aIr-1, a newly found locus on mouse chromosome 16 encoding a trans-acting activator factor for MHC class II gene expression.

RJ 2.2.5 is a human B cell line that has lost the capacity to express MHC class II genes. The human class II-positive phenotype is restored in somatic cell hybrids between RJ 2.2.5 and mouse spleen cells. By karyotype and molecular studies of an informative family of hybrids we have now shown that the reexpression of human class II gene products, as well as the maintenance of the mouse class II-positive phenotype, correlates with the presence of mouse chromosome 16. Thus, the existence on this mouse chromosome of a newly found locus, designated by us aIr-1, that determines a trans-acting activator function for class II gene expression, is established. Possible implications of this finding are discussed.

Prevalence of Acute Coronary Syndrome in Patients Suspected for Pulmonary Embolism or Acute Aortic Syndromes: Rational for "Double" and "Triple" Rule-Out Concepts

PURPOSE To evaluate the prevalence of acute coronary syndrome (ACS) in patients presenting initially with atypical chest pain and suspected to have pulmonary embolism (PE) or acute aortic syndromes (AAS). To evaluate the overlap between ACS, PE and AAS in routine practice and determine how many patients could have benefit from a single CT protocol to rule out ACS at the same time as PE and AAS. METHOD AND MATERIALS Our electronic hospital database revealed 1122 consecutive patients who underwent a thoracic CT angiography for PE or AAS from 2004 to 2006 (mean age, 63±13 years). Patients without chest pain were excluded from this study. Thus, 447 patients presented with isolated atypical chest were included in the analysis. All patients who underwent a thoracic CT scan previously received standard clinical care and were initially considered as non ACS. The final diagnosis was obtained by the hospital stay report. RESULTS Among the 447 patients with atypical chest pain, 25 (5.5%) were finally found to have ACS: 19 patients (4.2%) were suspected for PE and 6 (1. 3%) were suspected for AAS. There were 90 patients diagnosed to have PE, 89 (98.8%) of them were suspected for PE while only 1 (1%) was suspected for AAS. Eleven patients diagnosed to have AAS, 9 (82%) of them were suspected for AAS while 2 (18%) were suspected for PE. CONCLUSION In clinical practice, the overlap between PE, AAS and ACS is limited which make the triple rule-out studies less recommended to be done at the time being because of the high dose radiation. A double rule-out investigation is suggested to be done for patients being evaluated for atypical chest pain and suspected of having AAS or PE because of a significant overlap between the two entities as well it doesn't implicate any increment in radiation dose. CLINICAL RELEVANCE/APPLICATION With 64-slice CT, coronary circulation and total chest can be evaluated at the same time offering new opportunitie for the evaluation of three major life-threatening conditions :ACS,PE and AAS.

Ruling out coronary heart disease in primary care: external validation of a clinical prediction rule.

BACKGROUND: The Marburg Heart Score (MHS) aims to assist GPs in safely ruling out coronary heart disease (CHD) in patients presenting with chest pain, and to guide management decisions. AIM: To investigate the diagnostic accuracy of the MHS in an independent sample and to evaluate the generalisability to new patients. DESIGN AND SETTING: Cross-sectional diagnostic study with delayed-type reference standard in general practice in Hesse, Germany. METHOD: Fifty-six German GPs recruited 844 males and females aged ≥ 35 years, presenting between July 2009 and February 2010 with chest pain. Baseline data included the items of the MHS. Data on the subsequent course of chest pain, investigations, hospitalisations, and medication were collected over 6 months and were reviewed by an independent expert panel. CHD was the reference condition. Measures of diagnostic accuracy included the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, likelihood ratios, and predictive values. RESULTS: The AUC was 0.84 (95% confidence interval [CI] = 0.80 to 0.88). For a cut-off value of 3, the MHS showed a sensitivity of 89.1% (95% CI = 81.1% to 94.0%), a specificity of 63.5% (95% CI = 60.0% to 66.9%), a positive predictive value of 23.3% (95% CI = 19.2% to 28.0%), and a negative predictive value of 97.9% (95% CI = 96.2% to 98.9%). CONCLUSION: Considering the diagnostic accuracy of the MHS, its generalisability, and ease of application, its use in clinical practice is recommended.

