title stringlengths 0 1.13k | abstract stringlengths 1 15.7k | PMID int64 22 36.5M |
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A machine vision system for automated non-invasive assessment of cell viability via dark field microscopy, wavelet feature selection and classification. | Cell viability is one of the basic properties indicating the physiological state of the cell, thus, it has long been one of the major considerations in biotechnological applications. Conventional methods for extracting information about cell viability usually need reagents to be applied on the targeted cells. These reagent-based techniques are reliable and versatile, however, some of them might be invasive and even toxic to the target cells. In support of automated noninvasive assessment of cell viability, a machine vision system has been developed. This system is based on supervised learning technique. It learns from images of certain kinds of cell populations and trains some classifiers. These trained classifiers are then employed to evaluate the images of given cell populations obtained via dark field microscopy. Wavelet decomposition is performed on the cell images. Energy and entropy are computed for each wavelet subimage as features. A feature selection algorithm is implemented to achieve better performance. Correlation between the results from the machine vision system and commonly accepted gold standards becomes stronger if wavelet features are utilized. The best performance is achieved with a selected subset of wavelet features. The machine vision system based on dark field microscopy in conjugation with supervised machine learning and wavelet feature selection automates the cell viability assessment, and yields comparable results to commonly accepted methods. Wavelet features are found to be suitable to describe the discriminative properties of the live and dead cells in viability classification. According to the analysis, live cells exhibit morphologically more details and are intracellularly more organized than dead ones, which display more homogeneous and diffuse gray values throughout the cells. Feature selection increases the system's performance. The reason lies in the fact that feature selection plays a role of excluding redundant or misleading information that may be contained in the raw data, and leads to better results. | 18,939,996 |
Sense of coherence as a resource in relation to health-related quality of life among mentally intact nursing home residents - a questionnaire study. | Sense of coherence (SOC) is a strong determinant of positive health and successful coping. For older people living in the community or staying in a hospital, SOC has been shown to be associated with health-related quality of life (HRQOL). Studies focusing on this aspect among nursing home (NH) residents have been limited. This study investigated the relationship between SOC and HRQOL among older people living in NHs in Bergen, Norway. Based on the salutogenic theoretical framework, we used a descriptive correlation design using personal interviews. We collected data from 227 mentally intact NH residents for 14 months in 2004-2005. The residents' HRQOL and coping ability were measured using the SF-36 Health Survey and the Sense of Coherence Scale (SOC-13), respectively. We analyzed possible relationships between the SOC-13 variables and SF-36 subdimensions, controlling for age, sex, marital status, education and comorbidity, and investigated interactions between the SOC and demographic variables by using multiple regression. SOC scores were significantly correlated with all SF-36 subscales: the strongest with mental health (r = 0.61) and the weakest with bodily pain (r = 0.28). These did not change substantially after adjusting for the associations with demographic variables and comorbidity. SOC-13 did not interact significantly with the other covariates. These findings suggest that more coping resources improve HRQOL. This may indicate the importance of strengthening the residents' SOC to improve the perceived HRQOL. Such knowledge may help the international community in developing nursing regimens to improve HRQOL for older people living in NHs. | 18,940,001 |
Bluejay 1.0: genome browsing and comparison with rich customization provision and dynamic resource linking. | The Bluejay genome browser has been developed over several years to address the challenges posed by the ever increasing number of data types as well as the increasing volume of data in genome research. Beginning with a browser capable of rendering views of XML-based genomic information and providing scalable vector graphics output, we have now completed version 1.0 of the system with many additional features. Our development efforts were guided by our observation that biologists who use both gene expression profiling and comparative genomics gain functional insights above and beyond those provided by traditional per-gene analyses. Bluejay 1.0 is a genome viewer integrating genome annotation with: (i) gene expression information; and (ii) comparative analysis with an unlimited number of other genomes in the same view. This allows the biologist to see a gene not just in the context of its genome, but also its regulation and its evolution. Bluejay now has rich provision for personalization by users: (i) numerous display customization features; (ii) the availability of waypoints for marking multiple points of interest on a genome and subsequently utilizing them; and (iii) the ability to take user relevance feedback of annotated genes or textual items to offer personalized recommendations. Bluejay 1.0 also embeds the Seahawk browser for the Moby protocol, enabling users to seamlessly invoke hundreds of Web Services on genomic data of interest without any hard-coding. Bluejay offers a unique set of customizable genome-browsing features, with the goal of allowing biologists to quickly focus on, analyze, compare, and retrieve related information on the parts of the genomic data they are most interested in. We expect these capabilities of Bluejay to benefit the many biologists who want to answer complex questions using the information available from completely sequenced genomes. | 18,940,007 |
Impact of stress on paranoia: an experimental investigation of moderators and mediators. | Vulnerability-stress models ascribe stress a pivotal role in the development of psychosis. However, moderating and mediating mechanisms translating stress into psychosis and the specificity of the association are not clearly established. It is hypothesized that stress will trigger paranoid ideation in vulnerable individuals through an increase in negative emotion. Using a repeated-measures design, 64 healthy participants with varying levels of vulnerability [psychosis symptoms assessed by the Community Assessment of Psychic Experiences (CAPE)] were assigned to a stress and a non-stress condition in random order. Stress was induced by exposing participants to building-site noise (75 dB) applied concurrently with difficult knowledge questions. Symptoms of paranoia, depression and obsessive compulsive disorder (OCD) were assessed by state-adapted versions of clinical scales. In the stress condition there was an increase in paranoia, depression and negative emotion. Multilevel linear modeling (MLM) revealed the increase in paranoia under stress to be moderated by the level of vulnerability and mediated by anxiety. Although participants generally showed an increase in anxiety under stress, anxiety was more strongly related to paranoia in participants with higher baseline symptomatology. The results support and specify the role of emotional reactions to stressors on the pathway from vulnerability to psychosis and highlight the relevance of anxiety. | 18,940,024 |
[Child sexual abuse coping and long term psychological adjustment]. | The aim of the study was to analyze the consequences of Child Sexual Abuse (CSA) on the psychological adjustment of university students, as well as the way in which several avoidance and approach coping strategies affect that adjustment. The sample comprised 1162 students from the University of Granada. Data about CSA was obtained from a questionnaire developed with this aim. We used the How I Deal with Things Scale of Burt and Katz to evaluate coping strategies, whereas depression and self-esteem were assessed with the Beck Depression Inventory and the Rosenberg Self-Esteem Scale, respectively. Subjects who were victims of CSA showed significantly higher scores on depression and lower scores on self-esteem. An analysis of coping strategies revealed that only the use of avoidance strategies was related to psychological adjustment. Subjects who used these strategies obtained higher scores on depression and lower scores on self-esteem. These results confirm the idea of CSA as a risk experience that can affect victims' psychological adjustment, to a greater or lesser extent, according to the coping strategy employed. | 18,940,043 |
[Sociometric typologies during adolescence: contrasting different scoring techniques and formulas]. | Our aim in this work is to compare the different sociometric classification formulae and to analyze possible connections between each type of formula and each behaviour assessed by peers during adolescence. We classified a total of 1,009 Spanish fourth-grade secondary education students (15-year-olds) using four different systems: two were based on a nomination technique by Coie and Dodge, Newcomb and Bukowski, the third system was a modified version of the latter based on the revision of the neglected status, and a fourth system was based on the qualification scale by Maassen and Laandsheer. Results show a significant relation between all four classifications, but there are also differences among them. The classifications proceeding from the nomination technique share more similarities and also offer a better behavioural characterization of sociometric categories. | 18,940,066 |
Psychometric properties and dimensional structure of the Spanish version of the Coping Responses Inventory-Adult Form. | One of the goals of psychological assessment focuses on the adaptation of its instruments to different populations. The objective of this study is to establish the psychometric properties and dimensional structure of the Spanish version of the Coping Responses Inventory-Adult Form (CRI-Adult, Moos, 1993). The following criteria were analyzed: a) descriptive statistics; b) internal consistency reliability (Cronbach's alpha, and intercorrelations between scales); c) test-retest reliability (4-week interval); d) dimensionality of CRI-Adult (exploratory factor analysis); e) construct validity (confirmatory factor analysis); f) convergent criterion validity (correlations between CRI-Adult and Coping Strategies Indicator, CSI, Amirkhan, 1990), and g) predictive criterion validity (correlations between CRI-Adult, and SCL-90-R, Derogatis, 1983). The results, obtained with 800 adults from Barcelona and surrounding area (334 men and 466 women, aged between 18 to 76 years) indicate that the Spanish version of CRI-Adult has satisfactory psychometric properties that allow using this test with guarantee. | 18,940,101 |
[Patterns of interactive behavior in a multicultural school context]. | This paper is an empirical research based on observational methodology. It is an idiographic research with a mixed observational design of low intervention, of the following type: monitoring/nomothetical/multidimensional. We used a tool created in situ for the systematic multidimensional register of the complex occurrence of several types of behavioural events in real time, which combines the format of field investigation with the system of categories. The reliability of the observation tool is obtained through the researcher-observer's agreement with him- or herself. Our aim is to study the social relationships between first-grade peer students in a multicultural context. We present some structures of seeking social closeness, help and cooperation among children of similar and different cultures, which were discovered through the detection and analysis of temporal patterns of the interactive situation of boys and girls who were observed during their academic and leisure activities in the natural context of their school. | 18,940,108 |
[Psychometric properties of the Death Anxiety Scale (DAS) among HIV/AIDS patients]. | AIDS patients and HIV carriers who are aware of their condition are under multiple kinds of stress with adverse effects on their emotional state and personal and social activity. This paper reports the psychometric properties of the DAS (Death Anxiety Scale) using the Spanish version in the clinical setting. The sample is made up of 148 HIV/AIDS patients (109 men and 39 women). The internal consistency of the scale was .72 and its test-retest reliability was .70. Principal components analysis extracted five factors that jointly accounted for 56.5% of the total variance. As, on the whole, these results are very similar to those reported by other authors, it is concluded that the Spanish DAS is a valid instrument for the assessment of death anxiety in Spanish HIV/AIDS patients. | 18,940,110 |
Low amniotic fluid index in high-risk pregnancy and poor apgar score at birth. | To determine the accuracy of antepartum Amniotic Fluid Index (AFI) of < or = 5 cm as a predictor of adverse outcome at birth in high-risk pregnancies. Cross-sectional study. Obstetrics and Gynaecology Unit I, Holy Family Hospital and Railway Teaching Hospital Complex, Rawalpindi, from February 2003 to January 2004. One hundred pregnant women at term gestation were studied. Each high-risk woman at term with an AFI of < or = 5 cm admitted for delivery through emergency or outpatient department was labeled as predictor of poor outcome. The next high-risk pregnant woman at term with the same pregnancy complication but an AFI of > 5 cm was labeled as predictor of good outcome at birth. The subjects in both the groups were demographically matched and fulfilled the inclusion and exclusion criteria. The Apgar score was calculated at 5 minutes of birth. The newborns, with Apgar score < or = 6 at 5 minutes of birth were labeled as diseased and > 6 were labeled as healthy. AFI was compared with Apgar score, using Chi-square and a p-value was calculated to determine the statistical significance. Sensitivity, specificity, efficiency and the predictive values of AFI at a cut off point of < or = 5 cm as a predictor of adverse outcome at birth (Apgar score of < or =6 at 5 minutes of birth) in high-risk pregnancy were calculated. Only 8 neonates of 50 women with low AFI had low Apgar score. Similarly, 6 neonates of 50 women with normal AFI had poor Apgar score. The diagnostic sensitivity, specificity, positive predictive value, negative predictive value and efficiency of AFI as test were 57.1%, 51.3%, 16%, 88% and 52% respectively. Low AFI is a poor predictor of adverse outcome for high-risk term patients. AFI is not a good screening test for high-risk pregnant women at term for birth of an infant with low Apgar score. | 18,940,121 |
Non-fatal limb injuries in motorbike accidents. | To determine frequency and pattern of non-fatal limb injuries in motorbike accidents victims. Cross-sectional observational study. Study was conducted at Jinnah Postgraduate Medical Centre (JPMC), Karachi, from October 2006 to March 2007. Trained data collectors prospectively collected data from the emergency department of JPMC, Karachi using structured pre-tested questionnaires. All motorbike accident victims presented to Emergency department with single or multiple bone injury in body extremities were included. Head injury patients who had first presented to neuro-surgery department were excluded. Motorbike accident victims with soft tissue injuries were also excluded from this study. Chisquare test was applied to find out statistical significance at 95% confidence level. P-value < 0.05 was considered as significant. A total of 137 (39%) patients presented with tibial injury among the study sample of 348 patients, which was significantly higher than the bone injuries of the body part (p<0.001). Out of those, in 26% of patients, fibula was also involved along with tibia fracture. Other bone injuries included femur (16%), radius (9.2%), humerus (8.3%) and others. Radius was the commonest injured bone and in highest proportion among upper limb injuries (p<0.001). Overall, 66% of the injuries in motorbike involved lower limb fractures. The highest proportion of motorbike accidents were observed on Saturdays (31%). Majority of the accident victims were in the age group between 16 and 30 years (41% accident cases), 27% in age group 30 to 45 years, 15% in 45 to 60 years and 5% in >60 years. Those with less than 15 years accounted for 12% of cases. Tibial bone is at the greatest risk in motorbike accidents probably due to its superficiality and exposed position while riding motorbike. Protective measures need to be taken for the prevention of disability associated with lower limb involvement in motorbike accidents. | 18,940,122 |
Endoscopic removal of bullet from orbital apex. | Penetrating injuries of face are not uncommon. Bullets or pallets may be lodged anywhere in the cavities of skull as a result of firearm injury. Lodgment of a bullet within the orbit through nose is uncommon. An eighteen 18 years old married woman sustained a bullet injury, which entered through lateral wall of the nose and lodged at left orbital apex area. The bullet was removed endoscopically via left nostril without any damage to the eye or disturbance in vision. | 18,940,126 |
Gas-forming urinary tract infection. | Emphysematous or gas-forming infections, a very small percentage of bacterial infections of the urinary tract, attract importance because of their life threatening potential. Herein, we report a 60-year-old Saudi female patient who was a known case of Diabetes mellitus for 15 years. She was admitted with left flank pain of 5 days duration, abdominal distension, nausea, vomiting and chills associated with increased frequency of urine, urgency, and dysuria. She had leukocytosis, high blood sugar, elevated urea and creatinine and pyuria. Urine culture grew Escherichia coli. Ultrasound and CT scan showed left pelvicalyceal dilatation and air in the left kidney and urinary bladder. She was treated with a prolonged parenteral antibiotic course, and insulin, with complete recovery. | 18,940,128 |
