A genome-wide significant linkage for severe depression on chromosome 3: the depression network study.

Objective: The purpose of this study was to find loci for major depression via linkage analysis of a large sibling pair sample. Method: The authors conducted a genome-wide linkage analysis of 839 families consisting of 971 affected sibling pairs with severe recurrent major depression, comprising waves I and II of the Depression Network Study cohort. In addition to examining affected status, linkage analyses in the full data set were performed using diagnoses restricted by impairment severity, and association mapping of hits in a large case-control data set was attempted. Results: The authors identified genome-wide significant linkage to chromosome 3p25-26 when the diagnoses were restricted by severity, which was a maximum LOD score of 4.0 centered at the linkage marker D3S1515. The linkage signal identified was genome-wide significant after correction for the multiple phenotypes tested, although subsequent association mapping of the region in a genome-wide association study of a U.K. depression sample did not provide significant results. Conclusions: The authors report a genome-wide significant locus for depression that implicates genes that are highly plausible for involvement in the etiology of recurrent depression. Despite the fact that association mapping in the region was negative, the linkage finding was replicated by another group who found genome-wide-significant linkage for depression in the same region. This suggests that 3p25-26 is a new locus for severe recurrent depression. This represents the first report of a genome-wide significant locus for depression that also has an independent genome-wide significant replication.

A Bayesian network approach to the database serch problem in criminal proceedings

Background The 'database search problem', that is, the strengthening of a case - in terms of probative value - against an individual who is found as a result of a database search, has been approached during the last two decades with substantial mathematical analyses, accompanied by lively debate and centrally opposing conclusions. This represents a challenging obstacle in teaching but also hinders a balanced and coherent discussion of the topic within the wider scientific and legal community. This paper revisits and tracks the associated mathematical analyses in terms of Bayesian networks. Their derivation and discussion for capturing probabilistic arguments that explain the database search problem are outlined in detail. The resulting Bayesian networks offer a distinct view on the main debated issues, along with further clarity. Methods As a general framework for representing and analyzing formal arguments in probabilistic reasoning about uncertain target propositions (that is, whether or not a given individual is the source of a crime stain), this paper relies on graphical probability models, in particular, Bayesian networks. This graphical probability modeling approach is used to capture, within a single model, a series of key variables, such as the number of individuals in a database, the size of the population of potential crime stain sources, and the rarity of the corresponding analytical characteristics in a relevant population. Results This paper demonstrates the feasibility of deriving Bayesian network structures for analyzing, representing, and tracking the database search problem. The output of the proposed models can be shown to agree with existing but exclusively formulaic approaches. Conclusions The proposed Bayesian networks allow one to capture and analyze the currently most well-supported but reputedly counter-intuitive and difficult solution to the database search problem in a way that goes beyond the traditional, purely formulaic expressions. The method's graphical environment, along with its computational and probabilistic architectures, represents a rich package that offers analysts and discussants with additional modes of interaction, concise representation, and coherent communication.

Improvement of antibiotic prescription in outpatient care: a cluster-randomized intervention study using a sentinel surveillance network of physicians.

OBJECTIVES: To assess the effectiveness of implementing guidelines, coupled with individual feedback, on antibiotic prescribing behaviour of primary care physicians in Switzerland. METHODS: One hundred and forty general practices from a representative Swiss sentinel network of primary care physicians participated in this cluster-randomized prospective intervention study. The intervention consisted of providing guidelines on treatment of respiratory tract infections (RTIs) and uncomplicated lower urinary tract infections (UTIs), coupled with sustained, regular feedback on individual antibiotic prescription behaviour during 2 years. The main aims were: (i) to increase the percentage of prescriptions of penicillins for all RTIs treated with antibiotics; (ii) to increase the percentage of trimethoprim/sulfamethoxazole prescriptions for all uncomplicated lower UTIs treated with antibiotics; (iii) to decrease the percentage of quinolone prescriptions for all cases of exacerbated COPD (eCOPD) treated with antibiotics; and (iv) to decrease the proportion of sinusitis and other upper RTIs treated with antibiotics. The study was registered at ClinicalTrials.gov (NCT01358916). RESULTS: While the percentage of antibiotics prescribed for sinusitis or other upper RTIs and the percentage of quinolones prescribed for eCOPD did not differ between the intervention group and the control group, there was a significant increase in the percentage of prescriptions of penicillins for all RTIs treated with antibiotics [57% versus 49%, OR=1.42 (95% CI 1.08-1.89), P=0.01] and in the percentage of trimethoprim/sulfamethoxazole prescriptions for all uncomplicated lower UTIs treated with antibiotics [35% versus 19%, OR=2.16 (95% CI 1.19-3.91), P=0.01] in the intervention group. CONCLUSIONS: In our setting, implementing guidelines, coupled with sustained individual feedback, was not able to reduce the proportion of sinusitis and other upper RTIs treated with antibiotics, but increased the use of recommended antibiotics for RTIs and UTIs, as defined by the guidelines.

