Effects of strontium ranelate and alendronate on bone microstructure in women with osteoporosis. Results of a 2-year study.

A Strontium ranelate appears to influence more than alendronate distal tibia bone microstructure as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), and biomechanically relevant parameters as assessed by micro-finite element analysis (mu FEA), over 2 years, in postmenopausal osteoporotic women.Introduction Bone microstructure changes are a target in osteoporosis treatment to increase bone strength and reduce fracture risk.Methods Using HR-pQCT, we investigated the effects on distal tibia and radius microstructure of strontium ranelate (SrRan; 2 g/day) or alendronate (70 mg/week) for 2 years in postmenopausal osteoporotic women. This exploratory randomized, double-blind trial evaluated HR-pQCT and FEA parameters, areal bone mineral density (BMD), and bone turnover markers.Results In the intention-to-treat population (n = 83, age: 64 +/- 8 years; lumbar T-score: -2.8 +/- 0.8 [DXA]), distal tibia Cortical Thickness (CTh) and Density (DCort), and cancellous BV/TV increased by 6.3%, 1.4%, and 2.5%, respectively (all P < 0.005), with SrRan, but not with alendronate (0.9%, 0.4%, and 0.8%, NS) (P < 0.05 for all above between-group differences). Difference for CTh evaluated with a distance transformation method was close to significance (P = 0.06). The estimated failure load increased with SrRan (+2.1%, P < 0.005), not with alendronate (-0.6%, NS) (between-group difference, P < 0.01). Cortical stress was lower with SrRan (P < 0.05); both treatments decreased trabecular stress. At distal radius, there was no between-group difference other than DCort (P < 0.05). Bone turnover markers decreased with alendronate; bALP increased (+21%) and serum-CTX-I decreased (-1%) after 2 years of SrRan (between-group difference at each time point for both markers, P < 0.0001). Both treatments were well tolerated.Conclusions Within the constraints of HR-pQCT method, and while a possible artefactual contribution of strontium cannot be quantified, SrRan appeared to influence distal tibia bone microstructure and FEA-determined biomechanical parameters more than alendronate. However, the magnitude of the differences is unclear and requires confirmation with another method.

Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): a multicenter study.

Myelodysplastic syndromes (MDS) with del(5q) are considered to have a benign course of the disease. In order to address the issue of the propensity of those patients to progress to acute myeloid leukemia (AML), data on 381 untreated patients with MDS and del(5q) characterized by low or intermediate I International Prognostic Scoring System (IPSS) risk score were collected from nine centers and registries. Median survival of the entire group was 74 months. Transfusion-dependent patients had a median survival of 44 months vs 97 months for transfusion-independent patients (P<0.0001). Transfusion need at diagnosis was the most important patient characteristic for survival. Of the 381 patients, 48 (12.6%) progressed to AML. The cumulative progression rate calculated using the Kaplan-Meier method was 4.9% at 2 years and 17.6% at 5 years. Factors associated with the risk of AML transformation were high-risk World Health Organization adapted Prognostic Scoring System (WPSS) score, marrow blast count >5% and red-cell transfusion dependency at diagnosis. In conclusion, patients with MDS and del(5q) are facing a considerable risk of AML transformation. More detailed cytogenetic and molecular studies may help to identify the patients at risk of progression.

Rapid Site-Directed Mutagenesis Using Two-PCR-Generated DNA Fragments Reproducing the Plasmid Template.

We describe a new rapid and efficient polymerase chain reaction (PCR)-based site-directed mutagenesis method. This procedure is effective with any plasmid and it employs four oligonucleotide primers. One primer contains the desired mutation, the second is oriented in the opposite direction (one of these two primers should be phosphorylated), and the third and fourth should be coding in complementary fashion for a unique restriction site to be introduced in a nonessential region. The method consists of two simultaneous PCR reactions; the PCR products are digested with the enzyme that recognizes the newly introduced unique restriction site and then ligased and used to transform competent bacteria. Additionally, the use of Dpn I facilitates the elimination of template DNA. The newly introduced restriction site is essential for ligation in the correct orientation of the two-PCR products and is further used for mutant screening. Resulting plasmids carry both the new restriction site and the desired mutation. Using this method, more than 20 mutants have already been generated (using two different kinds of templates); all these mutants were sequenced for the desired mutation and transfected into AtT-20 cells and the expressed mutant proteins encoded by the vector were assayed.