Eosinophilic otitis media: a new middle ear disease entity. | Eosinophilic otitis media (EOM) is intractable otitis media characterized by the presence of a highly viscous yellow effusion containing eosinophils. It occurs mainly in patients with bronchial asthma and is resistant to conventional treatments for otitis media. Here we discuss the clinical features, pathogenesis, and management of EOM. EOM predominantly affects women and presents most often in patients in their 50s. The clinical features of the middle ear in EOM are roughly divided into the otitis media with effusion type and chronic otitis media type. The latter is further divided into two subtypes: simple perforation and granulation tissue formation. EOM is often complicated by rhinosinusitis (eosinophilic sinusitis). High-tone loss is more frequently found and more severe in EOM patients than in chronic otitis media control patients, and EOM patients sometimes become deaf suddenly. Systemic or topical steroid administration is the most effective treatment for patients with EOM. The instillation of triamcinolone acetonide, a suspension of steroids, into the middle ear is very effective for controlling eosinophilic inflammation. It is very important to explain to patients with EOM that the disease may last for a long period and that progressive and sudden hearing loss may occur. | 18,940,145 |
[Adenocarcinoma in a closed rectal stump in inflammatory bowel disease]. | We describe two cases of adenocarcinoma occurring in a closed rectal stump approximately 30 years after subtotal colectomy for ulcerative colitis, respectively, Cohn's disease. After many years disease-free, the patients presented with rectal secretions, including blood, and were diagnosed with metastasizing rectal cancer. Since malignant degeneration of a closed rectal stump may not give rise to symptoms until late in the disease process, it is suggested that the rectum should be controlled endoscopically every 2nd year following a subtotal colectomy for inflammatory bowel disease to enable radical surgery. | 18,940,161 |
Preparation and characterization of novel beta-chitin-hydroxyapatite composite membranes for tissue engineering applications. | Beta-chitin is a biopolymer principally found in shells of squid pen. It has the properties of biodegradability, biocompatibility, chemical inertness, wound healing, antibacterial and anti-inflammatory activities. Hydroxyapatite (HAp) is a natural inorganic component of bone and teeth and has osteoconductive property. In this work, beta-chitin-HAp composite membranes were prepared by alternate soaking of beta-chitin membranes in CaCl2 (pH 7.4) and Na2HPO4 solutions for 2 h in each solution. After 1, 3 and 5 cycles of immersion, beta-chitin membranes were characterized using the SEM, FT-IR, EDS and XRD analyses. The results showed the presence of apatite layer on surface of beta-chitin membranes, and the amounts of size and deposition of apatite layers were increased with increasing number of immersion cycles. Human mesenchymal stem cells (hMSCs) were used for evaluation of the biocompatibility of pristine as well as composite membranes for tissue engineering applications. The presence of apatite layers on the surface of beta-chitin membranes increased the cell attachment and spreading suggesting that beta-chitin-HAp composite membranes can be used for tissue engineering applications. | 18,940,197 |
Antimicrobial activity of a chimeric enzybiotic towards Staphylococcus aureus. | Phage lytic enzymes (enzybiotics) have gained attention as prospective tools to eradicate Gram-positive pathogens resistant to antibiotics. Attempts to purify the P16 endolysin of Staphylococcus aureus phage P68 were unsuccessful owing to the poor solubility of the protein. To overcome this limitation, we constructed a chimeric endolysin (P16-17) comprised of the inferred N-terminal d-alanyl-glycyl endopeptidase domain and the C-terminal cell wall targeting domain of the S. aureus phage P16 endolysin and the P17 minor coat protein, respectively. The domain swapping approach and the applied purification procedure resulted in soluble P16-17 protein, which exhibited antimicrobial activity towards S. aureus. In addition, P16-17 augmented the antimicrobial efficacy of the antibiotic gentamicin. This synergistic effect could be useful to reduce the effective dose of aminoglycoside antibiotics. | 18,940,209 |
Influenza-related disease: the cost to the Australian healthcare system. | The disease burden attributable to influenza is difficult to determine, as influenza infections are rarely virologically confirmed or recorded. Estimating the influenza-related disease burden is a prerequisite to estimate the costs. Age-specific regression models were used to estimate the number of excess hospitalisations attributable to influenza from influenza and respiratory syncytial virus surveillance data. The number of general practitioner consultations for influenza/influenza-like illness was estimated from a continuous randomly sampled national study of general practice activity. Utilising the associated costs for each of these events, a cost-of-illness study was developed from the perspective of the Australian healthcare system. There was an annual average of 310,000 general practitioner consultations for influenza/influenza-like illness and 18,400 hospitalisations attributable to influenza over the period of review. The estimated cost to the Australian healthcare system for these events was $115 million annually. Influenza-related disease places a significant financial burden on the Australian healthcare system. | 18,940,222 |
Perinatal PCP treatment alters the developmental expression of prefrontal and hippocampal muscarinic receptors. | Perinatal phencyclidine (PCP) treatment has been used to model brain pathological processes that may be present in schizophrenia such as increased apoptosis during early brain development, and long-term alterations in expression of parvalbumin-containing interneurons and glutamatergic N-methyl-D-aspartate (NMDA) receptors. We report that this treatment also affects receptor expression of another excitatory neurotransmitter receptor, the muscarinic receptor. Female rat pups received injections of the NMDA receptor antagonist PCP (10 mg/kg, s.c.) or saline on postnatal days (PN)7, 9 and 11. [3H]Pirenzepine binding to M1/4 receptors was examined at four time-points (PN12, 18, 32 and 96) following treatment cessation. Significant effects of treatment on [3H]pirenzepine binding were evident immediately after treatment cessation with a decrease in PCP-treated rats at PN12 in the prefrontal cortex (-24%, p<0.05) and hippocampus (-19%, p<0.05). After this initial decrease, binding subsequently increased to 47% above control levels in the prefrontal cortex of adolescent animals, which remained elevated in adulthood (+10%, p<0.05), while in the hippocampus there was a trend towards increased binding in adolescent animals and no change thereafter. This work adds to findings demonstrating that perinatal PCP exposure leads to long-term imbalance of excitatory and inhibitory neurotransmitter systems, supporting its relevance as a developmental model of schizophrenia pathology. Alterations in muscarinic receptor expression may contribute specifically to the cognitive impairments reported to occur after perinatal NMDA receptor antagonist treatment. | 18,940,225 |
Prokinetics and fundic relaxants in upper functional GI disorders. | Gastrointestinal prokinetics are a heterogeneous class of drugs that stimulate smooth muscle contractions to enhance gastric emptying and intestinal transit. Recently studied prokinetics include antidopaminergic agents (itopride), serotonergic agents (tegaserod and others), and motilin receptor agonists and ghrelin receptor agonists (mitemcinal, TZP101). It has been difficult to establish symptomatic benefit with prokinetic drugs in gastroparesis and functional dyspepsia, because of pathophysiological heterogeneity of the patient populations, a lack of well-accepted endpoints, and inconsistent relationships between changes in motor function and symptomatic outcome. Fundic relaxant drugs are a recent different approach to treatment of gastric motility disorders. Recently studied drugs include drugs under investigation including nitrates, serotonin reuptake blockers, 5-HT(1A) receptor agonists (buspirone and R137696), and muscarinc M1/M2 receptor antagonists (acotiamide or Z-338). | 18,940,266 |
Prognostic significance of increased left ventricular mass index to mortality and sudden death in patients with stable coronary heart disease (from the Heart and Soul Study). | Data are limited about the significance of left ventricular (LV) hypertrophy or mass in patients with coronary heart disease (CHD), particularly in the setting of normal ejection fraction (EF). The association of LV mass index with all-cause mortality and sudden death in a cohort with CHD was evaluated. Using transthoracic echocardiography, LV mass normalized to body surface area was measured in 1,016 subjects with stable CHD. Cox proportional hazards models were used to examine the association of LV mass index and LV hypertrophy (LV mass index >95 g/m(2) in women and >115 in men) with time to death and time to sudden or arrhythmic death. Mean LV mass index was 101 +/- 27 g/m(2) in men and 88 +/- 23 in women. During a mean follow-up of 3.55 years, there were 146 deaths and 34 sudden or arrhythmic deaths. Total mortality was higher in subjects with LV hypertrophy (25% vs 11%, p <0.001), as was mortality from sudden or arrhythmic death (6.7% vs 2.2%, p = 0.001). After adjustment for age, gender, cardiovascular risk factors, and medical therapy, LV hypertrophy was associated with both all-cause mortality (hazard ratio 2.0, p <0.001) and sudden or arrhythmic death (hazard ratio 3.1, p = 0.003). Findings were similar in the subgroup with EF > or =55% (mortality hazard ratio 1.8, p = 0.02; sudden and arrhythmic death hazard ratio 3.1, p = 0.02). Analyzed as a continuous variable, every 20-unit increase in LV mass index increased the adjusted hazard of death by 22% (p = 0.001) and adjusted hazard of sudden or arrhythmic death by 40% (p = 0.004). In conclusion, in patients with stable CHD, increased LV mass index was independently associated with all-cause mortality and sudden or arrhythmic death, even in subjects with normal EF. | 18,940,278 |
Comparison of left ventricular dyssynchrony by two-dimensional speckle tracking versus tissue Doppler imaging in patients with non-ST-elevation myocardial infarction and preserved left ventricular systolic function. | Assessment of left ventricular (LV) dyssynchrony after myocardial infarction has prognostic value. There were no reference ranges for 2-dimensional (2D) speckle tracking synchrony, and it was unclear whether color tissue Doppler imaging and 2D speckle tracking synchrony indexes were comparable. One hundred twenty-two healthy volunteers and 40 patients with non-ST-elevation myocardial infarction (NSTEMI) had LV systolic and diastolic synchrony, defined as the SD of time to peak systolic (2D-SDTs) and early diastolic (2D-SDTe) velocities in the 12 basal and mid segments using 2D speckle tracking, respectively. Mean 2D-SDTs and 2D-SDTe were 29.4 +/- 16.1 and 14.2 +/- 6.1 ms in healthy subjects, respectively. Gender and mean 2D systolic velocity independently predicted 2D-SDTs, and mean 2D early diastolic velocity independently predicted 2D-SDTe. Bland-Altman analysis showed suboptimal agreement between 2D speckle tracking and tissue Doppler imaging dyssynchrony indexes. 2D speckle tracking showed lower coefficients of variation for time to peak systolic and early diastolic velocities than tissue Doppler imaging. There were no significant differences in coefficients of variation for 2D speckle tracking systolic and diastolic synchrony for high versus low frame rates. Patients with NSTEMI had significantly lower ejection fraction, but higher LV mass and wall stress than healthy subjects. Only 2D-SDTs was significantly higher in patients with NSTEMI compared with healthy subjects (37.1 +/- 22.5 vs 29.4 +/- 16.1 ms; p = 0.02). In conclusion, 2D-SDTs was gender specific and influenced by global systolic function, and 2D-SDTe was influenced by global diastolic function. 2D speckle tracking and tissue Doppler imaging dyssynchrony indexes were not comparable. 2D speckle tracking may be a more sensitive discriminator of LV systolic dyssynchrony than tissue Doppler imaging. | 18,940,281 |
Rapid quantitative determination of hydrogen peroxide by oxidation decolorization of methyl orange using a Fenton reaction system. | In this study, a sensitive and rapid method for hydrogen peroxide (H(2)O(2)) determination has been developed with the aid of oxidation decolorization of methyl orange (MO) by using Fenton reactions, because the decolorization extent of MO solution (at the maximum absorption wavelength of 507 nm) is proportion to the concentration of H(2)O(2). Under optimum conditions, this spectrophotometric method for the H(2)O(2) analysis yields a dynamic range of H(2)O(2) concentration from 5.0 x 10(-7) to 1.0 x 10(-4) mol L(-1) (r=0.997) and a detection limit (3 sigma/k) of 2.0 x 10(-7) mol L(-1). This method for the determination of H(2)O(2) (0.04 mmol L(-1)) is able to tolerate the interference from NaCl (0-5.0 mmol L(-1)), Na(2)SO(4) (0-5.0 mmol L(-1)), MgCl(2) (0-5.0 mmol L(-1)), sodium humate (0-0.1 mmol L(-1)), benzene (0-0.2 mmol L(-1)), toluene (0-0.2 mmol L(-1)), chlorobenzene (0-0.2 mmol L(-1)) and chloroform (0-0.2 mmol L(-1)). The analysis results for practical rainwater samples are in good agreement with the classical N,N-diethyl-p-phenylenediamine (DPD) method for H(2)O(2) determination. | 18,940,316 |
The prevalence of self-harm behaviors among a sample of gastric surgery candidates. | The surgical treatment of obesity is becoming increasingly popular; yet, little is known about the self-harm characteristics and adjunctive self-regulation difficulties of those seeking such surgery. In the literature, one study has explored presurgery suicide attempts and several studies have explored the prevalence of postsurgical completed suicides. However, beyond suicide attempts and completions, little is known about the broader self-harm/self-regulation profiles of these patients. In this study, we examined the prevalence of 22 such behaviors among a sample of gastric surgery candidates. Using a cross-sectional approach, we examined 121 surgical candidates for 22 self-reported self-harm and self-regulatory behaviors. The studied behaviors with the highest prevalence rates in this cohort were sexual promiscuity (22.3%), torturing oneself with self-defeating thoughts (20.7%), alcohol abuse (19.0%), and engaging in emotionally abusive relationships (16.5%). With regard to suicide attempts, 9.1% of participants acknowledged a history and 9.1% reported past overdoses. These data suggest that (a) adjunctive self-regulatory difficulties may affect a substantial minority of individuals who are seeking gastric surgery for obesity (e.g., promiscuity and alcohol abuse), and (b) the anticipated prevalence rate for past suicide attempts in this population appears to be approximately 10%. | 18,940,374 |
Psychosocial consequences of developmental prosopagnosia: a problem of recognition. | To provide the first systematic in-depth description of the consequences of developmental prosopagnosia (DP; 'face blindness') for psychosocial functioning and occupational disability, in order to determine what kind of professional intervention may be needed. Semi-structured telephone interviews were carried out with 25 people whose self-reports of face recognition problems were confirmed by impaired scores on the Cambridge Face Recognition Test. Thematic analysis was used to inductively identify and understand common psychosocial consequences of DP. All participants described recurrent and sometimes traumatic social interaction difficulties caused by recognition problems, such as failing to recognize close friends, work colleagues, and family members. These problems often led to chronic anxiety about offending others and feelings of embarrassment, guilt, and failure. Most participants described some degree of fear and avoidance of social situations in which face recognition was important, including family and social gatherings, and meetings at work. Long-term consequences could include dependence on others, a restricted social circle, more limited employment opportunities, and loss of self-confidence. The potential for negative psychosocial consequences and occupational disability posed by DP is as great as that posed by conditions which are currently afforded professional recognition and support, such as stuttering and dyslexia. Wider recognition of the problems prosopagnosia can cause could reduce anxiety about social interaction difficulties by making it easier to explain and justify recognition problems to other people, including employers. Greater professional awareness could facilitate detection and referral of those requiring support with coping with social interactions. | 18,940,375 |
Insulin-stimulated mitochondrial adenosine triphosphate synthesis is blunted in skeletal muscles of high-fat-fed rats. | Physiologic elevation of insulin levels induces a significant increase in muscle adenosine triphosphate (ATP) synthesis rate in normal individuals, indicative of an appropriate acceleration in mitochondrial activity. However, the stimulatory effect of insulin is diminished in insulin-resistant patients. In the absence of similar data from preclinical models, the present study investigated the inhibitory effects of increased dietary fat intake on insulin-stimulated ATP synthesis rates in rats. After being placed on a high-fat diet for 8 weeks (n = 10), diet-induced obese male Sprague-Dawley rats were tested against age-matched control rats (n = 9) on a normal chow diet. Muscle ATP synthase flux rates were measured under anesthesia by in vivo (31)P saturation transfer both before and during a euglycemic-hyperinsulinemic clamp. The glucose infusion rates observed during the clamp revealed impaired peripheral insulin sensitivity in the high-fat-fed rats when compared with the age-matched control rats. Under baseline conditions (ie, low insulin), the muscle ATP synthesis rates of high-fat-fed rats were approximately 30% lower (P < .05) than those in chow-fed rats. Moreover, chow-fed animals showed a significant increase (25%, P < .05 vs basal) in muscle ATP synthesis activity upon insulin stimulation, whereas high-fat-fed animals displayed no substantial change. These data demonstrated for the first time in a preclinical model that the insulin challenge not only facilitates an improvement in the dynamic range of ATP turnover measurement by (31)P saturation transfer between normal and insulin-resistant rats, but also mimics challenge that is relevant for pharmacologic studies on antidiabetic drugs aimed at improving mitochondrial function. | 18,940,398 |
