Gene-Age Interactions in Blood Pressure Regulation: A Large-Scale Investigation with the CHARGE, Global BPgen, and ICBP Consortia.

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

Cetuximab in combination with chemoradiotherapy prior to surgery in patients with resectable, locally advanced esophageal carcinoma : a prospective, multicenter phase lb-ll trial of the Swiss Group for Clinical Cancer Research (SAKK 75/06) : 4570

Background: Cetuximab significantly enhances efficacy of radiotherapy and chemotherapy in head and neck cancer. We investigated the safety and feasibility of adding cetuximab to neoadjuvant chemoradiation of locally advanced esophageal cancer. Methods: Pts with resectable, locally advanced squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the thoracic esophagus or gastroesophageal junction (staged by EUS, CT and PET scan) were treated with 2 cycles of induction chemotherapy (docetaxel 75mg/m2, cisplatin 75mg/m2 q3w and weekly cetuximab 250mg/m2), followed by concomitant chemo- immuno-radiation therapy (CIRT: docetaxel 20mg/m2, cisplatin 25mg/m2 and cetuximab 250mg/m2 weekly five times concomitant with 45 Gy radiotherapy in 25 fractions); followed by surgery 4-8 weeks later. The phase I part consisted of 2 cohorts of 7 patients each, without and with docetaxel during CIRT, respectively. Interpatient dose-escalation (adding docetaxel during CIRT) was possible if < 2 out of 7 pts of the 1st cohort experienced limiting toxicity. Having finished the phase 1 part, 13 additional patients were treated with docetaxel-containing CIRT in a phase II part. Pathological response was evaluated according to the Mandard classification. Results: 27 pts from 12 institutions were included. As of today, results from 20 pts are available (cohort 1: 7, cohort 2: 7, phase ll : 6). Median age was 64yrs (range 47-71). 11 AC; 9 SCC. 19 pts (95%) completed CIRT (1 pt stopped treatment during induction therapy due to sepsis). 17 pts underwent resection (no surgery: 1pt for PD, 1pt for cardiac reasons). Grade 3 toxicities during CIRT included anorexia 15%, dysphagia/esophagitis 15%, fatigue 10%, nausea 10%, pruritus 5%, dehydration 5%, nail changes 5% and rash 5% .1 pt suffered from pulmonary embolism. 13 pts (65%, intention-to-treat) showed a complete or near complete pathological remission (cohort 1: 5, cohort 2: 4, phase II: 4). Conclusions: Adding cetuximab to preoperative chemoradiation for esophageal cancer is safe and feasible in a community-based multicenter setting. Antineoplastic activity is encouraging with 65% pathological responders.

From neuroprogression to neuroprotection: implications for clinical care.

Bipolar disorder follows a staged trajectory in which persistence of illness is associated with a number of clinical features such as progressive shortening of the inter-episode interval and decreased probability of treatment response. This neuroprogressive clinical process is reflected by both progressive neuroanatomical changes and evidence of cognitive decline. The biochemical foundation of this process appears to incorporate changes in inflammatory cytokines, cortisone, neurotrophins and oxidative stress. There is a growing body of evidence to suggest that these markers may differ between the early and late stages of the disorder. The presence of a series of tangible targets raises the spectre of development of rational neuroprotective strategies, involving judicious use of current therapies and novel agents. Most of the currently used mood stabilisers share effects on oxidative stress and neurotrophins, while novel potentially neuroprotective agents are being developed. These developments need to be combined with service initiatives to maximise the opportunities for early diagnosis and intervention.

Who wrote the Second Ave maris stella of Tomás Luis de Victoria?

