body image. The Body Image (BI-I) scale presented here representa an effort to quantify the transsexual's body attitude. It consists of 30 body features which the subject is asked to rate on a 5-point scale of satisfaction. This test, as part of a larger seven-test battery, was administered to 16 male and 16 female transsexuals. The data have been analyzed for comparisons between males and females, for the effects of endocrinological and surgical treatment on body attitude, and for the common denominators which characterize the transsexual's body attitude. This instrument is being used as an additional tool in evaluating the transsexual's request for sex-reassignment surgery and in following those individuals who have been accepted for treatment as they progress through the evaluation and treatment program.


Effects of cardiac medications for patients with obstructive coronary artery disease by coronary computed tomographic angiography: results from the multicenter CONFIRM registry.
This study sought to determine the correlation between baseline cardiac medications and cardiovascular outcomes in patients with obstructive coronary artery disease (CAD) diagnosed by coronary computed tomographic angiography (CCTA). 1637 patients (mean age 64.8 ± 10.2 years, 69.6% male) with obstructive CAD from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry were followed over the course of three years. Obstructive CAD was defined as a ≥50% stenosis in an epicardial vessel. Medications analyzed included statins, aspirin, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs). Using Cox proportional-hazards models, we calculated the hazard ratio (HR) with 95% confidence intervals (95% CIs) for incident major adverse cardiovascular events (MACE), defined as death, acute coronary syndrome, or myocardial infarction. At the time of CCTA, 59%, 54%, 40%, and 46% of patients were using statins, aspirin, beta-blockers, and ACE inhibitors or ARBs, respectively. Statins were associated with a 43% (95% CI = 0.38-0.87, p = 0.008) lower adjusted risk of MACE. Following adjustment, aspirin, beta-blockers, ACE inhibitors and ARBs did not attenuate the risk of MACE. When restricted to patients with multivessel obstructive CAD, only statins were associated with lower risk of MACE. In patients with obstructive CAD by CCTA, the baseline use of statins was associated with improved clinical outcomes. Other cardiac medications-including aspirin, beta-blockers, ACE inhibitors, and ARBs-were not associated with reduced risk of MACE.