Diazoxide enhances basal metabolic rate and fat oxidation in obese Zucker rats. | Persistent suppression of hyperinsulinemia in genetically obese (fa/fa) Zucker rats by diazoxide (DZ) reduces food intake and weight gain; improves insulin sensitivity, glycemic control, and lipid profile; and enhances beta(3)-adrenergic function and lipolysis in adipose tissue. The aim of this study was to elucidate the effects of DZ on basal metabolic rate (BMR), fat oxidation, and adrenergic function of lean and obese Zucker rats. Diazoxide (150 mg/kg/d) or vehicle (control) was administered for 4 weeks in 7-week-old obese and lean Zucker rats (n = 8-9 per subgroup). Animals underwent indirect calorimetry, body composition analysis, and determination of uncoupling proteins (UCPs) messenger RNA (mRNA) in brown and white adipose tissues (BAT and WAT) and skeletal muscle (SM), beta(3)-adrenergic receptor (AR) mRNA in BAT and WAT, beta(2)-AR in SM as well as WAT, and SM adenylate cyclase (AC) activity at the completion of study. Diazoxide treatment decreased food intake, weight gain, and body fat in obese rats (P < .01). Although DZ treatment lowered fasting plasma glucose, insulin, leptin, adiponectin, and lipids in obese rats (P < .01), it increased adiponectin-leptin ratio (P < .01). Plasma adiponectin-leptin ratio was inversely correlated with fat mass in obese and lean rats (r = -0.86, P < .0001). Diazoxide treatment resulted in higher BMR and fat oxidation rate in obese compared with control animals (P < .01), without any effect in lean animals. Furthermore, plasma adiponectin was inversely correlated with BMR (-0.56, P < .001) and lipid oxidation rate (-0.61, P < .0005) and was positively correlated with nonprotein respiratory quotient (r = 0.41, P < .01) in obese and lean rats. This was associated with increased beta(3)-AR mRNA expression in BAT and WAT (P < .01), UCP-1 and UCP-3 in BAT and AC activity in WAT (P < .02), and AC activity in SM of DZ obese rats compared with controls (P < .01), without significant change in SM beta(2)-AR mRNA expressions. Diazoxide attenuation of hyperinsulinemia decreased the rate of weight gain but enhanced insulin sensitivity, BMR, and fat oxidation in obese rats. This was associated with increased receptor- and non-receptor-mediated adrenergic function in adipose and muscle tissues in obese rats, respectively. These metabolic changes in obese Zucker rats suggest that antiobesity effects of DZ appear to be not only through its anorectic effect, modification of disturbed insulin metabolism, and inhibition of lipogenesis, but also due to augmentation of adrenergic function, energy expenditure, and fat utilization. | 18,940,400 |
Hereditary spherocytosis. | Hereditary spherocytosis is a common inherited disorder that is characterised by anaemia, jaundice, and splenomegaly. It is reported worldwide and is the most common inherited anaemia in individuals of northern European ancestry. Clinical severity is variable with most patients having a well-compensated haemolytic anaemia. Some individuals are asymptomatic, whereas others have severe haemolytic anaemia requiring erythrocyte transfusion. The primary lesion in hereditary spherocytosis is loss of membrane surface area, leading to reduced deformability due to defects in the membrane proteins ankyrin, band 3, beta spectrin, alpha spectrin, or protein 4.2. Many isolated mutations have been identified in the genes encoding these membrane proteins; common hereditary spherocytosis-associated mutations have not been identified. Abnormal spherocytes are trapped and destroyed in the spleen and this is the main cause of haemolysis in this disorder. Common complications are cholelithiasis, haemolytic episodes, and aplastic crises. Splenectomy is curative but should be undertaken only after careful assessment of the risks and benefits. | 18,940,465 |
Do the benefits of rigid internal fixation of mandible fractures justify the added costs? Results from a randomized controlled trial. | Owing to its putative advantages over conventional maxillomandibular fixation (MMF), open-reduction and rigid internal fixation (ORIF) is used frequently to treat mandible fractures, particularly in noncompliant patients. The resource-intensive nature of ORIF, the large variation in its use, and the lack of systematic studies substantiating ORIF attributed benefits compel a randomized controlled investigation comparing ORIF to MMF treatment. The objective of this study was to determine whether ORIF provides better clinical and functional outcomes than MMF in noncomplying type of patients with a similar range of mandible fracture severity. From a total of 336 patients who sought treatment for mandible fractures, 142 patients with moderately severe mandible fractures were assigned randomly to receive MMF or ORIF and followed prospectively for 12 months. A variety of clinician and patient-reported measures were used to assess outcomes at the 1, 6, and 12 months follow-up visits. These measures included clinician-reported number of surgical complications, patient-reported number of complaints, as well as cumulative costs of treatment. Pain intensity was measured on a 10-point scale and the 12-item General Oral Health Assessment Index was used to assess the patients' oral health-related quality of life. Because the protocol allowed clinical judgment to overrule the randomly assigned treatment, outcomes were compared on an "intent-to-treat" basis as well as in terms of actual treatment received. The sociodemographic and clinical characteristics of the injury did not differ among the 2 groups. On an intent-to-treat basis, the difference in complication rates was not significant but favored MMF; 8.1% of patients developed complications with MMF versus 12.5% with ORIF. Differences in the rate of patient complaints were not significant on an intent-to-treat basis, but a significant between-group difference (P = .012) favoring MMF was noted on an as-treated basis at the 1 month recall, with 40% of ORIF patients reporting greater than 1 complaint versus 18.8% of MMF patients. No significant differences were detected between the 2 treatment groups at any time point with respect to oral health-related quality of life reflected by the General Oral Health Assessment Index scores. In-patient days and total costs did not differ significantly on an intent-to-treat basis, but on an as-treated basis, patients treated with MMF had fewer in-patient days on average (1.64 vs 5.50 for ORIF) and lower average costs of treatment ($7,206 vs $26,089 for ORIF). In the intent-to-treat analyses, patients receiving MMF treatment had significantly lower (P = .05) pain scores at the 12-month recall (mean = 0.58, SE = 0.30) compared with patients assigned to ORIF (mean = 1.78, SE = 0.52). Our study did not show a clear overall benefit of the resource-intensive ORIF over conventional MMF treatment in the management of moderately severe mandible fractures in at-risk patients; our data instead suggest some cost as well as oral health quality-of-life advantages for the use of MMF in this patient population. | 18,940,481 |
Effects of simvastatin on mandibular distraction osteogenesis. | The aim of this study was to evaluate the effects of local and systemic simvastatin application on distraction osteogenesis. Eighteen New Zealand white rabbits underwent unilateral mandibular distraction osteogenesis. After 7 days of neutral fixation, 0.4 mm twice per day, distraction was performed for 10 days. Simvastatin was applied locally during the osteotomy phase with a gelatin sponge carrier and systemically during the distraction osteogenesis period by oral gavage. All animals were killed at the end of the consolidation period of 14 days. The distracted mandibles were harvested and evaluated by plain radiography, by peripheral quantitative computed tomography, and with histomorphometry. Radiographic evaluation with peripheral quantitative computed tomography showed that the area of the regenerate increased by 9.6% in the local simvastatin group and by 19.3% in the systemic simvastatin group as compared with the control group. In both experimental groups the density of the regenerate increased by 6.7% as compared with the control group. Statistical evaluation of radiographic data showed that all of these changes were not significant. Histomorphometric evaluation determined that there was no statistical difference among groups with regard to the ratios of bone tissue volume to fibrous tissue volume and bone tissue volume to marrow tissue volume. The results of this study suggest that simvastatin's effect on enhancing distraction regenerate is limited with the applied doses and methods. | 18,940,485 |
Central malignant salivary gland tumors of the jaw: retrospective clinical analysis of 22 cases. | As a review of central malignant salivary gland tumor cases in Southwest China in the past 20 years, this study provided the clinical, radiologic, and pathologic information of these rare lesions. In our study, 22 cases of central malignant salivary gland tumor treated between 1986 to 2006 at West China Stomatology Hospital of Sichuan University were retrospectively analyzed. A thorough review of clinical records was carried out and the histologic diagnosis was revised using the 2005 WHO criteria. The average age of patients was 46.5 years old, and the peak incidence age of the tumors was in the fourth, fifth, and sixth decades. The male:female ratio was 0.47:1. The clinical manifestation included swelling of the jaw, pain, paraesthesia, tooth mobility, and pain. All the lesions were radiolucent regions with an ill-defined margin. The most frequent histologic type was the mucoepidermoid carcinoma. Local extensive resection of the primary focus was the primary treatment. Central malignant salivary gland tumors often occurred in the middle-aged patients, and there were more cases in the mandible than in the maxilla. The diagnosis should be based on the case history, clinical, pathologic, and radiologic examinations. The major treatment was extensive resection of primary focus. | 18,940,488 |
Microvascular free tissue transfer for tongue reconstruction after hemiglossectomy: a functional assessment of radial forearm versus anterolateral thigh flap. | The purpose of this study was to evaluate tongue function and donor site morbidity in patients with oral cancer surgically treated and reconstructed with radial or anterolateral thigh free flaps. Twenty patients underwent primary reconstruction after hemiglossectomy between January 2002 and June 2004. Ten patients were reconstructed using a free forearm flap and the remaining with an anterolateral thigh flap. Eight patients on each group underwent postoperative radiotherapy (average, 60 Gy). All of them were followed postoperatively to determine after 6 months their functional outcome as it related to speech, deglutition, tongue mobility, and donor site morbidity. The intelligibility, deglutition, and tongue mobility were each scored on a scale ranging from 1 to 7 by an independent investigator. Data were analyzed by the 2-tail Mann-Whitney U test. No differences in mean speech intelligibility, tongue mobility, or deglutition mean scores were seen between radial forearm flap and anterolateral thigh flap (P > .05). In all anterolateral thigh flap-treated cases, the donor site was closed directly and no complications were seen. However, in all forearm flaps donor site closure was carried out with skin grafts and dorsal forearm splinting was applied for 1 week postoperatively. In 4 cases a partial skin graft failure was observed and donor sites healed for second intention. Anterolateral thigh flap, with its versatility in design, long pedicle with a suitable vessel diameter, and low donor site morbidity, could be the ideal flap for hemiglossectomy defect reconstruction. | 18,940,491 |
The cosmeceutical realm. | The cosmeceutical realm is composed of functional cosmetics designed to adorn face and body without changing the structure of the human form. Although this may seem confusing, indeed cosmeceuticals have never been well defined. Cosmeceuticals developed for facial application typically claim to induce more even skin tone, improve skin texture, increase skin radiance, decrease the appearance of skin wrinkling, and provide antiaging benefits. Nondrug active ingredients are usually incorporated into moisturizing vehicles designed to accomplish the aforementioned claims. There is no doubt that cosmeceuticals represent the most rapidly expanding frontier in dermatology. | 18,940,543 |
Aging skin and food supplements: the myth and the truth. | The frenzied rhythm of our times leads our patients not only to resource to diet integrators-remorselessly overcoming difficulties or prejudices-to fulfill increasingly frequent nutritional needs due to decreasingly "correct" eating habits, but also to fight against a myriad of skin conditions. The rationale of a combined approach for the antiaging treatment of skin is based on the synergic effect between functional substances applied locally, where the problem arises, and other agents working from the inside to correct a need, to restore altered functions or conditions and to guarantee the correct intake of nutrients or active substances. This work discusses the active ingredients mostly used in the oral treatment of skin aging, together with the scientific evidences that do or do not support their use. | 18,940,546 |
Brain damage by mild metabolic derangements in methylmalonic acidemia. | Methylmalonic acidemia caused by an l-methylmalonyl-CoA mutase deficiency. The mut(0) type is associated with significant mortality and morbidity, but tandem mass spectrometry has made early detection possible. Five patients were identified through newborn screening for elevated propionylcarnitine (C3-carnitine) levels. These patients received a positive screening result at a median age of 10 days (range, 5-18 days). When treated at a median age of 11 days (range, 3-50 days), 2 patients were asymptomatic, and only one was significantly acidotic (pH <7.2), but all had various degrees of hyperammonemia (range, 127-1,244 mumol/L). Magnetic resonance imaging of the brain was performed in 4 patients shortly after diagnosis, and the results were all abnormal. Four patients were followed. There was no further metabolic decompensation after the initial episodes, but their mean developmental quotient was only 50. These results suggest that early hyperammonemia can lead to significant brain damage in methylmalonic acidemia. Therefore, treatment of this disease in newborns must be more aggressive. | 18,940,555 |
Effect of nutritional support in children with spastic quadriplegia. | Malnutrition is a common problem in patients with cerebral palsy. We evaluated the effect of nutritional support on clinical findings in children with spastic quadriplegia. Feeding history, numbers of lower respiratory tract infections, and gastrointestinal and neurologic findings were evaluated via questionnaire. Weight, height, head circumference, midarm circumference, and triceps skinfold thickness were measured. Height for age, weight for age, weight for height, body mass index, and weight and height z-scores were calculated. Clinical findings and anthropometric parameters were re-evaluated after nutritional support for 6 months. Forty-five patients were enrolled. No difference was evident between the first and the last height z-scores of 31 patients who completed the follow-up. Weight, height, weight z-scores, weight for age, weight for height, body mass index, midarm circumference, and triceps skinfold thickness exhibited improvement. Moreover, a significant decrease in number of infections was evident. Frequency of seizures and Gross Motor Function Classification System status did not change. Constipation decreased significantly. Nutritional therapy revealed improvements in some anthropometric findings and a decrease in number of infections. Although there was no difference regarding motor development or seizure frequency, further studies with a longer follow-up are required. | 18,940,556 |
CNS relapse of acute myelogenous leukemia masquerading as pseudotumor cerebri. | An 18-year-old man in remission from acute myelogenous leukemia 3 years after a bone marrow transplant presented with signs of pseudotumor cerebri, including headache, visual changes, and papilledema. He manifested elevated opening pressure on lumbar puncture and positive cytology, with a concurrent normal bone marrow aspirate and biopsy. He was diagnosed with an isolated central nervous system relapse of acute myeloid leukemia. Although the precise etiology remains elusive, this case demonstrates that pseudotumor cerebri must remain within the differential diagnosis after other complications are excluded, particularly in persons with underlying hematologic malignancies. | 18,940,560 |
Hypogammaglobulinaemia. | This article reviews the primary immunodeficiencies that result in hypogammaglobulinemia or predominantly antibody deficiency disorders. This group makes up the largest proportion of patients with primary immunodeficiency. Significant advances have been made in understanding the molecular basis and clinical characteristics of patients with the more severe forms of antibody deficiency in the last 6 years. Recognition of these disorders remains poor with significant diagnostic delay. The milder forms of antibody deficiency disorders, especially those with normal total serum immunoglobulin G levels, remain poorly characterized and understood. Further work remains to be done in understanding and recognizing these syndromes to benefit patient care and foster further knowledge of the immune system. | 18,940,570 |
Immunoglobulin replacement therapy in children. | The benefit of immunoglobulin (IG) replacement in primary antibody deficiencies is unquestionable. Many of these congenital disorders present early in life and this therapy is often first implemented in the young. This article focuses on the indications of IG replacement in children, with an emphasis on the specific diagnostic problems encountered in this population. Also presented is an overview of the practical aspects of IG administration in the pediatric setting, including the recognition and management of adverse reactions. Finally, the advent of subcutaneous IG, a therapeutic IG modality with the potential to have a great impact on the quality of life of children with antibody deficiencies and their families, is discussed. | 18,940,577 |
Insulinoma-associated 1 has a panneurogenic role and promotes the generation and expansion of basal progenitors in the developing mouse neocortex. | Basal (intermediate) progenitors are the major source of neurons in the mammalian neocortex. The molecular machinery governing basal progenitor biogenesis is unknown. Here, we show that the zinc-finger transcription factor Insm1 (insulinoma-associated 1) is expressed specifically in progenitors undergoing neurogenic divisions, has a panneurogenic role throughout the brain, and promotes basal progenitor formation in the neocortex. Mouse embryos lacking Insm1 contained half the number of basal progenitors and showed a marked reduction in cortical plate radial thickness. Forced premature expression of Insm1 in neuroepithelial cells resulted in their mitosis occurring at the basal (rather than apical) side of the ventricular zone and induced expression of the basal progenitor marker Tbr2. Remarkably, these cells remained negative for Tis21, a marker of neurogenic progenitors, and did not generate neurons but underwent self-amplification. Our data imply that Insm1 is involved in the generation and expansion of basal progenitors, a hallmark of neocortex evolution. | 18,940,587 |