Expression of genes encoding cytotoxic cell-associated serine proteases in thymocytes.

A family of homologous serine esterases designated granzyme A-H and the pore-forming protein perforin are present in cytoplasmic granules of mature peripheral cytolytic T lymphocytes and natural killer cells. In vivo, the majority of cytotoxic T cells containing these granule-associated proteins are of the CD4-CD8+ phenotype. It is generally assumed that these cells are derived from immature CD4-CD8- thymocytes. However, the precise intrathymic differentiation steps leading to functionally mature cytotoxic T cells are unclear. Thus we decided to analyze the expression of genes in the thymus which are preferentially expressed in mature cytotoxic cells, i.e. granzyme A, granzyme B, and perforin. In situ hybridization on tissue sections revealed the expression of genes coding for granzyme A and granzyme B in the thymus. No evidence was found, however, for thymocytes expressing the perforin gene. Granzyme A and granzyme B mRNA positive cells in the thymus are almost exclusively CD4-CD8- thymocytes, particularly of the CD3- IL2R- phenotype.

The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata.

Our previous investigation on Candida glabrata azole-resistant isolates identified two isolates with unaltered expression of CgCDR1/CgCDR2, but with upregulation of another ATP-binding cassette transporter, CgSNQ2, which is a gene highly similar to ScSNQ2 from Saccharomyces cerevisiae. One of the two isolates (BPY55) was used here to elucidate this phenomenon. Disruption of CgSNQ2 in BPY55 decreased azole resistance, whereas reintroduction of the gene in a CgSNQ2 deletion mutant fully reversed this effect. Expression of CgSNQ2 in a S. cerevisiae strain lacking PDR5 mediated not only resistance to azoles but also to 4-nitroquinoline N-oxide, which is a ScSNQ2-specific substrate. A putative gain-of-function mutation, P822L, was identified in CgPDR1 from BPY55. Disruption of CgPDR1 in BPY55 conferred enhanced azole susceptibility and eliminated CgSNQ2 expression, whereas introduction of the mutated allele in a susceptible strain where CgPDR1 had been disrupted conferred azole resistance and CgSNQ2 upregulation, indicating that CgSNQ2 was controlled by CgPDR1. Finally, CgSNQ2 was shown to be involved in the in vivo response to fluconazole. Together, our data first demonstrate that CgSNQ2 contributes to the development of CgPDR1-dependent azole resistance in C. glabrata. The overlapping in function and regulation between CgSNQ2 and ScSNQ2 further highlight the relationship between S. cerevisiae and C. glabrata.

Comparison of human and rhesus macaque T-cell responses elicited by boosting with NYVAC encoding human immunodeficiency virus type 1 clade C immunogens.

Rhesus macaques (Macaca mulatta) have played a valuable role in the development of human immunodeficiency virus (HIV) vaccine candidates prior to human clinical trials. However, changes and/or improvements in immunogen quality in the good manufacturing practice (GMP) process or changes in adjuvants, schedule, route, dose, or readouts have compromised the direct comparison of T-cell responses between species. Here we report a comparative study in which T-cell responses from humans and macaques to HIV type 1 antigens (Gag, Pol, Nef, and Env) were induced by the same vaccine batches prepared under GMP and administered according to the same schedules in the absence and presence of priming. Priming with DNA (humans and macaques) or alphavirus (macaques) and boosting with NYVAC induced robust and broad antigen-specific responses, with highly similar Env-specific gamma interferon (IFN-gamma) enzyme-linked immunospot assay responses in rhesus monkeys and human volunteers. Persistent cytokine responses of antigen-specific CD4(+) and CD8(+) T cells of the central memory as well as the effector memory phenotype, capable of simultaneously eliciting multiple cytokines (IFN-gamma, interleukin 2, and tumor necrosis factor alpha), were induced. Responses were highly similar in humans and primates, confirming earlier data indicating that priming is essential for inducing robust NYVAC-boosted IFN-gamma T-cell responses. While significant similarities were observed in Env-specific responses in both species, differences were also observed with respect to responses to other HIV antigens. Future studies with other vaccines using identical lots, immunization schedules, and readouts will establish a broader data set of species similarities and differences with which increased confidence in predicting human responses may be achieved.