Contrary to what Felipe Pedrell indicates, the second Ave maris stella in his Victoria's collected works (vol. V, 1908, pp. 100-3, n° 33) doesn't appear in the collection published in 1600 in Madrid by the composer, nor in any other of the musician's books. In the 1600 edition, Victoria reissues the two first verses (plainchant followed by polyphony) of the Ave maris stella published in 1576 and then again in 1581. The earliest source of the problematic Ave maris stella is Munich, Bayerische Staatsbibliothek, Musik-Abteilung, 2 Mus. pr. 23 handschriftlicher Beiband, dating from the third quarter oft he seventeenth century. This source is a manuscrit that runs as an appendix to the 1581 edition of Victoria's hymns. No attributions are given in the manuscript. The first attributions of the piece to Victoria arise in the nineteenth century, in manuscripts copied by Johann Michael Hauber, Johann Caspar Aiblinger, August Baumgartner and Carl Proske, and preserved in Munich and Regensburg. Proske pubished the piece in his Musica divina in 1859 (Annus primus, vol. III, pp. 419-24). The most probable hypothesis ist that Pedrell had knowledge of the second Ave maris stella, under the spanish composer's name, via Proske's Musica divina. In all likelihood the piece is not by Victoria, not least because the composer has never written odd polyphonic verses of hymns. In his Studies in the Music of Tomás Luis de Victoria (2001), Eugene Casjen Cramer relies on the supposed authenticity of the work to ascribe the others pieces of Munich, Bayerische Staatsbibliothek, Musik-Abteilung, 2 Mus. pr. 23 handschriftlicher Beiband to the composer. These attributions should therefore be refuted.

Authentication of vegetable oils by bulk and molecular carbon isotope analyses with emphasis on olive oil and pumpkin seed oil

The authenticity of vegetable oils consumed in Slovenia and Croatia was investigated by carbon isotope analysis of the individual fatty acids by the use of gas chromatography-combustion-isotope ratio mass spectrometry (GC/C/IRMS), and through carbon isotope analysis of the bulk oil. The fatty acids from samples of olive, pumpkin, sunflower, maize, rape, soybean, and sesame oils were separated by alkaline hydrolysis and derivatized to methyl esters for chemical characterization by capillary gas chromatography/mass spectrometry (GC/MS) prior to isotopic analysis. Enrichment in heavy carbon isotope (C-13) of th, bulk oil and of the individual fatty acids are related to (1) a thermally induced degradation during processing (deodorization, steam washing, or bleaching), (2) hydrolytic rancidity (lipolysis) and oxidative rancidity of the vegetable oils during storage, and (3) the potential blend with refined oil or other vegetable oils. The impurity or admixture of different oils may be assessed from the delta C-13(16:0) VS. delta C-13(18:1) covariations. The fatty acid compositions of Slovenian and Croatian olive oils are compared with those from the most important Mediterranean producer countries (Spain, Italy, Greece, and France).

A study of the effect of sartorius transposition on lymph flow after ilioinguinal node dissection.

Ilioinguinal dissection is associated with a high rate of lymphatic complications. Prolonged lymph flow causes greatest concern and preventive strategies are needed. A retrospective study of 28 consecutive patients undergoing groin dissection for melanoma metastases was performed to evaluate the influence of sartorius muscle transposition on lymph flow. Modification of the surgical technique with transposition of the sartorius muscle was not associated with reduced drainage time (P = 0.66). A 2-staged approach, with initial sentinel lymph node resection and lymph node dissection in a second operation, however, lead to shortened duration of the lymph flow (P = 0.01). Prolonged lymphorrhea was more frequent in older (P = 0.03), obese (P = 0.02) patients affected by diabetes mellitus (P = 0.03) and hypertension (P = 0.04).

A proposal for an international retinoblastoma staging system.