Genetic ablation of V2a ipsilateral interneurons disrupts left-right locomotor coordination in mammalian spinal cord. | The initiation and coordination of activity in limb muscles are the main functions of neural circuits that control locomotion. Commissural neurons connect locomotor circuits on the two sides of the spinal cord, and represent the known neural substrate for left-right coordination. Here we demonstrate that a group of ipsilateral interneurons, V2a interneurons, plays an essential role in the control of left-right alternation. In the absence of V2a interneurons, the spinal cord fails to exhibit consistent left-right alternation. Locomotor burst activity shows increased variability, but flexor-extensor coordination is unaffected. Anatomical tracing studies reveal a direct excitatory input of V2a interneurons onto commissural interneurons, including a set of molecularly defined V0 neurons that drive left-right alternation. Our findings imply that the neural substrate for left-right coordination consists of at least two components; commissural neurons and a class of ipsilateral interneurons that activate commissural pathways. | 18,940,589 |
Architecture of the pontin/reptin complex, essential in the assembly of several macromolecular complexes. | Pontin and reptin belong to the AAA+ family, and they are essential for the structural integrity and catalytic activity of several chromatin remodeling complexes. They are also indispensable for the assembly of several ribonucleoprotein complexes, including telomerase. Here, we propose a structural model of the yeast pontin/reptin complex based on a cryo-electron microscopy reconstruction at 13 A. Pontin/reptin hetero-dodecamers were purified from in vivo assembled complexes forming a double ring. Two rings interact through flexible domains projecting from each hexamer, constituting an atypical asymmetric form of oligomerization. These flexible domains and the AAA+ cores reveal significant conformational changes when compared with the crystal structure of human pontin that generate enlarged channels. This structure of endogenously assembled pontin/reptin complexes is different than previously described structures, suggesting that pontin and reptin could acquire distinct structural states to regulate their broad functions as molecular motors and scaffolds for nucleic acids and proteins. | 18,940,606 |
Sjögren syndrome: a review for the maxillofacial surgeon. | Sjögren syndrome is a multisystemic condition that predominantly involves the salivary and lacrimal glands. Also known as sicca complex, the disease often is underdiagnosed and poorly understood. This article provides a comprehensive review on Sjögren syndrome, with an emphasis on diagnosis and treatment modalities. | 18,940,623 |
Systemic lymphoproliferative diseases. | With advancements in diagnosis and treatment for lymphoma, it is important that physicians be up to date in the management of these lymphoproliferative disorders, their associated complications, and the complications of treatment. The importance of a thorough examination of the oro-facial complex and neck on all patients cannot be overemphasized. Oral and maxillofacial surgeons continue to make significant contributions in what has become a multidisciplinary approach to managing lymphoproliferative disease. | 18,940,625 |
Head and neck manifestations of distant carcinomas. | Metastatic tumors to the head and neck from distant carcinomas are rare lesions that epitomize the "zebras." They represent a diagnostic and therapeutic challenge for clinicians and health providers. These lesions usually rank low in the differential diagnosis list, but a history of cancer should prompt clinicians about the possibility of a metastatic lesion from a distant carcinoma. The presence of these lesions usually represents a poor prognosis. The surgeon's role in treating these lesions is to improve or maintain the patient's quality of life, taking into consideration the overall prognosis. | 18,940,627 |
Estimation of adipose pools in hemodialysis patients from anthropometric measures. | Adiposity, measured as increased body mass index (BMI), is associated with reduced all-cause and cardiovascular (CV) mortality in hemodialysis (HD) patients, whereas CV risk increases with BMI in the general population. A major limitation of BMI as a measure of adiposity is its failure to distinguish muscle and fat compartments. In addition, the biology of different adipose compartments is not the same. The visceral adipose tissue (VAT) mass is especially biologically active, secreting a variety of cytokines and adipokines. Alternate methods of estimating body composition were found to have a greater association with CV risk factors than BMI in several populations. We measured total adipose tissue, subcutaneous adipose tissue, and VAT in 48 prevalent HD patients, using magnetic resonance imaging. Based on these measurements, we developed parsimonious multiple-regression models to estimate these adipose compartments using age, sex, BMI, weight, maximum abdominal circumference (MAC), and race. The parsimonious models for VAT included only age, race, and MAC (adjusted r(2) = 0.776, P < .0001), whereas the subcutaneous adipose tissue model included sex, weight, age, and BMI (adjusted r(2) = 0.91, P < .0001) rather than MAC. The total adipose tissue model included BMI, sex, weight, and age (adjusted r(2) = 0.905, P < .0001). We propose that measurements of MAC, in addition to height and weight, be included in studies relating body composition to outcomes, because this measure provides a better estimate of the metabolically active VAT pool. | 18,940,649 |
Fracturing rings to understand lantibiotics. | Haloduracin is a bacterially produced antibiotic system of two alkali-stable peptides (Halalpha and Halbeta) that have extensive posttranslational modifications, including lanthionine rings. Now, Cooper et al. (2008) revise the structure of Halbeta and demonstrate that some of the lanthionine rings are not essential for bioactivity. | 18,940,660 |
Adoptive immunotherapy against allogeneic kidney grafts in dogs with stable hematopoietic trichimerism. | Dogs given nonmyeloablative conditioning and marrow grafts from 2 dog leukocyte antigen (DLA)-identical littermate donors developed stable trichimerism and stably accepted a subsequent kidney graft from one of the marrow donors without the need for immunosuppression. In this study, we used trichimeras to evaluate strategies for adoptive immunotherapy to solid tumors, using the kidney as a tumor surrogate. Three DLA-identical trichimeric recipients were established by simultaneously infusing marrow from 2 DLA-identical donor dogs into a DLA-identical recipient conditioned with 2 Gy of total body irradiation (TBI) and given a short course of postgraft immunosuppression. After stable hematopoietic engraftment was confirmed, a kidney was transplanted from 1 of the 2 marrow donors into each respective trichimeric recipient. Peripheral blood lymphocytes from each kidney donor were then used to sensitize the alternate marrow donor. The trichimeric recipients were given donor lymphocyte infusions (DLIs) from the sensitized dogs and monitored for chimerism, graft-versus-host disease (GVHD), and kidney rejection. After DLI, we observed both prompt rejection of the transplanted marrow and donor kidney and disappearance of corresponding hematopoietic chimerism. Presumably due to shared minor histocompatibility antigens, host chimerism also disappeared, and GVHD in skin, gut, and liver developed. The native kidneys, although exhibiting lymphocytic infiltration, remained functionally normal. This study demonstrates that under certain experimental conditions, the kidney--an organ ordinarily not involved in graft-versus-host reactions--can be targeted by sensitized donor lymphocytes. | 18,940,673 |
Factors associated with peripheral blood stem cell yield in volunteer donors mobilized with granulocyte colony-stimulating factors: the impact of donor characteristics and procedural settings. | Peripheral blood stem cells (PBSCs) are increasingly used as the source of hematopoietic stem cells, but there are large variations in harvest outcome between individuals mobilized by granulocyte colony-stimulating factor (G-CSF). We examined the effects of donor characteristics and procedure factors on the day 1 CD34+ cell yield in 373 unrelated healthy donors. G-CSF was administered subcutaneously at a planned dose of 8.3 to 11 microg/kg daily for 5 days, followed by harvest started on day 5 of G-CSF treatment. Of the 373 donors, 159 (42.6%) had the radial artery as the inlet access for harvest. Poor day 1 cell yield was defined as <10x10(6) CD34+ cells/L of processed blood for the first apheresis; 62 donors (16.6%) did not attain this threshold. The male donors had significantly higher yields at harvest compared with the female donors. The female donors had higher CD34+ cell yields if the circulation access was through an artery than if is was through a vein. In a multiple regression analysis, donor age, sex, body mass index (BMI), preharvest white blood cell and circulating immature cell counts, access type, and flow rate correlated with day 1 yield. Female sex, older age, venous access, and a higher flow rate were significantly associated with greater risk for a day 1 poor yield of CD34+ cells (odds ratio=3.0074, 1.045, 4.3362, and 1.1131, respectively). A higher BMI may decrease the risk (odds ratio=0.8472). In donors at higher risk for poor CD34+ cell yield, strategies for increasing CD34+ cells must be considered. | 18,940,686 |
Genome-wide association studies in neurological disorders. | During the past decade, the genetic causes of monogenic forms of disease have been successfully defined; this work has helped the progression of basic scientific investigation into many disorders, and has helped to characterise several molecular biological processes. An important goal of genetic research is to extend this work and define genetic risk factor loci for complex disorders. The aim is for these data not only to offer further basic understanding of the disease process, but also to provide the opportunity to obtain genetic risk assessments that could be generalised to the public. The development of resources such as the Human Genome Project and the International Human Haplotype Map Project, coupled with technological advances in ultra-high-throughput genotyping, have provided the basis for genome-wide association studies (GWAS). This approach has been successful for several complex disorders in a short time. Although GWAS are still a new method, these studies have been used for a small number of neurological disorders and, despite varied results for these conditions, GWAS can usefully show the power and limitations of this approach. WHERE NEXT?: GWAS have the potential to show and emphasise common genetic variability associated with disease. However, a challenge of this approach is that large sample series and considerable resources are required. One important consideration will be the interpretation of the results of GWAS in a clinically meaningful way and to discern the implications for all therapy areas, including neurological disorders; this challenge will require specialised skills and resources from both the medical and the scientific communities. | 18,940,696 |
Identification of new molecules extracted from Quercus suber L. cork. | Various methods of suberin extraction have been used in order to identify monomers of this complex polymer. Pre-extraction of waxes has allowed us to identify for the first time 3-friedelanol as a terpen from cork. Moreover, the wax chemical composition found here varied from previous results since cerin was not identified while friedelin and betulin were. Three fractions were obtained: a polymeric, a monomeric and a low molecular weight fraction, the last of which has never before been described. 2,6-heptanediol was found to be the main compound of this fraction. Furthermore, depolymerisation at room temperature gives the same yields as those obtained at reflux, defining an easier and cheaper methodology. | 18,940,700 |
Delayed chain termination protects the anti-hepatitis B virus drug entecavir from excision by HIV-1 reverse transcriptase. | Entecavir (ETV) is a potent antiviral nucleoside analogue that is used to treat hepatitis B virus (HBV) infection. Recent clinical studies have demonstrated that ETV is also active against the human immunodeficiency virus type 1 (HIV-1). Unlike all approved nucleoside analogue reverse transcriptase RT) inhibitors (NRTIs), ETV contains a 3'-hydroxyl group that allows further nucleotide incorporation events to occur. Thus, the mechanism of inhibition probably differs from classic chain termination. Here, we show that the incorporated ETV-monophosphate (MP) can interfere with three distinct stages of DNA synthesis. First, incorporation of the next nucleotide at position n + 1 following ETV-MP is compromised, although DNA synthesis eventually continues. Second, strong pausing at position n + 3 suggests a long range effect, referred to as "delayed chain-termination." Third, the incorporated ETV-MP can also act as a "base pair confounder" during synthesis of the second DNA strand, when the RT enzyme needs to pass the inhibitor in the template. Enzyme kinetics revealed that delayed chain termination is the dominant mechanism of action. High resolution foot-printing experiments suggest that the incorporated ETV-MP "repels" the 3'-end of the primer from the active site of HIV-1 RT, which, in turn, diminishes incorporation of the natural nucleotide substrate at position n + 4. Most importantly, delayed chain termination protects ETV-MP from phosphorolytic excision, which represents a major resistance mechanism for approved NRTIs. Collectively, these findings provide a rationale and important tools for the development of novel, more potent delayed chain terminators as anti-HIV agents. | 18,940,786 |
Coprinus cinereus rad50 mutants reveal an essential structural role for Rad50 in axial element and synaptonemal complex formation, homolog pairing and meiotic recombination. | The Mre11/Rad50/Nbs1 (MRN) complex is required for eukaryotic DNA double-strand break (DSB) repair and meiotic recombination. We cloned the Coprinus cinereus rad50 gene and showed that it corresponds to the complementation group previously named rad12, identified mutations in 15 rad50 alleles, and mapped two of the mutations onto molecular models of Rad50 structure. We found that C. cinereus rad50 and mre11 mutants arrest in meiosis and that this arrest is Spo11 dependent. In addition, some rad50 alleles form inducible, Spo11-dependent Rad51 foci and therefore must be forming meiotic DSBs. Thus, we think it likely that arrest in both mre11-1 and the collection of rad50 mutants is the result of unrepaired or improperly processed DSBs in the genome and that Rad50 and Mre11 are dispensable in C. cinereus for DSB formation, but required for appropriate DSB processing. We found that the ability of rad50 mutant strains to form Rad51 foci correlates with their ability to promote synaptonemal complex formation and with levels of stable meiotic pairing and that partial pairing, recombination initiation, and synapsis occur in the absence of wild-type Rad50 catalytic domains. Examination of single- and double-mutant strains showed that a spo11 mutation that prevents DSB formation enhances axial element (AE) formation for rad50-4, an allele predicted to encode a protein with intact hook region and hook-proximal coiled coils, but not for rad50-1, an allele predicted to encode a severely truncated protein, or for rad50-5, which encodes a protein whose hook-proximal coiled-coil region is disrupted. Therefore, Rad50 has an essential structural role in the formation of AEs, separate from the DSB-processing activity of the MRN complex. | 18,940,790 |
Survey of mammography practice in Croatia: equipment performance, image quality and dose. | A national audit of mammography equipment performance, image quality and dose has been conducted in Croatia. Film-processing parameters, optical density (OD), average glandular dose (AGD) to the standard breast, viewing conditions and image quality were examined using TOR(MAM) test object. Average film gradient ranged from 2.6 to 3.7, with a mean of 3.1. Tube voltage used for imaging of the standard 45 mm polymethylmethacrylate phantom ranged from 24 to 34 kV, and OD ranged from 0.75 to 1.94 with a mean of 1.26. AGD to the standard breast ranged from 0.4 to 2.3 mGy with a mean of 1.1 mGy. Besides clinical conditions, the authors have imaged the standard phantom in the referent conditions with 28 kV and OD as close as possible to 1.5. Then, AGD ranged from 0.5 to 2.6 mGy with a mean of 1.3 mGy. Image viewing conditions were generally unsatisfying with ambient light up to 500 lx and most of the viewing boxes with luminance between 1000 and 2000 cd per m(2). TOR(MAM) scoring of images taken in clinical and referent conditions was done by local radiologists in local image viewing conditions and by the referent radiologist in good image viewing conditions. Importance of OD and image viewing conditions for diagnostic information were analysed. The survey showed that the main problem in Croatia is the lack of written quality assurance/quality control (QA/QC) procedures. Consequently, equipment performance, image quality and dose are unstable and activities to improve image quality or to reduce the dose are not evidence-based. This survey also had an educational purpose, introducing in Croatia the QC based on European Commission Guidelines. | 18,940,818 |
Exposure to infections through day-care attendance and risk of childhood leukaemia. | There is growing evidence supporting a role for infections in the aetiology of childhood leukaemia. Hypotheses proposed by both Greaves and Kinlen describe childhood leukaemia to be a rare response to one or more common infections acquired through personal contacts. Previous epidemiological studies have used day-care attendance as an indicator of the increased likelihood of early and frequent exposure to infections. It is well-documented that in developed countries, exposures to common infections occur more frequently in this type of setting. Within the Northern California Childhood Leukaemia Study, the role of social contact has been assessed and a unique 'child-hours' summary measure incorporating information on the number of months attending a day-care, mean hours per week at this day-care and the number of children in the day-care setting was constructed. In this review, the previously reported day-care results have been described, showing that in non-Hispanic White children, children in the highest category of total child-hours of exposure had a reduced risk of acute lymphoblastic leukaemia (ALL), particularly common B-cell precursor ALL (c-ALL), compared with children without such exposures, with evidence of a dose-response effect. In addition, a literature review of relevant studies has been conducted, examining the relationship between day-care attendance and risk of childhood ALL. Overall, the 14 studies identified provided consistent support for this hypothesis, with the majority of studies reporting some evidence of a reduced risk. A meta-analysis is currently underway, which will provide a quantitative evaluation of the overall consistency and strength of the association between day-care attendance or social contact and risk of childhood ALL. | 18,940,822 |