The pulmonary embolism rule-out criteria (PERC) rule does not safely exclude pulmonary embolism.

Background: The Pulmonary Embolism Rule-out Criteria (PERC) rule is a clinical diagnostic rule designed to exclude pulmonary embolism (PE) without further testing. We sought to externally validate the diagnostic performance of the PERC rule alone and combined with clinical probability assessment based on the revised Geneva score. Methods: The PERC rule was applied retrospectively to consecutive patients who presented with a clinical suspicion of PE to six emergency departments, and who were enrolled in a randomized trial of PE diagnosis. Patients who met all eight PERC criteria [PERC(-)] were considered to be at a very low risk for PE. We calculated the prevalence of PE among PERC(-) patients according to their clinical pretest probability of PE. We estimated the negative likelihood ratio of the PERC rule to predict PE. Results: Among 1675 patients, the prevalence of PE was 21.3%. Overall, 13.2% of patients were PERC(-). The prevalence of PE was 5.4% [95% confidence interval (CI): 3.1-9.3%] among PERC(-) patients overall and 6.4% (95% CI: 3.7-10.8%) among those PERC(-) patients with a low clinical pretest probability of PE. The PERC rule had a negative likelihood ratio of 0.70 (95% CI: 0.67-0.73) for predicting PE overall, and 0.63 (95% CI: 0.38-1.06) in low-risk patients. Conclusions: Our results suggest that the PERC rule alone or even when combined with the revised Geneva score cannot safely identify very low risk patients in whom PE can be ruled out without additional testing, at least in populations with a relatively high prevalence of PE.

A Mutation in CALM1 Encoding Calmodulin in Familial Idiopathic Ventricular Fibrillation in Childhood and Adolescence.

OBJECTIVES: This study aimed to identify the genetic defect in a family with idiopathic ventricular fibrillation (IVF) manifesting in childhood and adolescence. BACKGROUND: Although sudden cardiac death in the young is rare, it frequently presents as the first clinical manifestation of an underlying inherited arrhythmia syndrome. Gene discovery for IVF is important as it enables the identification of individuals at risk, because except for arrhythmia, IVF does not manifest with identifiable clinical abnormalities. METHODS: Exome sequencing was carried out on 2 family members who were both successfully resuscitated from a cardiac arrest. RESULTS: We characterized a family presenting with a history of ventricular fibrillation (VF) and sudden death without electrocardiographic or echocardiographic abnormalities at rest. Two siblings died suddenly at the ages of 9 and 10 years, and another 2 were resuscitated from out-of-hospital cardiac arrest with documented VF at ages 10 and 16 years, respectively. Exome sequencing identified a missense mutation affecting a highly conserved residue (p.F90L) in the CALM1 gene encoding calmodulin. This mutation was also carried by 1 of the siblings who died suddenly, from whom DNA was available. The mutation was present in the mother and in another sibling, both asymptomatic but displaying a marginally prolonged QT interval during exercise. CONCLUSIONS: We identified a mutation in CALM1 underlying IVF manifesting in childhood and adolescence. The causality of the mutation is supported by previous studies demonstrating that F90 mediates the direct interaction of CaM with target peptides. Our approach highlights the utility of exome sequencing in uncovering the genetic defect even in families with a small number of affected individuals.

Mutual trust and cooperation in the evolutionary hawks-doves game

Using a new dynamical network model of society in which pairwise interactions are weighted according to mutual satisfaction, we show that cooperation is the norm in the hawks-doves game when individuals are allowed to break ties with undesirable neighbors and to make new acquaintances in their extended neighborhood. Moreover, cooperation is robust with respect to rather strong strategy perturbations. We also discuss the empirical structure of the emerging networks, and the reasons that allow cooperators to thrive in the population. Given the metaphorical importance of this game for social interaction, this is an encouraging positive result as standard theory for large mixing populations prescribes that a certain fraction of defectors must always exist at equilibrium.