BACKGROUND: Although intra-retinal tumor has long been staged presurgically according to the Reese-Ellsworth (R-E) system, retinoblastoma differs from other pediatric neoplasms in never having had a widely accepted classification system that encompasses the entire spectrum of the disease. Comparisons among studies that consider disease extension, risk factors for extra-ocular relapse, and response to therapy require a universally accepted staging system for extra-ocular disease. PROCEDURE: A committee of retinoblastoma experts from large centers worldwide has developed a consensus classification that can encompass all retinoblastoma cases and is presented herein. Patients are classified according to extent of disease and the presence of overt extra-ocular extension. In addition, a proposal for substaging considering histopathological features of enucleated specimens is presented to further discriminate between Stage I and II patients. RESULTS: The following is a summary of the classification system developed-Stage 0: Patients treated conservatively (subject to presurgical ophthalmologic classifications); Stage I: Eye enucleated, completely resected histologically; Stage II: Eye enucleated, microscopic residual tumor; Stage III: Regional extension [(a) overt orbital disease, (b) preauricular or cervical lymph node extension]; Stage IV: Metastatic disease [(a) hematogenous metastasis: (1) single lesion, (2) multiple lesions; (b) CNS extension: (1) prechiasmatic lesion, (2) CNS mass, (3) leptomeningeal disease]. A proposal is also presented for substaging of enucleated Stages I and II eyes. CONCLUSIONS: The proposed staging system is the product of an international effort to adopt a uniform staging system for patients with retinoblastoma to cover the whole spectrum of the disease.

Nestmate recognition and levels of aggression are not altered by changes in genetic diversity in a socially polymorphic ant

The ability to distinguish nestmates from foreign individuals is central to the functioning of insect societies. In ants, workers from multiple-queen colonies are often less aggressive than workers from single-queen ones. In line with this observation, it has been hypothesized that workers from multiple-queen colonies have less precise recognition abilities than workers from single-queen ones because their colonies contain genetically more diverse individuals, which results in a broader template of recognition cues. Here, we assessed the impact of social structure ( queen number) variation on nestmate recognition and aggression in a large population of the socially polymorphic ant Formica selysi. We staged unilateral aggression tests on the nest surface. Workers from single-and multiple-queen colonies had good nestmate recognition ability and did not differ significantly in their level of aggression towards foreign, immobilized workers ( cue-bearers). In particular, workers from multiple-queen colonies efficiently recognized non-nestmates despite the higher genetic diversity in their colony. Cue-bearers from single- and multiple-queen colonies elicited similar reactions. However, the level of aggression was higher between than within social forms, suggesting that workers detect a signal that is specific to the colony social structure. Finally, the level of aggression was not correlated with the genetic distance between colonies. Overall, we found no evidence for the hypothesis that the presence of multiple breeders in the same colony decreases recognition abilities and found no simple relationship between genetic diversity and aggression level. (c) 2007 The Association for the Study of Animal Behaviou

Patient-adapted treatment for prosthetic hip joint infection.

Hip joint replacement is 1 of the most successful surgical procedures of the last century and the number of replacements implanted is steadily growing. An infected hip arthroplasty is a disaster, it leads to patient suffering, surgeon's frustration and significant costs to the health system. The treatment of an infected hip replacement is challenging, healing rates can be low, functional results poor with decreased patient satisfaction. However, if a patient-adapted treatment of infected hip joints is used a success rate of above 90% can be obtained.Patient-adapted treatment is based on 5 important concepts: teamwork; understanding the biofilm; diagnostic accuracy; correct definition and classification of PJI; and patient-tailored treatment.This review presents a patient-adapted treatment strategy to prosthetic hip infection. It incorporates the best aspects of the single and staged surgical strategies and promotes the short interval philosophy for the 2-stage approach.

Determinants of male fitness: disentangling intra- and inter-sexual selection.

Both intra- and inter-sexual selection may crucially determine a male's fitness. Their interplay, which has rarely been experimentally investigated, determines a male's optimal reproductive strategy and thus is of fundamental importance to the understanding of a male's behaviour. Here we investigated the relative importance of intra- and inter-sexual selection for male fitness in the common lizard. We investigated which male traits predict a male's access to reproduction allowing for both selective pressures and comparing it with a staged mating experiment excluding all types of intra-sexual selection. We found that qualitatively better males were more likely to reproduce and that sexual selection was two times stronger when allowing for both selective pressures, suggesting that inter- and intra-sexual selection determines male fitness and confirming the existence of multi-factorial sexual selection. Consequently, to optimize fitness, males should trade their investment between the traits, which are important for inter- and intra-sexual selection.