Residential exposures to pesticides and childhood leukaemia. | Like many chemicals, carcinogenicity of pesticides is poorly characterised in humans, especially in children, so that the present knowledge about childhood leukaemia risk derives primarily from epidemiological studies. Overall, case-control studies published in the last decade have reported positive associations with home use of insecticides, mostly before the child's birth, while findings for herbicides are mixed. Previous studies relied solely on self-reports, therefore lacking information on active ingredients and effects of potential recall bias. Few series to date have examined the influence of children's genetic susceptibility related to transport and metabolism of pesticides. To overcome these limitations, investigators of the Northern California Childhood Leukaemia Study (NCCLS) have undertaken, in collaboration with a multidisciplinary team, a comprehensive assessment of residential pesticide exposure, including: (1) quality control of self-reports; (2) home pesticide inventory and linkage to the Environmental Protection Agency to obtain data on active ingredients; (3) collection and laboratory analyses of approximately 600 home dust samples for over 60 pesticides and (4) geographic information studies using California environmental databases to assess exposure to agricultural pesticides. The NCCLS is also conducting large-scale genotyping to evaluate the role of genes in xenobiotic pathways relevant to the transport and metabolism of pesticides. A better quantification of children's exposures to pesticides at home is critical to the evaluation of childhood leukaemia risk, especially for future gene-environment interaction studies. | 18,940,823 |
Prediction of kinase-specific phosphorylation sites using conditional random fields. | Phosphorylation is a crucial post-translational protein modification mechanism with important regulatory functions in biological systems. It is catalyzed by a group of enzymes called kinases, each of which recognizes certain target sites in its substrate proteins. Several authors have built computational models trained from sets of experimentally validated phosphorylation sites to predict these target sites for each given kinase. All of these models suffer from certain limitations, such as the fact that they do not take into account the dependencies between amino acid motifs within protein sequences in a global fashion. We propose a novel approach to predict phosphorylation sites from the protein sequence. The method uses a positive dataset to train a conditional random field (CRF) model. The negative training dataset is used to specify the decision threshold corresponding to a desired false positive rate. Application of the method on experimentally verified benchmark phosphorylation data (Phospho.ELM) shows that it performs well compared to existing methods for most kinases. This is to our knowledge that the first report of the use of CRFs to predict post-translational modification sites in protein sequences. The source code of the implementation, called CRPhos, is available from http://www.ptools.ua.ac.be/CRPhos/ | 18,940,828 |
Cellular basis of growth suppression by submergence in azuki bean epicotyls. | Complete submergence severely reduces growth rate and productivity of terrestrial plants, but much remains to be elucidated regarding the mechanisms involved. The aim of this study was to clarify the cellular basis of growth suppression by submergence in stems. The effects of submergence on the viscoelastic extensibility of the cell wall and the cellular osmotic concentration were studied in azuki bean epicotyls. Modifications by submergence to chemical properties of the cell wall; levels of osmotic solutes and their translocation from the seed to epicotyls; and apoplastic pH and levels of ATP and ethanol were also examined. These cellular events underwater were compared in etiolated and in light-grown seedlings. Under submergence, the osmotic concentration of the cell sap was substantially decreased via decreased concentrations of organic compounds including sugars and amino acids. In contrast, the viscoelastic extensibility of the cell wall was kept high. Submergence also decreased ATP and increased the pH of the apoplastic solution. Alcoholic fermentation was stimulated underwater, but the resulting accumulated ethanol was not directly involved in growth suppression. Light partially relieved the inhibitory effects of submergence on growth, osmoregulation and sugar translocation. A decrease in the levels of osmotic solutes is a main cause of underwater growth suppression in azuki bean epicotyls. This may be brought about by suppression of solute uptake via breakdown of the H(+) gradient across the plasma membrane due to a decrease in ATP. The involvement of cell wall properties in underwater growth suppression remains to be fully elucidated. | 18,940,853 |
Nematode.net update 2008: improvements enabling more efficient data mining and comparative nematode genomics. | Nematode.net (http://nematode.net) is a publicly available resource dedicated to the study of parasitic nematodes. In 2000, the Genome Center at Washington University (GC) joined a consortium including the Nematode Genomics group in Edinburgh, and the Pathogen Sequencing Unit of the Sanger Institute to generate expressed sequence tags (ESTs) as an inexpensive and efficient solution for gene discovery in parasitic nematodes. As of 2008 the GC, sampling key parasites of humans, animals and plants, has generated over 500,000 ESTs and 1.2 million genome survey sequences from more than 30 non-Caenorhabditis elegans nematodes. Nematode.net was implemented to offer user-friendly access to data produced by this project. In addition to sequence data, the site hosts: assembled NemaGene clusters in GBrowse views characterizing composition and protein homology, functional Gene Ontology annotations presented via the AmiGO browser, KEGG-based graphical display of NemaGene clusters mapped to metabolic pathways, codon usage tables, NemFam protein families which represent conserved nematode-restricted coding sequences not found in public protein databases, a web-based WU-BLAST search tool that allows complex querying and other assorted resources. The primary aim of Nematode.net is the dissemination of this diverse collection of information to the broader scientific community in a way that is useful, consistent, centralized and enduring. | 18,940,860 |
Comparison of correspondence analysis methods for synonymous codon usage in bacteria. | Synonymous codon usage varies both between organisms and among genes within a genome, and arises due to differences in G + C content, replication strand skew, or gene expression levels. Correspondence analysis (CA) is widely used to identify major sources of variation in synonymous codon usage among genes and provides a way to identify horizontally transferred or highly expressed genes. Four methods of CA have been developed based on three kinds of input data: absolute codon frequency, relative codon frequency, and relative synonymous codon usage (RSCU) as well as within-group CA (WCA). Although different CA methods have been used in the past, no comprehensive comparative study has been performed to evaluate their effectiveness. Here, the four CA methods were evaluated by applying them to 241 bacterial genome sequences. The results indicate that WCA is more effective than the other three methods in generating axes that reflect variations in synonymous codon usage. Furthermore, WCA reveals sources that were previously unnoticed in some genomes; e.g. synonymous codon usage related to replication strand skew was detected in Rickettsia prowazekii. Though CA based on RSCU is widely used, our evaluation indicates that this method does not perform as well as WCA. | 18,940,873 |
The effect of atorvastatin in patients with polycystic ovary syndrome: a randomized double-blind placebo-controlled study. | Polycystic ovary syndrome (PCOS) is associated with increased risk of cardiovascular morbidity, whereas statins are proven to reduce cardiovascular mortality and morbidity through lipid-lowering and perhaps through their pleiotropic effects. Statins can also reduce testosterone in vitro by inhibiting ovarian theca-interstitial cell proliferation and steroidogenesis and reducing inflammation in vivo. Our objective was to assess the effect of atorvastatin on inflammatory markers, insulin resistance, and biochemical hyperandrogenemia in patients with PCOS. We conducted a randomized, double-blind, placebo-controlled study at a tertiary care setting in United Kingdom. Patients included 40 medication-naive patients with PCOS and biochemical hyperandrogenemia. Patients were randomized to either atorvastatin 20 mg daily or placebo. The primary endpoint of the study was a change in the inflammatory marker high-sensitivity C-reactive protein. The secondary endpoints were a change in insulin resistance and total testosterone. After 12 wk atorvastatin, there was a significant reduction (mean +/- sem) in total cholesterol (4.6 +/- 0.2 vs. 3.4 +/- 0.2 mmol/liter, P < 0.01), low-density lipoprotein cholesterol (2.9 +/- 0.2 vs. 1.8 +/- 0.2 mmol/liter, P < 0.01), triglycerides (1.34 +/- 0.08 vs. 1.08 +/- 0.13 mmol/liter, P <0.01), high-sensitivity C-reactive protein (4.9 +/- 1.4 vs. 3.4 +/- 1.1 mg/liter, P = 0.04), free androgen index (13.4 +/- 0.6 vs. 8.7 +/- 0.4, P < 0.01), testosterone (4.1 +/- 0.2 vs. 2.9 +/- 0.1 nmol/liter, P < 0.01) and insulin resistance as measured by homeostasis model assessment for insulin resistance (HOMA-IR) (3.3 +/- 0.4 vs. 2.7 +/- 0.4). There was a significant increase in SHBG (31.1 +/- 1.0 vs. 35.3 +/- 1.2 nmol/liter, P < 0.01). There was a positive correlation between the reduction in HOMA-IR in the atorvastatin group with the reduction in triglycerides and the reduction of free androgen index. There was a significant deterioration of HOMA-IR in the placebo group (3.0 +/- 0.4 vs. 3.8 +/- 0.5). This study suggests that atorvastatin is effective in reducing inflammation, biochemical hyperandrogenemia, and metabolic parameters in patients with PCOS after a 12-wk period. | 18,940,877 |
Association of type 1 diabetes with two Loci on 12q13 and 16p13 and the influence coexisting thyroid autoimmunity in Japanese. | Recent genome-wide association studies have identified several novel type 1 diabetes (T1D) loci in white populations. In line with recent findings, we conducted a replication study of two loci on chromosome 12p13 and 16p13 and assessed their potential associations with thyroid autoimmunity in a Japanese population. Two single-nucleotide polymorphisms (SNPs), rs2292399 in ERBB3 on 12q13 and rs2903692 in CLEC16A (or KIAA0350) on 16p13, were analyzed in Japanese subjects consisting of 735 T1D patients, 330 patients with autoimmune thyroid disease (AITD), and 621 control subjects. According to a case-control study and logistic regression adjusting for sex and age, we observed that these SNPs in ERBB3 and CLEC16A were both significantly associated with T1D, with the risk alleles being consistent with those in white populations [adjusting odds ratio by multiplicative model: 1.37 (1.13-1.67), P = 0.001; and 1.28 (1.02-1.60), P = 0.030, respectively]. In both SNPs, the association was suggested to be stronger in T1D complicated with AITD (Graves' disease, Hashimoto's thyroiditis, or thyroid autoantibodies). Furthermore, a joint analysis, with the INS and CTLA4 SNPs, revealed that CTLA4 rs3087243, ERBB3 rs2292399, and CLEC16A rs2903692, but not INS rs689, were significant risk factors for the cooccurrence of AITD in Japanese T1D. We confirmed two loci on 12q13 and 16p13 that were identified by the independent genome-wide association studies in white populations, thus suggesting that these loci contribute to T1D susceptibility across different ethnic groups. In addition, these loci may also be associated with the cooccurrence of thyroid autoimmunity in T1D. | 18,940,880 |
HPV vaccines: are they the answer? | The burden of human papillomavirus (HPV)-associated ano-genital disease is significant but the ability to generate HPV virus-like particles by the synthesis and self-assembly in vitro of the major virus coat protein L1 has transformed our prospects for preventing benign and malignant ano-genital disease caused by the common genital HPV types. Peer reviewed journals. Two HPV L1 vaccines have been developed, a quadrivalent HPV 6/11/16/18, and a bivalent HPV 16/18 product. Both vaccines are very immunogenic and well tolerated. They have been shown in the various randomized Control trials to be very effective at preventing infection and premalignant disease related to the vaccine HPV genotypes in women who were DNA negative and sero negative for the vaccine HPV types at base line. The protection against disease generated by the vaccines persists for at least 5 years. HPV vaccines containing HPV 6/11 will reduce the incidence of genital warts by 80-90% in the medium term. The vaccines will reduce but not eliminate the risk of cervical cancer since at the present they only target two of the oncogenic genital types. Cervical cancer screening programmes will remain as important secondary interventions for cervical cancer even in vaccinated populations. The duration of protection remains unknown but there is evidence of good immune memory, it is possible that protection will be long lasting. The primary target group for cost effective immunization with HPV vaccines are peri-pubertal females. There may be benefit in vaccinating other groups (men, sexually active women of all ages) but the cost effectiveness of these interventions will need to be evaluated. In societies in which organized screening programmes are not available, HPV vaccines are probably the most realistic intervention against HPV-associated disease. Second generation vaccines that offer protection against additional types, are thermostable and delivered by non-injection methods are an important area of investigation. | 18,940,889 |
Substitution of Brown Norway chromosome 16 preserves cardiac function with aging in a salt-sensitive Dahl consomic rat. | Determination of the genetic factors that control the progression of left ventricular hypertrophy (LVH) to heart failure has been difficult despite extensive study in animal models. Here we have characterized a consomic rat model of LVH resulting from the introgression of chromosome 16 from the normotensive Brown Norway (BN) rat onto the genetic background of the Dahl salt-sensitive (SS/Mcwi) rat by marker assisted breeding. The SS-16BN/Mcwi consomic rats are normotensive but display LVH equivalent to the hypertensive SS/Mcwi rats at early ages. In this study we tracked the development of LVH by echocardiography and analyzed changes in cardiac function and morphology with aging in the SS-16BN/Mcwi, SS/Mcwi, and BN to determine if the consomic SS-16BN/Mcwi was a model of hypertrophic cardiomyopathy (HCM). Aging SS-16BN/Mcwi rats showed no evidence of heart failure or impaired cardiac function upon extensive analysis of left ventricle function by echocardiography and pressure-volume relationships, while their parental SS/Mcwi experienced deterioration in function between 18 and 36 wk of age. In addition aging SS-16BN/Mcwi did not exhibit tissue remodeling common to pathological hypertrophy and HCM such as increased fibrosis and reduced capillary density in the myocardium. In fact, SS-16BN/Mcwi were better protected from developing LV fibrosis with age than either the hypertensive SS/Mcwi or normotensive BN parental strains. This suggests that a gene or genes on chromosome 16 may be involved with both blood pressure regulation and preservation of cardiac function with aging. | 18,940,898 |
The association of acute exercise-induced ischaemia with systemic vasodilator function in patients with peripheral arterial disease. | Patients with peripheral arterial disease (PAD) frequently experience ischaemic attacks of the affected tissues during exercise. The present study assesses the association of transient exercise-induced leg ischaemia with vasodilator function of the clinically unaffected brachial artery over the course of 4 hours. Thirty male patients with symptomatic PAD and 14 age- and sex-matched healthy controls were included in the study. They performed a treadmill exercise until intolerable exercise-induced ischaemic pain occurred in the affected lower extremity, or for at most 10 min. Flow-mediated dilation (FMD) of the brachial artery was measured at baseline, 30 minutes, 2 hours and 4 hours after exercise. Baseline FMD values were significantly diminished in patients (7.03 +/- 1.99% vs 8.22 +/- 1.60% in controls, p = 0.009). A significant decrease in FMD was observed in patients after exercise (at 30 minutes: 3.92 +/- 1.78% vs 7.03 +/- 1.99% at baseline, p < 0.001; at 2 hours: 6.36 +/- 2.12% vs 7.03 +/- 1.99% at baseline, p = 0.005), followed by a gradual return to its baseline value, whereas FMD in controls non-significantly increased after exercise. The difference in the pattern of FMD change over time between patients and controls was significant (p < 0.001). This study shows that in PAD patients ischaemia during intermittent claudication is related to a transitory functional deterioration of the distant arteries. This indicates the harmful systemic effects of repeated ischaemic attacks during exercise and might explain the generalized and advanced nature of atherosclerotic disease in PAD patients. | 18,940,901 |
Delayed plasticity of inhibitory neurons in developing visual cortex. | During postnatal development, altered sensory experience triggers the rapid reorganization of neuronal responses and connections in sensory neocortex. This experience-dependent plasticity is disrupted by reductions of intracortical inhibition. Little is known about how the responses of inhibitory cells themselves change during plasticity. We investigated the time course of inhibitory cell plasticity in mouse primary visual cortex by using functional two-photon microscopy with single-cell resolution and genetic identification of cell type. Initially, local inhibitory and excitatory cells had similar binocular visual response properties, both favoring the contralateral eye. After 2 days of monocular visual deprivation, excitatory cell responses shifted to favor the open eye, whereas inhibitory cells continued to respond more strongly to the deprived eye. By 4 days of deprivation, inhibitory cell responses shifted to match the faster changes in their excitatory counterparts. These findings reveal a dramatic delay in inhibitory cell plasticity. A minimal linear model reveals that the delay in inhibitory cell plasticity potently accelerates Hebbian plasticity in neighboring excitatory neurons. These findings offer a network-level explanation as to how inhibition regulates the experience-dependent plasticity of neocortex. | 18,940,923 |