Parental influences on pathogen resistance in brown trout embryos and effects of outcrossing within a river network.

Phenotypic plasticity can increase tolerance to heterogeneous environments but the elevations and slopes of reaction norms are often population specific. Disruption of locally adapted reaction norms through outcrossing can lower individual viability. Here, we sampled five genetically distinct populations of brown trout (Salmo trutta) from within a river network, crossed them in a full-factorial design, and challenged the embryos with the opportunistic pathogen Pseudomonas fluorescens. By virtue of our design, we were able to disentangle effects of genetic crossing distance from sire and dam effects on early life-history traits. While pathogen infection did not increase mortality, it was associated with delayed hatching of smaller larvae with reduced yolk sac reserves. We found no evidence of a relationship between genetic distance (W, FST) and the expression of early-life history traits. Moreover, hybrids did not differ in phenotypic means or reaction norms in comparison to offspring from within-population crosses. Heritable variation in early life-history traits was found to remain stable across the control and pathogen environments. Our findings show that outcrossing within a rather narrow geographical scale can have neutral effects on F1 hybrid viability at the embryonic stage, i.e. at a stage when environmental and genetic effects on phenotypes are usually large.

High throughput 3D super-resolution microscopy reveals Caulobacter crescentus in vivo Z-ring organization.

We created a high-throughput modality of photoactivated localization microscopy (PALM) that enables automated 3D PALM imaging of hundreds of synchronized bacteria during all stages of the cell cycle. We used high-throughput PALM to investigate the nanoscale organization of the bacterial cell division protein FtsZ in live Caulobacter crescentus. We observed that FtsZ predominantly localizes as a patchy midcell band, and only rarely as a continuous ring, supporting a model of "Z-ring" organization whereby FtsZ protofilaments are randomly distributed within the band and interact only weakly. We found evidence for a previously unidentified period of rapid ring contraction in the final stages of the cell cycle. We also found that DNA damage resulted in production of high-density continuous Z-rings, which may obstruct cytokinesis. Our results provide a detailed quantitative picture of in vivo Z-ring organization.

Organisation des secours extrahospitaliers lors du sommet 2003 du G8: nouveau concept de poste médical mobile (PMM) [Prehospital medical care organization during the 2003 G8 summit: a new concept of Mobile Medical Squadrons (MMS)].

OBJECTIVE: The occurrence of the 2003 G8 summit in Evian and the threat of major civil riots or even terrorist attacks in the Swiss neighbourhood forced us to imagine a new system of rescue and medical care in case of numerous victims. Previous occurrences of the G8 in Europe or America have demonstrated the need of flexible and mobile structures, able to respond quickly to crowd movements, unlike the usual static structure of rescue systems designed for major accidents. METHODS: We developed a new concept of Mobile Medical Squadrons (MMS) consisting of several vehicles and medical care and rescue human resources. In our concept, each MMS consisted of 3 emergency doctors, 5 paramedics and 9 first-aid workers. They were designed to handle 15 patients, with a large autonomy in terms of rescue, medical care, evacuation and medical authority. The equipment included medical, resuscitation, simple decontamination, evacuation and communication materials. RESULTS: The MMS were dispatched four times during the G8 summit following civil riots. They took care of 12 injured patients. CONCLUSION: The concept of MMS as a reinforcement of the existing rescue and health care resources appears as a new flexible, a modular and useful concept for the medical management of collective prehospital emergency situations. Its use is suggested instead of the traditional static concept of rescue systems designed for major accidents.

A miR-34a-SIRT6 axis in the squamous cell differentiation network.

Squamous cell carcinomas (SCCs) are highly heterogeneous tumours, resulting from deranged expression of genes involved in squamous cell differentiation. Here we report that microRNA-34a (miR-34a) functions as a novel node in the squamous cell differentiation network, with SIRT6 as a critical target. miR-34a expression increases with keratinocyte differentiation, while it is suppressed in skin and oral SCCs, SCC cell lines, and aberrantly differentiating primary human keratinocytes (HKCs). Expression of this miRNA is restored in SCC cells, in parallel with differentiation, by reversion of genomic DNA methylation or wild-type p53 expression. In normal HKCs, the pro-differentiation effects of increased p53 activity or UVB exposure are miR-34a-dependent, and increased miR-34a levels are sufficient to induce differentiation of these cells both in vitro and in vivo. SIRT6, a sirtuin family member not previously connected with miR-34a function, is a direct target of this miRNA in HKCs, and SIRT6 down-modulation is sufficient to reproduce the miR-34a pro-differentiation effects. The findings are of likely biological significance, as SIRT6 is oppositely expressed to miR-34a in normal keratinocytes and keratinocyte-derived tumours.