DNA vaccine encoding nucleocapsid and surface proteins of wild type canine distemper virus protects its natural host against distemper.

Canine distemper virus (CDV), a member of the genus Morbillivirus induces a highly infectious, frequently lethal disease in dogs and other carnivores. Current vaccines against canine distemper consisting of attenuated viruses have been in use for many years and have greatly reduced the incidence of distemper in the dog population. However, certain strains may not guarantee adequate protection and others can induce post vaccinal encephalitis. We tested a DNA vaccine for its ability to protect dogs, the natural host of CDV, against distemper. We constructed plasmids containing the nucleocapsid, the fusion, and the attachment protein genes of a virulent canine distemper virus strain. Mice inoculated with these plasmids developed humoral and cellular immune responses against CDV antigens. Dogs immunized with the expression plasmids developed virus-neutralizing antibodies. Significantly, vaccinated dogs were protected against challenge with virulent CDV, whereas unvaccinated animals succumbed to distemper.

A generalization of Cope's rule

For numerous shelly invertebrates, Cope's rule is shown in this paper to merely describe the particular case where volume increase is strictly coupled with diameter or length. Allometries, which are frequently observed in the evolution of the shells' geometry, mean that their size, volume and surface can vary independently. The consequences of this can be summarized as follows : 1) volume increase not coupled with an increase of diameter or length of the organisms generates increasing involution and/or lateral width in the shell of cephalopods, foraminifera and radiolarians; 2) an increase of the biomineralizing surface, not coupled with volume increase, generates increasing apparent complexity in the sutures and growth lines in ammonites, and an increase in the complexity and number of chambers in foraminifera.

Effect of orthographic processes on letter identity and letter-position encoding in dyslexic children.

The ability to identify letters and encode their position is a crucial step of the word recognition process. However and despite their word identification problem, the ability of dyslexic children to encode letter identity and letter-position within strings was not systematically investigated. This study aimed at filling this gap and further explored how letter identity and letter-position encoding is modulated by letter context in developmental dyslexia. For this purpose, a letter-string comparison task was administered to French dyslexic children and two chronological age (CA) and reading age (RA)-matched control groups. Children had to judge whether two successively and briefly presented four-letter strings were identical or different. Letter-position and letter identity were manipulated through the transposition (e.g., RTGM vs. RMGT) or substitution of two letters (e.g., TSHF vs. TGHD). Non-words, pseudo-words, and words were used as stimuli to investigate sub-lexical and lexical effects on letter encoding. Dyslexic children showed both substitution and transposition detection problems relative to CA-controls. A substitution advantage over transpositions was only found for words in dyslexic children whereas it extended to pseudo-words in RA-controls and to all type of items in CA-controls. Letters were better identified in the dyslexic group when belonging to orthographically familiar strings. Letter-position encoding was very impaired in dyslexic children who did not show any word context effect in contrast to CA-controls. Overall, the current findings point to a strong letter identity and letter-position encoding disorder in developmental dyslexia.

Observational methodology in football: Development of an instrument to study the offensiva game in football.

The following paper introduces a new approach to the analysis of offensive game in football. Therefore, the main aim of this study was to create an instrument for collecting information for the analysis of offensive action and interactions game. The observation instrument that was used to accomplish the main objective of this work consists of a combination of format fields (FC) and systems of categories (SC). This methodology is a particular strategy of the scientific method that has as an objective to analyse the perceptible behaviour that occurs in habitual contexts, allowing them to be formally recorded and quantified and using an ad hoc instrument in order to obtain a behaviour systematic registration that, since they have been transformed in quantitative data with the necessary reliability and validity determined level, will allow analysis of the relations between these behaviours. The codifications undertaken to date in various games of football have shown that it serves the purposes for which it was developed, allowing more research into the offensive game methods in football.