Current concepts in instrumented knee-laxity testing. | Instrumented knee laxity testing devices have been used in both the clinical and research setting to evaluate persons with injuries about the knee. The ability to accurately and reproducibly quantify knee motion has the potential to greatly benefit both clinical practice and research by improving the validity of the research involving treatment of knee-ligament injuries. Systematic review; Level of evidence, 4. A thorough literature review was performed, and a systematic overview is provided evaluating the methods of use and the evidence for the use of instrumented knee laxity testing devices. Devices that provide measurements of knee laxity have evolved during the past 30 years. The authors describe in detail their proper use and the best estimates of their validity based on clinical studies. The review suggests that the KT-1000 knee arthrometer and the Rolimeter provide best results when testing anterior laxity at the knee, whereas the Telos device is superior for the assessment of posterior laxity. | 18,940,931 |
IL-18 induces a marked gene expression profile change and increased Ccl1 (I-309) production in mouse mucosal mast cell homologs. | Helminthic infections, which are particularly common in the developing world, are associated with the accumulation of mucosal mast cells (MMCs) in the epithelial layer of the gut. Although intestinal parasite infection models argue that IL-18 plays a role in MMC differentiation and function, the direct effect of IL-18 on MMCs is still not well understood. To clarify the role of IL-18 in mast cell biology, we analyzed gene expression changes in MMCs in vitro. DNA microarray technology uncovered a group of chemokines regulated by IL-18, among which Ccl1 (I-309, TCA-3) showed the highest up-regulation. Ccl1 induction was only transient in mast cells and was characteristic for both immature and mature MMCs, but not for connective tissue-type mast cells. IL-18 exerts its Ccl1-inducing effect in MMCs primarily via the activation of NFkappaB. Moreover, IL-18 was effective both in the absence and the presence of IgE-antigen complex. The Ccl1 receptor (CCR8) is known to be expressed by T(h)2 cells and is involved in their recruitment. Our present findings suggest that IL-18 may contribute to mast cell-influenced Th2 responses by inducing Ccl1 production. | 18,940,934 |
LPS and proinflammatory cytokines decrease lipin-1 in mouse adipose tissue and 3T3-L1 adipocytes. | Infection and inflammation affect adipose triglyceride metabolism, resulting in increased plasma free fatty acid (FFA) and VLDL levels during the acute-phase response. Lipin-1, a multifunctional protein, plays a critical role in adipose differentiation, mitochondrial oxidation, and triglyceride synthesis. Here, we examined whether LPS [a Toll-like receptor (TLR)-4 activator], zymosan (a TLR-2 activator), and proinflammatory cytokines regulate lipin-1 in adipose tissue. LPS administration caused a marked decrease in the levels of lipin-1 mRNA and protein in adipose tissue. The decrease in lipin-1 mRNA levels occurred rapidly and lasted for at least 24 h. In contrast, lipin-2 and -3 mRNA levels did not change, suggesting specific repression of lipin-1. Zymosan similarly decreased lipin-1 mRNA without affecting lipin-2 or lipin-3 mRNA levels. To determine the pathways by which LPS repressed lipin-1, we examined the effect of proinflammatory cytokines on cultured adipocytes. In 3T3-L1 adipocytes, TNF-alpha, IL-1beta, and IFN-gamma, but not LPS or IL-6, caused a decrease in lipin-1 mRNA levels. Furthermore, TNF-alpha and IL-1beta administration also decreased mRNA levels of lipin-1 in adipose tissue in mice. Importantly, the LPS-induced decrease in lipin-1 mRNA levels was significantly but not totally blunted in TNF-alpha/IL-1 receptor-null mice compared with controls, suggesting key roles for TNF-alpha/IL-1beta and other cytokines in mediating LPS-induced repression of lipin-1. Together, our results demonstrate that expression of lipin-1, one of the essential triglyceride synthetic enzymes, was suppressed by LPS, zymosan, and proinflammatory cytokines in mouse adipose tissue and in cultured 3T3-L1 adipocytes, which could contribute to a decrease in the utilization of FFA to synthesize triglycerides in adipose tissue, thus promoting the release of FFA into the circulation. | 18,940,942 |
Inhalation dosimetry of diacetyl and butyric acid, two components of butter flavoring vapors. | Occupational exposure to butter flavoring vapors (BFV) is associated with significant pulmonary injury. The goal of the current study was to characterize inhalation dosimetric patterns of diacetyl and butyric acid, two components of BFV, and to develop a hybrid computational fluid dynamic-physiologically based pharmacokinetic model (CFD-PBPK) to describe these patterns. Uptake of diacetyl and butyric acid vapors, alone and in combination, was measured in the upper respiratory tract of anesthetized male Sprague-Dawley rats under constant velocity flow conditions and the uptake data were used to validate the CFD-PBPK model. Diacetyl vapor (100 or 300 ppm) was scrubbed from the airstream with 76-36% efficiency at flows of 100-400 ml/min. Butryic acid (30 ppm) was scrubbed with >90% efficiency. Concurrent exposure to butyric acid resulted in a small but significant reduction of diacetyl uptake (36 vs. 31%, p < 0.05). Diacetyl was metabolized in nasal tissues in vitro, likely by diacetyl reductase, an enzyme known to be inhibited by butyric acid. The CFD-PBPK model closely described diacetyl uptake; the reduction in diacetyl uptake by butyric acid could be explained by inhibition of diacetyl reductase. Extrapolation to the human via the model suggested that inspired diacetyl may penetrate to the intrapulmonary airways to a greater degree in the human than in the rat. Thus, based on dosimetric relationships, extrapulmonary airway injury in the rat may be predictive of intrapulmonary airway injury in humans. Butyric acid may modulate diacetyl toxicity by inhibiting its metabolism and/or altering its inhalation dosimetric patterns. | 18,940,962 |
Towards an understanding of sex differences in functional outcome following moderate to severe traumatic brain injury: a systematic review. | A clear understanding of the impact sex differences play in clinical traumatic brain injury (TBI) outcome remains elusive. Animal research suggests that females have better functional outcomes following TBI than males. Therefore, this paper aims to systematically review all studies that have examined sex differences in functional outcome measures following moderate to severe TBI in humans. It was predicted that women would exhibit better functional outcome than men. A predefined study selection criteria was adopted to screen studies eligible for inclusion. A comprehensive and systematic search of various databases, up to the end of April 2007, was undertaken. Two independent reviewers screened studies for eligibility. Selected studies were assessed for methodological quality. 13 studies were included. Because of the heterogeneity of the functional outcome measures and lack of appropriate statistical information, a qualitative analysis was performed. More than half of the papers were considered high quality. Strong evidence was found to suggest that women do not have better functional outcome than men following moderate to severe TBI. The results of this review are contrary to the suggestions from animal literature. Consideration of factors such as the woman patient's hormonal status at the time of injury and other sources of heterogeneity such as age and injury severity should be addressed in future prospective studies. | 18,940,988 |
Dynamic contrast-enhanced MRI for prediction of breast cancer response to neoadjuvant chemotherapy: initial results. | The aim of this study was to establish changes in contrast-enhanced MRI of breast cancer during neoadjuvant chemotherapy that are indicative of pathology outcome. In 54 patients with breast cancer, dynamic contrast-enhanced MRI was performed before chemotherapy and after two chemotherapy cycles. Imaging was correlated with final histopathology. Multivariate analysis with cross-validation was performed on MRI features describing kinetics and morphology of contrast uptake in the early and late phases of enhancement. Receiver operating characteristic (ROC) analysis was used to develop a guideline that switches patients at high risk for incomplete remission to a different chemotherapy regimen while maintaining first-line therapy in 95% of patients who are not at risk (i.e., high specificity). Change in largest diameter of late enhancement during chemotherapy was the single most predictive MRI characteristic for tumor response in multivariate analysis (A(z) [area under the ROC curve] = 0.73, p < 0.00001). Insufficient (< 25%) decrease in largest diameter of late enhancement during chemotherapy was most indicative of residual tumor at final pathology. Using this criterion, the fraction of unfavorable responders indicated by MRI was 41% (22/54). Approximately half (44%, 14/32) of the patients who showed favorable response at MRI achieved complete remission at pathology. Conversely, 95% (21/22) of patients who showed unfavorable response at MRI had residual tumor at pathology. Reduction of less than 25% in largest diameter of late enhancement during neoadjuvant chemotherapy shows the potential to predict residual tumor after therapy with high specificity. | 18,941,065 |
Multiple hepatic adenomas associated with liver steatosis at CT and MRI: a case-control study. | The objective of our study was to investigate the relationship between hepatic adenoma and liver steatosis. Radiology and pathology records from January 1999 to March 2007 were reviewed to identify 24 patients (22 women and two men; mean age, 40 years) with a pathology-proven diagnosis of hepatic adenoma (mean size +/- SD, 7.2 +/- 3.7 cm) who underwent helical contrast-enhanced CT (n = 23) and/or gadolinium-enhanced MRI (n = 8). The control group was composed of 24 patients of similar age and sex (21 women and three men; mean age, 43 years) with hepatic hemangioma who underwent CT or MR evaluation during the same time period. Two radiologists independently interpreted the imaging studies to determine the number of lesions and whether steatosis was present. The difference in prevalence of steatosis between the adenoma group versus the control group and the difference between patients with a single hepatic adenoma versus those with multiple hepatic adenomas were assessed (chi-square test). Hepatic steatosis was present in 14 of 24 patients (58%) with hepatic adenoma versus seven of 24 patients (29%) with hemangioma (p = 0.042). Steatosis was more common in patients with multiple hepatic adenomas (9/11, 82%) than in those with a single hepatic adenoma (5/13, 38%) (p = 0.047). Hepatic adenomas occur more frequently and more often are multiple in patients with hepatic steatosis. | 18,941,081 |
Properties and structure-function relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibody. | Veltuzumab is a humanized anti-CD20 monoclonal antibody with complementarity-determining regions (CDRs) identical to rituximab, except for one residue at the 101st position (Kabat numbering) in CDR3 of the variable heavy chain (V(H)), having aspartic acid (Asp) instead of asparagine (Asn), with framework regions of epratuzumab, a humanized anti-CD22 antibody. When compared with rituximab, veltuzumab has significantly reduced off-rates in 3 human lymphoma cell lines tested, as well as increased complement-dependent cytotoxicity in 1 of 3 cell lines, but no other in vitro differences. Mutation studies confirmed that the differentiation of the off-rate between veltuzumab and rituximab is related to the single amino acid change in CDR3-V(H). Studies of intraperitoneal and subcutaneous doses in mouse models of human lymphoma and in normal cynomolgus monkeys disclosed that low doses of veltuzumab control tumor growth or deplete circulating or sessile B cells. Low- and high-dose veltuzumab were significantly more effective in vivo than rituximab in 3 lymphoma models. These findings are consistent with activity in patients with non-Hodgkin lymphoma given low intravenous or subcutaneous doses of veltuzumab. Thus, changing Asn(101) to Asp(101) in CDR3-V(H) of rituximab is responsible for veltuzumab's lower off-rate and apparent improved potency in preclinical models that could translate into advantages in patients. | 18,941,114 |
Depressed mood, positive affect, and heart rate variability in patients with suspected coronary artery disease. | To test associations between heart rate variability (HRV), depressed mood, and positive affect in patients with suspected coronary artery disease (CAD). Depression is associated with impaired HRV post acute cardiac events, but evidence in patients with stable coronary artery disease (CAD) is inconsistent. Seventy-six patients (52 men, 24 women; mean age = 61.1 years) being investigated for suspected CAD on the basis of symptomatology and positive noninvasive tests, completed 24-hour electrocardiograms. The Beck Depression Inventory (BDI) was administered, and positive and depressed affect was measured over the study period with the Day Reconstruction Method (DRM). A total of 46 (60.5%) patients were later found to have definite CAD. HRV was analyzed, using spectral analysis. Typical diurnal profiles of HRV were observed, with greater normalized high frequency (HF) and lower normalized low frequency (LF) power in the night compared with the day. BDI depression scores were not consistently associated with HRV. But positive affect was associated with greater normalized HF power (p = .039) and reduced normalized LF power (p = .007) independently of age, gender, medication with beta blockers, CAD status, body mass index, smoking, and habitual physical activity level. In patients with definite CAD, depressed affect assessed using the DRM was associated with reduced normalized HF power and heightened normalized LF power (p = .007) independently of covariates. Relationships between depression and HRV in patients with CAD may depend on affective experience over the monitoring period. Enhanced parasympathetic cardiac control may be a process through which positive affect protects against cardiovascular disease. | 18,941,130 |
Systems- and molecular-level elucidation of signaling processes through chemistry. | Complete understanding of the molecular mechanisms of signal transduction is a major focus of research in the postgenomic era. Efforts to realize this goal have benefited from interdisciplinary approaches, specifically through the development of new technologies. Several groups have now described new chemical strategies to probe signaling with broadly different degrees of focus. The first report employs an enzymatic tagging strategy to monitor global proteolytic cleavage events that occur during apoptosis. The second study illustrates a general method to functionally characterize a specific kinase through the identification of its substrates. Finally, the third report describes a synthetic route to generate ubiquitinated proteins and demonstrates the utility of protein chemistry in understanding the detailed biochemical mechanisms of signaling. Together, these papers highlight the power of chemical tools to examine specific networks, thereby expanding our understanding of signaling pathways. | 18,941,136 |
Estimation of the size of the alloreactive NK cell repertoire: studies in individuals homozygous for the group A KIR haplotype. | Stem cell transplantation across HLA barriers may trigger NK cell-mediated graft-vs-leukemia effects leading to improved survival for patients with hematological malignancies. However, the genetic algorithm based on killer cell Ig-like receptor (KIR) and HLA genes used to predict NK cell alloreactivity have yielded discrepant results. Accordingly, it has been difficult to define transplantation settings that favor NK cell alloreactivity. In this study, we have used multiparameter flow cytometry to simultaneously analyze the cell surface expression of all four major inhibitory KIR and CD94/NKG2A to determine the size of the alloreactive NK cell repertoires in 31 individuals homozygous for the group A KIR haplotype. We observed a vast variability in the frequencies of cells with an alloreactive potential, ranging from 0 to 62% of the total NK cell population depending on which, and how many, KIR ligands were missing in theoretical recipients. This analysis required a functional examination of KIR3DL2-single positive NK cells, showing that this subset was hyporesponsive in individuals harboring the cognate ligands HLA-A3/A11. The results provide new insights into the variability of the functional alloreactive NK cell repertoire and have implications for donor selection in hematopoietic stem cell transplantation and adoptive NK cell-based immunotherapy. | 18,941,190 |
Mycobacterium bovis bacille Calmette-Guérin infection in the CNS suppresses experimental autoimmune encephalomyelitis and Th17 responses in an IFN-gamma-independent manner. | Multiple sclerosis and an animal model resembling multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), are inflammatory demyelinating diseases of the CNS that are suppressed by systemic mycobacterial infection in mice and BCG vaccination in humans. Host defense responses against Mycobacterium in mice are influenced by T lymphocytes and their cytokine products, particularly IFN-gamma, which plays a protective regulatory role in EAE. To analyze the counter-regulatory role of mycobacterial infection-induced IFN-gamma in the CNS on the function of the pathological Th17 cells and the clinical outcome of EAE, we induced EAE in mice that were intracerebrally infected with Mycobacterium bovis bacille Calmette-Guerin (BCG). In this study, we demonstrate that intracerebral (i.c.) BCG infection prevented inflammatory cell recruitment to the spinal cord and suppressed the development of EAE. Concomitantly, there was a significant decrease in the frequency of myelin oligodendrocyte glycoprotein-specific IFN-gamma-producing CD4(+) T cells in the CNS. IL-17(+)CD4(+) T cell responses were significantly suppressed in i.c. BCG-infected mice following EAE induction regardless of T cell specificity. The frequency of Foxp3(+)CD4(+) T cells in these mice was equivalent to that of control mice. Intracerebral BCG infection-induced protection of EAE and suppression of myelin oligodendrocyte glycoprotein-specific IL-17(+)CD4(+) T cell responses were similar in both wild-type and IFN-gamma-deficient mice. These data show that live BCG infection in the brain suppresses CNS autoimmunity. These findings also reveal that the regulation of Th17-mediated autoimmunity in the CNS can be independent of IFN-gamma-mediated mechanisms. | 18,941,210 |