Inference about the number of contributors to a DNA mixture: Comparative analyses of a Bayesian network approach and the maximum allele count method.

In the forensic examination of DNA mixtures, the question of how to set the total number of contributors (N) presents a topic of ongoing interest. Part of the discussion gravitates around issues of bias, in particular when assessments of the number of contributors are not made prior to considering the genotypic configuration of potential donors. Further complication may stem from the observation that, in some cases, there may be numbers of contributors that are incompatible with the set of alleles seen in the profile of a mixed crime stain, given the genotype of a potential contributor. In such situations, procedures that take a single and fixed number contributors as their output can lead to inferential impasses. Assessing the number of contributors within a probabilistic framework can help avoiding such complication. Using elements of decision theory, this paper analyses two strategies for inference on the number of contributors. One procedure is deterministic and focuses on the minimum number of contributors required to 'explain' an observed set of alleles. The other procedure is probabilistic using Bayes' theorem and provides a probability distribution for a set of numbers of contributors, based on the set of observed alleles as well as their respective rates of occurrence. The discussion concentrates on mixed stains of varying quality (i.e., different numbers of loci for which genotyping information is available). A so-called qualitative interpretation is pursued since quantitative information such as peak area and height data are not taken into account. The competing procedures are compared using a standard scoring rule that penalizes the degree of divergence between a given agreed value for N, that is the number of contributors, and the actual value taken by N. Using only modest assumptions and a discussion with reference to a casework example, this paper reports on analyses using simulation techniques and graphical models (i.e., Bayesian networks) to point out that setting the number of contributors to a mixed crime stain in probabilistic terms is, for the conditions assumed in this study, preferable to a decision policy that uses categoric assumptions about N.

Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593.

PURPOSE: Patients with primary cutaneous melanoma > or = 1.5 mm in thickness are at high risk of having regional micrometastases at the time of initial surgical treatment. A phase III international study was designed to evaluate whether prophylactic isolated limb perfusion (ILP) could prevent regional recurrence and influence survival. PATIENTS AND METHODS: A total of 832 assessable patients from 16 centers entered the study; 412 were randomized to wide excision (WE) only and 420 to WE plus ILP with melphalan and mild hyperthermia. Median age was 50 years, 68% of patients were female, 79% of melanomas were located on a lower limb, and 47% had a thickness > or = 3 mm. RESULTS: Median follow-up duration is 6.4 years. There was a trend for a longer disease-free interval (DFI) after ILP. The difference was significant for patients who did not undergo elective lymph node dissection (ELND). The impact of ILP was clearly on the occurrence-as first site of progression - of in-transit metastases (ITM), which were reduced from 6.6% to 3.3%, and of regional lymph node (RLN) metastases, with a reduction from 16.7% to 12.6%. There was no benefit from ILP in terms of time to distant metastasis or survival. Side effects were higher after ILP, but transient in most patients. There were two amputations for limb toxicity after ILP. CONCLUSION: Prophylactic ILP with melphalan cannot be recommended as an adjunct to standard surgery in high-risk primary limb melanoma.

Additive functions in boolean models of gene regulatory network modules.

Gene-on-gene regulations are key components of every living organism. Dynamical abstract models of genetic regulatory networks help explain the genome's evolvability and robustness. These properties can be attributed to the structural topology of the graph formed by genes, as vertices, and regulatory interactions, as edges. Moreover, the actual gene interaction of each gene is believed to play a key role in the stability of the structure. With advances in biology, some effort was deployed to develop update functions in Boolean models that include recent knowledge. We combine real-life gene interaction networks with novel update functions in a Boolean model. We use two sub-networks of biological organisms, the yeast cell-cycle and the mouse embryonic stem cell, as topological support for our system. On these structures, we substitute the original random update functions by a novel threshold-based dynamic function in which the promoting and repressing effect of each interaction is considered. We use a third real-life regulatory network, along with its inferred Boolean update functions to validate the proposed update function. Results of this validation hint to increased biological plausibility of the threshold-based function. To investigate the dynamical behavior of this new model, we visualized the phase transition between order and chaos into the critical regime using Derrida plots. We complement the qualitative nature of Derrida plots with an alternative measure, the criticality distance, that also allows to discriminate between regimes in a quantitative way. Simulation on both real-life genetic regulatory networks show that there exists a set of parameters that allows the systems to operate in the critical region. This new model includes experimentally derived biological information and recent discoveries, which makes it potentially useful to guide experimental research. The update function confers additional realism to the model, while reducing the complexity and solution space, thus making it easier to investigate.

A neuron-glia signalling network in the active brain.

Glial cells are active partners of neurons in processing information and synaptic integration. They receive coded signals from synapses and elaborate modulatory responses. The active properties of glia, including long-range signalling and regulated transmitter release, are beginning to be elucidated. Recent insights suggest that the active brain should no longer be regarded as a circuitry of neuronal contacts, but as an integrated network of interactive neurons and glia.

Accès aux soins d'urgence: organisation et utilité de la chaîne des secours [Access to prehospital medical care: organization and utility of the chain of survival].

In order to be effective, access to prehospital care must be integrated into a system described as "the chain of survival". This system is composed of 5 essential phases: 1) basic help by witnesses; 2) call for help; 3) basic life support; 4) professional rescue and transport to the appropriate institution and 5) access to emergency ward and hospital management. Each phase is characterized by a specific organization, dedicated skills and means in order to increase the level of care brought to the patient. This article describes the organization, the utility and the specificity of the chain of survival allowing access to prehospital medical care in the western part of Switzerland.

A temporal hierarchy for conspecific vocalization discrimination in humans.

Introduction: Discrimination of species-specific vocalizations is fundamental for survival and social interactions. Its unique behavioral relevance has encouraged the identification of circumscribed brain regions exhibiting selective responses (Belin et al., 2004), while the role of network dynamics has received less attention. Those studies that have examined the brain dynamics of vocalization discrimination leave unresolved the timing and the inter-relationship between general categorization, attention, and speech-related processes (Levy et al., 2001, 2003; Charest et al., 2009). Given these discrepancies and the presence of several confounding factors, electrical neuroimaging analyses were applied to auditory evoked-potential (AEPs) to acoustically and psychophysically controlled non-verbal human and animal vocalizations. This revealed which region(s) exhibit voice-sensitive responses and in which sequence. Methods: Subjects (N=10) performed a living vs. man-made 'oddball' auditory discrimination task, such that on a given block of trials 'target' stimuli occurred 10% of the time. Stimuli were complex, meaningful sounds of 500ms duration. There were 120 different sound files in total, 60 of which represented sounds of living objects and 60 man-made objects. The stimuli that were the focus of the present investigation were restricted to those of living objects within blocks where no response was required. These stimuli were further sorted between human non-verbal vocalizations and animal vocalizations. They were also controlled in terms of their spectrograms and formant distributions. Continuous 64-channel EEG was acquired through Neuroscan Synamps referenced to the nose, band-pass filtered 0.05-200Hz, and digitized at 1000Hz. Peri-stimulus epochs of continuous EEG (-100ms to 900ms) were visually inspected for artifacts, 40Hz low-passed filtered and baseline corrected using the pre-stimulus period . Averages were computed from each subject separately. AEPs in response to animal and human vocalizations were analyzed with respect to differences of Global Field Power (GFP) and with respect to changes of the voltage configurations at the scalp (reviewed in Murray et al., 2008). The former provides a measure of the strength of the electric field irrespective of topographic differences; the latter identifies changes in spatial configurations of the underlying sources independently of the response strength. In addition, we utilized the local auto-regressive average distributed linear inverse solution (LAURA; Grave de Peralta Menendez et al., 2001) to visualize and statistically contrast the likely underlying sources of effects identified in the preceding analysis steps. Results: We found differential activity in response to human vocalizations over three periods in the post-stimulus interval, and this response was always stronger than that to animal vocalizations. The first differential response (169-219ms) was a consequence of a modulation in strength of a common brain network localized into the right superior temporal sulcus (STS; Brodmann's Area (BA) 22) and extending into the superior temporal gyrus (STG; BA 41). A second difference (291-357ms) also followed from strength modulations of a common network with statistical differences localized to the left inferior precentral and prefrontal gyrus (BA 6/45). These two first strength modulations correlated (Spearman's rho(8)=0.770; p=0.009) indicative of functional coupling between temporally segregated stages of vocalization discrimination. A third difference (389-667ms) followed from strength and topographic modulations and was localized to the left superior frontal gyrus (BA10) although this third difference did not reach our spatial criterion of 12 continuous voxels. Conclusions: We show that voice discrimination unfolds over multiple temporal stages, involving a wide network of brain regions. The initial stages of vocalization discrimination are based on modulations in response strength within a common brain network with no evidence for a voice-selective module. The latency of this effect parallels that of face discrimination (Bentin et al., 2007), supporting the possibility that voice and face processes can mutually inform one another. Putative underlying sources (localized in the right STS; BA 22) are consistent with prior hemodynamic imaging evidence in humans (Belin et al., 2004). Our effect over the 291-357ms post-stimulus period overlaps the 'voice-specific-response' reported by Levy et al. (Levy et al., 2001) and the estimated underlying sources (left BA6/45) were in agreement with previous findings in humans (Fecteau et al., 2005). These results challenge the idea that circumscribed and selective areas subserve con-specific vocalization processing.