Endoplasmic reticulum aminopeptidase associated with antigen processing regulates quality of processed peptides presented by MHC class I molecules. | Effective immune surveillance by CD8 T cells depends on the presentation of diverse peptides by MHC class I (pMHC I) molecules on the cell surface. The pMHC I repertoire is shaped in the endoplasmic reticulum (ER) by the ER aminopeptidase associated with Ag processing (ERAAP). The ERAAP activity is required for producing peptides of appropriate length for generating optimal pMHC I. Paradoxically, ERAAP also inhibits generation of certain peptides such as the SVL9 (SSVVGVWYL) peptide encoded by the H13(a) histocompatibility gene and presented by D(b) MHC by an unknown mechanism. In this study, we show that the presentation of the SVL9-D(b) complex is inhibited when other peptides compete for binding D(b). Conversely, improving the binding of SVL9 peptide to D(b) suppresses the inhibition. Interestingly, the inhibitory effect of competitor peptides is observed only when ERAAP is expressed in the same cells. Thus, ERAAP, in concert with MHC I molecules, regulates the quality of processed peptides presented on the cell surface. | 18,941,218 |
Polymorphic sites away from the Bw4 epitope that affect interaction of Bw4+ HLA-B with KIR3DL1. | KIR3DL1 is a polymorphic, inhibitory NK cell receptor specific for the Bw4 epitope carried by subsets of HLA-A and HLA-B allotypes. The Bw4 epitope of HLA-B*5101 and HLA-B*1513 is determined by the NIALR sequence motif at positions 77, 80, 81, 82, and 83 in the alpha(1) helix. Mutation of these positions to the residues present in the alternative and nonfunctional Bw6 motif showed that the functional activity of the Bw4 epitopes of B*5101 and B*1513 is retained after substitution at positions 77, 80, and 81, but lost after substitution of position 83. Mutation of leucine to arginine at position 82 led to loss of function for B*5101 but not for B*1513. Further mutagenesis, in which B*1513 residues were replaced by their B*5101 counterparts, showed that polymorphisms in all three extracellular domains contribute to this functional difference. Prominent were positions 67 in the alpha(1) domain, 116 in the alpha(2) domain, and 194 in the alpha(3) domain. Lesser contributions were made by additional positions in the alpha(2) domain. These positions are not part of the Bw4 epitope and include residues shaping the B and F pockets that determine the sequence and conformation of the peptides bound by HLA class I molecules. This analysis shows how polymorphism at sites throughout the HLA class I molecule can influence the interaction of the Bw4 epitope with KIR3DL1. This influence is likely mediated by changes in the peptides bound, which alter the conformation of the Bw4 epitope. | 18,941,220 |
Prolonged microglial cell activation and lymphocyte infiltration following experimental herpes encephalitis. | Experimental murine herpes simplex virus (HSV)-1 brain infection stimulates microglial cell-driven proinflammatory chemokine production which precedes the presence of brain-infiltrating systemic immune cells. In the present study, we investigated the phenotypes and infiltration kinetics of leukocyte trafficking into HSV-infected murine brains. Using real-time bioluminescence imaging, the infiltration of luciferase-positive splenocytes, transferred via tail vein injection into the brains of HSV-infected animals, was followed over an 18-day time course. Flow cytometric analysis of brain-infiltrating leukocytes at 5, 8, 14, and 30 days postinfection (d.p.i.), was performed to assess their phenotype. A predominantly macrophage (CD45(high)CD11b(+)Ly6C(high)) and neutrophil (CD45(high)CD11b(+)Ly6G(+)) infiltration was seen early during infection, with elevated levels of TNF-alpha mRNA expression. By 14 d.p.i., the phenotypic profile shifted to a predominantly lymphocytic (CD45(high)CD3(+)) infiltrate. This lymphocyte infiltrate was detected until 30 d.p.i., when infectious virus could not be recovered, with CD8(+) and CD4(+) T cells present at a 3:1 ratio, respectively. This T lymphocyte infiltration paralleled increased IFN-gamma mRNA expression in the brain. Activation of resident microglia (CD45(int)CD11b(+)) was also detected until 30 d.p.i., as assessed by MHC class II expression. Activated microglial cells were further identified as the predominant source of IL-1beta. In addition, infected mice given primed immunocytes at 4 d.p.i. showed a significant increase in mortality. Taken together, these results demonstrate that intranasal infection results in early macrophage and neutrophil infiltration into the brain followed by prolonged microglial activation and T lymphocyte retention. Similar prolonged neuroimmune activation may contribute to the neuropathological sequelae observed in herpes encephalitis patients. | 18,941,232 |
12/15-Lipoxygenase regulates the inflammatory response to bacterial products in vivo. | The peritoneal macrophage (Mphi) is the site of greatest 12/15-lipoxygenase (12/15-LOX) expression in the mouse; however, its immunoregulatory role in this tissue has not been explored. Herein, we show that 12/15-LOX is expressed by 95% of resident peritoneal CD11b(high) cells, with the remaining 5% being 12/15-LOX(-). 12/15-LOX(+) cells are phenotypically defined by high F4/80, SR-A, and Siglec1 expression, and enhanced IL-10 and G-CSF generation. In contrast, 12/15-LOX(-) cells are a dendritic cell population. Resident peritoneal Mphi numbers were significantly increased in 12/15-LOX(-/-) mice, suggesting alterations in migratory trafficking or cell differentiation in vivo. In vitro, Mphi from 12/15-LOX(-/-) mice exhibit multiple abnormalities in the regulation of cytokine/growth factor production both basally and after stimulation with Staphylococcus epidermidis cell-free supernatant. Resident adherent cells from 12/15-LOX(-/-) mice generate more IL-1, IL-3, GM-CSF, and IL-17, but less CCL5/RANTES than do cells from wild-type mice, while Staphylococcus epidermidis cell-free supernatant-elicited 12/15-LOX(-/-) adherent cells release less IL-12p40, IL-12p70, and RANTES, but more GM-CSF. This indicates a selective effect of 12/15-LOX on peritoneal cell cytokine production. In acute sterile peritonitis, 12/15-LOX(+) cells and LOX products were cleared, then reappeared during the resolution phase. The peritoneal lavage of 12/15-LOX(-/-) mice showed elevated TGF-beta1, along with increased immigration of monocytes/Mphi, but decreases in several cytokines including RANTES/CCL5, MCP-1/CCL2, G-CSF, IL-12-p40, IL-17, and TNF-alpha. No changes in neutrophil or lymphocyte numbers were seen. In summary, endogenous 12/15-LOX defines the resident MPhi population and regulates both the recruitment of monocytes/Mphi and cytokine response to bacterial products in vivo. | 18,941,242 |
Differential regulation of chemokines by IL-17 in colonic epithelial cells. | The IL-23/IL-17 pathway plays an important role in chronic inflammatory diseases, including inflammatory bowel disease. In inflammatory bowel disease, intestinal epithelial cells are an important source of chemokines that recruit inflammatory cells. We examined the effect of IL-17 on chemokine expression of HT-29 colonic epithelial cells. IL-17 strongly repressed TNF-alpha-stimulated expression of CXCL10, CXCL11, and CCL5, but synergized with TNF-alpha for induction of CXCL8, CXCL1, and CCL20 mRNAs. For CXCL10, IL-17 strongly inhibited promoter activity but had no effect on mRNA stability. In contrast, for CXCL8, IL-17 slightly decreased promoter activity but stabilized its normally unstable mRNA, leading to a net increase in steady-state mRNA abundance. IL-17 synergized with TNF-alpha in transactivating the epidermal growth factor receptor (EGFR) and in activating ERK and p38 MAPK. The p38 and ERK pathway inhibitors SB203580 and U0126 reversed the repressive effect of IL-17 on CXCL10 mRNA abundance and promoter activity and also reversed the inductive effect of IL-17 on CXCL8 mRNA, indicating that MAPK signaling mediates both the transcriptional repression of CXCL10 and the stabilization of CXCL8 mRNA by IL-17. The EGFR kinase inhibitor AG1478 partially reversed the effects of IL-17 on CXCL8 and CXCL10 mRNA, demonstrating a role for EGFR in downstream IL-17 signaling. The overall results indicate a positive effect of IL-17 on chemokines that recruit neutrophils (CXCL8 and CXCL1), and Th17 cells (CCL20). In contrast, IL-17 represses expression of CXCL10, CXCL11, and CCR5, three chemokines that selectively recruit Th1 but not other effector T cells. | 18,941,244 |
Activation of an immunoregulatory and antiviral gene expression program in poly(I:C)-transfected human neutrophils. | Neutrophils, historically known for their involvement in acute inflammation, are also targets for infection by many different DNA and RNA viruses. However, the mechanisms by which they recognize and respond to viral components are poorly understood. Polyinosinic:polycytidylic acid (poly(I:C)) is a synthetic mimetic of viral dsRNA that is known to interact either with endosomal TLR3 (not expressed by human neutrophils) or with cytoplasmic RNA helicases such as melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIG-I). In this study, we report that intracellularly administered poly(I:C) stimulates human neutrophils to specifically express elevated mRNA levels encoding type I IFNs, immunoregulatory cytokines, and chemokines, such as TNF-alpha, IL-12p40, CXCL10, CXCL8, CCL4, and CCL20, as well as classical IFN-responsive genes (IRG), including IFIT1 (IFN-induced protein with tetratricopeptide repeats 1)/IFN-stimulated gene (ISG)56, G1P2/ISG15, PKR (dsRNA-dependent protein kinase), and IFN-regulatory factor (IRF)7. Investigations into the mechanisms whereby transfected poly(I:C) promotes gene expression in neutrophils uncovered a crucial involvement of the MAPK-, PKR-, NF-kappaB-, and TANK (TNF receptor-associated NF-kappaB kinase)-binding kinase (TBK1)/IRF3-signaling transduction pathways, as illustrated by the use of specific pharmacological inhibitors. Consistent with the requirement of the cytoplasmic dsRNA pathway for antiviral signaling, human neutrophils were found to constitutively express significant levels of both MDA5 and RIG-I, but not TLR3. Accordingly, neutrophils isolated from MDA5-deficient mice had a partial impairment in the production of IFN-beta and TNF-alpha upon infection with encephalomyocarditis virus. Taken together, our data demonstrate that neutrophils are able to activate antiviral responses via helicase recognition, thus acting at the frontline of immunity against viruses. | 18,941,247 |
Issues in the measurement of social determinants of health. | This article focuses on the measurement of the social determinants of health, and specifically on issues relating to two key variables relevant to the analysis of public health information: poverty and inequality. Although the paper has been written from the perspective of economics, the discipline of the two authors, it is also of relevance to researchers in other disciplines. It is argued that there is a need to ensure that, when considering measurement in this largely neglected area of research, sufficient thought is given to the relationships that are being examined or assessed. We argue further that any attempt at measurement in this area must take into account the historical backdrop and the complex nature of the relationships between these key variables. | 18,941,263 |
Discovery and synthetic applications of novel silicon-carbon bond cleavage reactions based on the coordination number change of organosilicon compounds. | Some synthetically useful transformations of organosilicon compounds have been developed since the mid 1970s, based on the new concept that the silicon-carbon bonds are activated toward electrophilic cleavage via the formation of penta- and hexa-coordinate species. This review mainly consists of the following aspects: (1) a general concept for the activation of the silicon-carbon bond via penta- and hexa-coordinate species, (2) synthetic application of hexa-coordinate organopentafluorosilicates, and (3) development of the H(2)O(2) oxidation of the silicon-carbon bond and its synthetic applications via the intramolecular hydrosilylation, silicon-tethered intramolecular radical cyclization and Diels-Alder reaction, and some silicon-containing organometallic reagents for nucleophilic hydroxymethylation and hydroxyallylation synthons.(Communicated by Hitosi NOZAKI, M.J.A.). | 18,941,292 |
Assessment of renal function in elderly patients. | The proportion of elderly individuals is growing rapidly in all societies and the incidence of chronic kidney disease among elderly people increases constantly. Accurate monitoring of kidney function, that is, glomerular filtration rate, in elderly people is therefore of considerable clinical interest in order to detect individuals who are at risk for developing chronic kidney disease. This paper reviews the currently used methods for assessment of glomerular filtration rate and their utility in elderly people. Serum creatinine is an unreliable indicator of glomerular filtration rate in elderly people, particularly in those who are sick or malnourished or both. Thus, more reliable glomerular filtration rate estimates should be employed whenever indicated, for example, timed creatinine clearance, serum creatinine-based equations such as the Modification of Diet in Renal Disease formula, or serum cystatin C. However, no single method may be satisfactory. Accurate assessment of renal function is a prerequisite for the correct management of elderly people at risk of developing chronic kidney disease; for example, those with diabetes, hypertension, and other clinical conditions that may considerably accelerate an age-related decrease in glomerular filtration rate. The Modification of Diet in Renal Disease formula should be used in most cases, but serum cystatin C or even an isotope clearance method may be helpful if there is concern about the reliability of the Modification of Diet in Renal Disease equation in an elderly individual in whom precise assessment of kidney function is mandatory. | 18,941,354 |
Asymmetric dimethylarginine: a novel marker of risk and a potential target for therapy in chronic kidney disease. | Asymmetric dimethylarginine (ADMA) is a naturally occurring amino acid that reduces the bioavailability of nitric oxide. ADMA opposes important antiatherosclerotic effects of nitric oxide. ADMA not only correlates with traditional and nontraditional risk factors but is also considered a common pathway mediating the adverse vascular effects of traditional and nontraditional risk factors. Over the past 15 years, ADMA has generated increasing interest from both clinical scientist and basic researchers. The present study summarizes the latest developments in the field. Modulating (increasing) activity of dimethylamine dimethylaminohydrolase, the main enzyme metabolizing ADMA, emerges as a possible therapeutic option to lower ADMA and favorably influence organ dysfunction. These preclinical findings are thought to be of major importance as ADMA predicts cardiovascular events and mortality in the general population and in patients with chronic kidney disease. Also, ADMA uniformly predicts the progression of moderate and severe chronic kidney disease. Symmetrical dimethylarginine, the structural isomer of ADMA, which was mistakenly thought to be without biological relevance, indicates the degree of renal impairment. ADMA also beautifully explains many facets of the pathophysiology of chronic kidney disease. Future preclinical and especially clinical studies are required to prove the importance of ADMA in renal and cardiovascular disease. | 18,941,355 |
Mullerian adenosarcoma: a clinicopathologic and immunohistochemical study of 55 cases challenging the existence of adenofibroma. | Mullerian adenosarcomas are rare mixed tumors of low malignant potential that occur mainly in the uterus and also in extrauterine locations. Microscopically, they may be difficult to distinguish from adenofibromas. In this clinicopathologic study of 55 adenosarcomas, the mean patient age was 50 years (range: 13 to 83 y). Thirty-seven tumors were of the uterine corpus, 11 of the cervix, 4 of the ovary, and 1 each of the fallopian tube, vagina, and Douglas peritoneum. Abdominal pain and vaginal bleeding were the usual complaints. Treatment was known in 50 patients: 10 had polypectomy, 1 cone biopsy, and 39 hysterectomy, which was accompanied by bilateral salpingo-oophorectomy in 24 and lymphadenectomy in 4. Five patients had radiotherapy and 2 of them had chemotherapy. Stage was known in 41 cases. Of 30 tumors of the uterine corpus, 17 were stage IA, 11 stage IB, 1 stage IC, and 1 stage IIIC. Four cervical tumors were stage IB. Three of the 4 ovarian tumors were stage IA and the other was stage IIIC. The tumor of the fallopian tube was stage IC, and the tumors of the vagina and recto-uterine pouch were confined to their site of origin. Most uterine tumors were polypoid masses ranging from 1 to 20 cm (mean: 6.5 cm). Microscopically, sarcomatous overgrowth was found in 18 cases (33%), heterologous elements in 13 (24%), and sex cordlike differentiation in 7 (13%). Fourteen of 30 uterine tumors (47%) had myometrial invasion that was minimal in 5, involved one-third of the myometrial thickness in 7, and more than 50% in 2. Of 4 cervical tumors, 2 were endocervical polyps, 1 invaded one-third of the cervical wall, and the other invaded its full thickness. Follow-up information (2 mo to 18 y; average: 7.5 y) was available in 29 patients. Six developed metastases and 5 of them died of tumor. Four had adenosarcomas with sarcomatous overgrowth; however, the other 2 patients had typical low-grade adenosarcomas of the uterine corpus and cervix, respectively, exhibiting only mild nuclear atypia of the stromal component and </=2 mitotic figures/10 high power fields. Both were initially underdiagnosed as adenofibromas. The finding of such cases, which raises the controversy of whether or not adenofibroma exists as a tumor entity, prompted us to make a comparative immunohistochemical analysis of 23 typical adenosarcomas, 8 adenosarcomas with sarcomatous overgrowth, and 29 benign and malignant related lesions, including 7 clinically benign adenofibromas. Adenosarcomas with sarcomatous overgrowth showed strong immunoreaction for Ki-67 and p53 and loss of CD10 and progesterone receptors immunostaining; in contrast, the immunoreaction for these tumor markers in typical adenosarcomas without sarcomatous overgrowth was similar to that of adenofibromas associated with favorable outcome and other benign lesions such as endometrial polyps and endometriosis. These findings suggest that some of the tumors currently classified as adenofibromas, on the basis of their low mitotic count and lack of significant nuclear atypia, are, in fact, well-differentiated adenosarcomas. | 18,941,402 |
Increased apparent diffusion coefficients on MRI linked with matrix metalloproteinases and edema in white matter after bilateral carotid artery occlusion in rats. | White matter (WM) injury after bilateral common carotid artery occlusion (BCAO) in rat is associated with disruption of the blood-brain barrier (BBB) by matrix metalloproteinases (MMPs). We hypothesized that WM injury as seen on magnetic resonance imaging (MRI) would correlate with regions of increased MMP activity. MRI was performed 3 days after BCAO surgery in rats. Apparent diffusion coefficients (ADC) were calculated and vascular permeability was quantified by the multiple-time graphical analysis (MTGA) method, using gadolinium-diethylenetriamine pentaacid (Gd-DTPA). After MRI, one group of animals had BBB permeability measured in the WM with (14)C-sucrose, and another had Evans blue (EB) injected for fluorescent microscopy for MMP-2, MMP-9, tight junction proteins (TJPs), and in situ zymography. We found that ADC values were increased in WM in BCAO rats compared with controls (P<0.05). WM with increased ADC had leakage of EB. MMP-2 and MMP-9 activity on in situ zymograms corresponded with leakage of EB. Although increased permeability to EB could be visualized, permeability quantification with (14)C-sucrose and Gd-DTPA failed to show increases and TJPs were intact. We propose that increased ADC, which is a marker of vasogenic edema, is related to activity of MMP-2 and MMP-9. MRI provides unique information that can be used to guide tissue studies of WM injury. | 18,941,468 |
Decline of melanism in two British moths: spatial, temporal and inter-specific variation. | The decline in industrial melanism over the last quarter century constitutes an exceptional case of an evolutionary change, varying in both time and space, and between species. In Biston betularia and Odontoptera bidentata, the change in melanic frequency is closely replicated at two sites 0.5 km apart. Between seven sites 50-100 km apart, there is heterogeneity in both the speed and timing of change. At sites that were heavily industrialized, the change is faster, from an initially higher frequency, and starts later than at sites which are more rural.We propose a method for estimating systematic change during sigmoid declines in melanic frequencies. This fails to show any significant change over time in selective coefficients. It is concluded that the overall pattern of change has been driven largely by events in the most polluted and industrialized parts of the country. Although migration may contribute to the estimated selective values, natural selection is the only credible explanation for the overall decline. | 18,941,471 |
Enantioselective nucleophilic difluoromethylation of aromatic aldehydes with Me3SiCF2SO2Ph and PhSO2CF2H reagents catalyzed by chiral quaternary ammonium salts. | Although the nucleophilic difluoromethylation of aldehydes, ketones, and imines has been realized with PhSO(2)CF(2)H and related reagents, there are still no reports on the enantioselective nucleophilic reactions. With a chiral quaternary ammonium salt as the catalyst and KOH as the base, we describe the first enantioselective difluoromethylation of aromatic aldehydes with PhSO(2)CF(2)H or Me(3)SiCF(2)SO(2)Ph. The enantioselectivity is substrate-dependent and for 2-chlorinated benzaldehyde an ee up to 64% was obtained. These results provide some insights into the enantioselective nucleophilic difluoromethylation chemistry, which will stimulate further progress in this field. | 18,941,491 |
Long lasting persistence of Bacillus thuringiensis Subsp. israelensis (Bti) in mosquito natural habitats. | The detrimental effects of chemical insecticides on the environment and human health have lead to the call for biological alternatives. Today, one of the most promising solutions is the use of spray formulations based on Bacillus thuringiensis subsp. israelensis (Bti) in insect control programs. As a result, the amounts of Bti spread in the environment are expected to increase worldwide, whilst the common belief that commercial Bti is easily cleared from the ecosystem has not yet been clearly established. In this study, we aimed to determine the nature and origin of the high toxicity toward mosquito larvae found in decaying leaf litter collected in several natural mosquito breeding sites in the Rhône-Alpes region. From the toxic fraction of the leaf litter, we isolated B. cereus-like bacteria that were further characterized as B. thuringiensis subsp. israelensis using PCR amplification of specific toxin genes. Immunological analysis of these Bti strains showed that they belong to the H14 group. We finally used amplified length polymorphism (AFLP) markers to show that the strains isolated from the leaf litter were closely related to those present in the commercial insecticide used for field application, and differed from natural worldwide genotypes. Our results raise the issue of the persistence, potential proliferation and environmental accumulation of human-spread Bti in natural mosquito habitats. Such Bti environmental persistence may lengthen the exposure time of insects to this bio-insecticide, thereby increasing the risk of resistance acquisition in target insects, and of a negative impact on non-target insects. | 18,941,501 |
Glucose uptake and its effect on gene expression in prochlorococcus. | The marine cyanobacteria Prochlorococcus have been considered photoautotrophic microorganisms, although the utilization of exogenous sugars has never been specifically addressed in them. We studied glucose uptake in different high irradiance- and low irradiance-adapted Prochlorococcus strains, as well as the effect of glucose addition on the expression of several glucose-related genes. Glucose uptake was measured by adding radiolabelled glucose to Prochlorococcus cultures, followed by flow cytometry coupled with cell sorting in order to separate Prochlorococcus cells from bacterial contaminants. Sorted cells were recovered by filtration and their radioactivity measured. The expression, after glucose addition, of several genes (involved in glucose metabolism, and in nitrogen assimilation and its regulation) was determined in the low irradiance-adapted Prochlorococcus SS120 strain by semi-quantitative real time RT-PCR, using the rnpB gene as internal control. Our results demonstrate for the first time that the Prochlorococcus strains studied in this work take up glucose at significant rates even at concentrations close to those found in the oceans, and also exclude the possibility of this uptake being carried out by eventual bacterial contaminants, since only Prochlorococcus cells were used for radioactivity measurements. Besides, we show that the expression of a number of genes involved in glucose utilization (namely zwf, gnd and dld, encoding glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase and lactate dehydrogenase, respectively) is strongly increased upon glucose addition to cultures of the SS120 strain. This fact, taken together with the magnitude of the glucose uptake, clearly indicates the physiological importance of the phenomenon. Given the significant contribution of Prochlorococcus to the global primary production, these findings have strong implications for the understanding of the phytoplankton role in the carbon cycle in nature. Besides, the ability of assimilating carbon molecules could provide additional hints to comprehend the ecological success of Prochlorococcus. | 18,941,506 |
Diaphanous-related formin 2 and profilin I are required for gastrulation cell movements. | Intensive cellular movements occur during gastrulation. These cellular movements rely heavily on dynamic actin assembly. Rho with its associated proteins, including the Rho-activated formin, Diaphanous, are key regulators of actin assembly in cellular protrusion and migration. However, the function of Diaphanous in gastrulation cell movements remains unclear. To study the role of Diaphanous in gastrulation, we isolated a partial zebrafish diaphanous-related formin 2 (zdia2) clone with its N-terminal regulatory domains. The GTPase binding domain of zDia2 is highly conserved compared to its mammalian homologues. Using a yeast two-hybrid assay, we showed that zDia2 interacts with constitutively-active RhoA and Cdc42. The zdia2 mRNAs were ubiquitously expressed during early embryonic development in zebrafish as determined by RT-PCR and whole-mount in situ hybridization analyses. Knockdown of zdia2 by antisense morpholino oligonucleotides (MOs) blocked epiboly formation and convergent extension in a dose-dependent manner, whereas ectopic expression of a human mdia gene partially rescued these defects. Time-lapse recording further showed that bleb-like cellular processes of blastoderm marginal deep marginal cells and pseudopod-/filopod-like processes of prechordal plate cells and lateral cells were abolished in the zdia2 morphants. Furthermore, zDia2 acts cell-autonomously since transplanted zdia2-knockdown cells exhibited low protrusive activity with aberrant migration in wild type host embryos. Lastly, co-injection of antisense MOs of zdia2 and zebrafish profilin I (zpfn 1), but not zebrafish profilin II, resulted in a synergistic inhibition of gastrulation cell movements. These results suggest that zDia2 in conjunction with zPfn 1 are required for gastrulation cell movements in zebrafish. | 18,941,507 |
Functional dorsoventral symmetry in relation to lift-based swimming in the ocean sunfish Mola mola. | The largest (up to 2 tons) and a globally distributed teleost--the ocean sunfish Mola mola--is commonly regarded as a planktonic fish because of its unusual shape including absence of caudal fin. This common view was recently questioned because the horizontal movements of the ocean sunfish tracked by acoustic telemetry were independent of ocean currents. However, direct information regarding their locomotor performance under natural conditions is still lacking. By using multi-sensor tags, we show that sunfish indeed swam continuously with frequent vertical movements at speeds of 0.4-0.7 m s(-1), which is similar to the records of other large fishes such as salmons, marlins, and pelagic sharks. The acceleration data revealed that they stroked their dorsal and anal fins synchronously (dominant frequency, 0.3-0.6 Hz) to generate a lift-based thrust, as penguins do using two symmetrical flippers. Morphological studies of sunfish (mass, 2-959 kg) showed that the dorsal and anal fins had similar external (symmetrical shape and identical area) and internal (identical locomotory muscle mass) features; however, the muscle shape differed markedly. We conclude that ocean sunfish have functional dorsoventral symmetry with regards to the non-homologous dorsal and anal fins that act as a pair of vertical hydrofoils. Although sunfish lack a swimbladder, we found that they are neutrally buoyant independent of depth because of their subcutaneous gelatinous tissue that has low density and is incompressible. Efficient lift-based swimming in conjunction with neutral buoyancy enables sunfish to travel long distances both horizontally and vertically. | 18,941,510 |
Mycolactone diffuses from Mycobacterium ulcerans-infected tissues and targets mononuclear cells in peripheral blood and lymphoid organs. | Buruli ulcer (BU) is a progressive disease of subcutaneous tissues caused by Mycobacterium ulcerans. The pathology of BU lesions is associated with the local production of a diffusible substance, mycolactone, with cytocidal and immunosuppressive properties. The defective inflammatory responses in BU lesions reflect these biological properties of the toxin. However, whether mycolactone diffuses from infected tissues and suppresses IFN-gamma responses in BU patients remains unclear. Here we have investigated the pharmacodistribution of mycolactone following injection in animal models by tracing a radiolabeled form of the toxin, and by directly quantifying mycolactone in lipid extracts from internal organs and cell subpopulations. We show that subcutaneously delivered mycolactone diffused into mouse peripheral blood and accumulated in internal organs with a particular tropism for the spleen. When mice were infected subcutaneously with M. ulcerans, this led to a comparable pattern of distribution of mycolactone. No evidence that mycolactone circulated in blood serum during infection could be demonstrated. However, structurally intact toxin was identified in the mononuclear cells of blood, lymph nodes and spleen several weeks before ulcerative lesions appear. Importantly, diffusion of mycolactone into the blood of M. ulcerans-infected mice coincided with alterations in the functions of circulating lymphocytes. In addition to providing the first evidence that mycolactone diffuses beyond the site of M. ulcerans infection, our results support the hypothesis that the toxin exerts immunosuppressive effects at the systemic level. Furthermore, they suggest that assays based on mycolactone detection in circulating blood cells may be considered for diagnostic tests of early disease. | 18,941,518 |
Extended driving impairs nocturnal driving performances. | Though fatigue and sleepiness at the wheel are well-known risk factors for traffic accidents, many drivers combine extended driving and sleep deprivation. Fatigue-related accidents occur mainly at night but there is no experimental data available to determine if the duration of prior driving affects driving performance at night. Participants drove in 3 nocturnal driving sessions (3-5 am, 1-5 am and 9 pm-5 am) on open highway. Fourteen young healthy men (mean age [+/-SD] = 23.4 [+/-1.7] years) participated Inappropriate line crossings (ILC) in the last hour of driving of each session, sleep variables, self-perceived fatigue and sleepiness were measured. Compared to the short (3-5 am) driving session, the incidence rate ratio of inappropriate line crossings increased by 2.6 (95% CI, 1.1 to 6.0; P<.05) for the intermediate (1-5 am) driving session and by 4.0 (CI, 1.7 to 9.4; P<.001) for the long (9 pm-5 am) driving session. Compared to the reference session (9-10 pm), the incidence rate ratio of inappropriate line crossings were 6.0 (95% CI, 2.3 to 15.5; P<.001), 15.4 (CI, 4.6 to 51.5; P<.001) and 24.3 (CI, 7.4 to 79.5; P<.001), respectively, for the three different durations of driving. Self-rated fatigue and sleepiness scores were both positively correlated to driving impairment in the intermediate and long duration sessions (P<.05) and increased significantly during the nocturnal driving sessions compared to the reference session (P<.01). At night, extended driving impairs driving performances and therefore should be limited. | 18,941,525 |
Does the committee peer review select the best applicants for funding? An investigation of the selection process for two European molecular biology organization programmes. | Does peer review fulfill its declared objective of identifying the best science and the best scientists? In order to answer this question we analyzed the Long-Term Fellowship and the Young Investigator programmes of the European Molecular Biology Organization. Both programmes aim to identify and support the best post doctoral fellows and young group leaders in the life sciences. We checked the association between the selection decisions and the scientific performance of the applicants. Our study involved publication and citation data for 668 applicants to the Long-Term Fellowship programme from the year 1998 (130 approved, 538 rejected) and 297 applicants to the Young Investigator programme (39 approved and 258 rejected applicants) from the years 2001 and 2002. If quantity and impact of research publications are used as a criterion for scientific achievement, the results of (zero-truncated) negative binomial models show that the peer review process indeed selects scientists who perform on a higher level than the rejected ones subsequent to application. We determined the extent of errors due to over-estimation (type I errors) and under-estimation (type 2 errors) of future scientific performance. Our statistical analyses point out that between 26% and 48% of the decisions made to award or reject an application show one of both error types. Even though for a part of the applicants, the selection committee did not correctly estimate the applicant's future performance, the results show a statistically significant association between selection decisions and the applicants' scientific achievements, if quantity and impact of research publications are used as a criterion for scientific achievement. | 18,941,530 |
Role of alphaBI5 and alphaBT162 residues in subunit interaction during oligomerization of alphaB-crystallin. | To determine whether the residues in the NH(2)- and COOH-terminal extensions interact with one another during oligomerization of alphaB-crystallin. Site-directed mutagenesis was used to mutate alphaBI5 and alphaBT162 residues to Cys. The recombinant I5C and T162C proteins were expressed in Escherichia coli cells and purified using chromatographic techniques. These proteins were analyzed by SDS-PAGE and mass spectrometry and characterized by multi-angle light scattering and circular dichroism (CD) spectroscopy methods. Fluorescence resonance energy transfer (FRET) assay was used to determine the interaction between the subunits. Dimer formation was observed in both alphaBI5C and alphaBT162C in storage at 4 degrees C. During air oxidation at room temperature, alphaBT162C formed dimers to a greater extent than alphaBI5C. The average molar masses, secondary structures, and chaperone-like activities of the reduced forms of I5C and T162C were comparable to that of wild type alphaB-crystallin. The oligomeric assembly of reduced forms of I5C and T162C appeared homogenous under JEOL 1200EX Electron microscope whereas the oxidized proteins appeared as irregular aggregates. FRET assay demonstrated interactions between alphaBI5C-alphaBI5C and alphaBT162C-alphaBT162C. However, there was no evidence of an interaction between alphaBI5C and alphaBT162C residues during oligomerization. This study suggests that residues from the NH(2)- and COOH-terminal regions in alphaB-crystallin interact with residues from the corresponding regions of another subunit, but there exists no interaction between the residues at the COOH-terminal extension region and the residues at the NH(2)-terminal region. | 18,941,542 |
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