Analysis and spatial modeling of the indoor radon Swiss data

The present research deals with an important public health threat, which is the pollution created by radon gas accumulation inside dwellings. The spatial modeling of indoor radon in Switzerland is particularly complex and challenging because of many influencing factors that should be taken into account. Indoor radon data analysis must be addressed from both a statistical and a spatial point of view. As a multivariate process, it was important at first to define the influence of each factor. In particular, it was important to define the influence of geology as being closely associated to indoor radon. This association was indeed observed for the Swiss data but not probed to be the sole determinant for the spatial modeling. The statistical analysis of data, both at univariate and multivariate level, was followed by an exploratory spatial analysis. Many tools proposed in the literature were tested and adapted, including fractality, declustering and moving windows methods. The use of Quan-tité Morisita Index (QMI) as a procedure to evaluate data clustering in function of the radon level was proposed. The existing methods of declustering were revised and applied in an attempt to approach the global histogram parameters. The exploratory phase comes along with the definition of multiple scales of interest for indoor radon mapping in Switzerland. The analysis was done with a top-to-down resolution approach, from regional to local lev¬els in order to find the appropriate scales for modeling. In this sense, data partition was optimized in order to cope with stationary conditions of geostatistical models. Common methods of spatial modeling such as Κ Nearest Neighbors (KNN), variography and General Regression Neural Networks (GRNN) were proposed as exploratory tools. In the following section, different spatial interpolation methods were applied for a par-ticular dataset. A bottom to top method complexity approach was adopted and the results were analyzed together in order to find common definitions of continuity and neighborhood parameters. Additionally, a data filter based on cross-validation was tested with the purpose of reducing noise at local scale (the CVMF). At the end of the chapter, a series of test for data consistency and methods robustness were performed. This lead to conclude about the importance of data splitting and the limitation of generalization methods for reproducing statistical distributions. The last section was dedicated to modeling methods with probabilistic interpretations. Data transformation and simulations thus allowed the use of multigaussian models and helped take the indoor radon pollution data uncertainty into consideration. The catego-rization transform was presented as a solution for extreme values modeling through clas-sification. Simulation scenarios were proposed, including an alternative proposal for the reproduction of the global histogram based on the sampling domain. The sequential Gaussian simulation (SGS) was presented as the method giving the most complete information, while classification performed in a more robust way. An error measure was defined in relation to the decision function for data classification hardening. Within the classification methods, probabilistic neural networks (PNN) show to be better adapted for modeling of high threshold categorization and for automation. Support vector machines (SVM) on the contrary performed well under balanced category conditions. In general, it was concluded that a particular prediction or estimation method is not better under all conditions of scale and neighborhood definitions. Simulations should be the basis, while other methods can provide complementary information to accomplish an efficient indoor radon decision making.

Results of computer assisted navigation in Total Knee Arthroplasty (TKA): comparison with the conventional method

The aim of this retrospective study was to compare the clinical and radiographic results after TKA (PFC, DePuy), performed either by computer assisted navigation (CAS, Brainlab, Johnson&Johnson) or by conventional means. Material and methods: Between May and December 2006 we reviewed 36 conventional TKA performed between 2002 and 2003 (group A) and 37 navigated TKA performed between 2005 and 2006 (group B) by the same experienced surgeon. The mean age in group A was 74 years (range 62-90) and 73 (range 58-85) in group B with a similar age distribution. The preoperative mechanical axes in group A ranged from -13° varus to +13° valgus (mean absolute deviation 6.83°, SD 3.86), in group B from -13° to +16° (mean absolute deviation 5.35, SD 4.29). Patients with a previous tibial osteotomy or revision arthroplasty were excluded from the study. Examination was done by an experienced orthopedic resident independent of the surgeon. All patients had pre- and postoperative long standing radiographs. The IKSS and the WOMAC were utilized to determine the clinical outcome. Patient's degree of satisfaction was assessed on a visual analogous scale (VAS). Results: 32 of the 37 navigated TKAs (86,5%) showed a postoperative mechanical axis within the limits of 3 degrees of valgus or varus deviation compared to only 24 (66%) of the 36 standard TKAs. This difference was significant (p = 0.045). The mean absolute deviation from neutral axis was 3.00° (range -5° to +9°, SD: 1.75) in group A in comparison to 1.54° (range -5° to +4°, SD: 1.41) in group B with a highly significant difference (p = 0.000). Furthermore, both groups showed a significant postoperative improvement of their mean IKSS-values (group A: 89 preoperative to 169 postoperative, group B 88 to 176) without a significant difference between the two groups. Neither the WOMAC nor the patient's degree of satisfaction - as assessed by VAS - showed significant differences. Operation time was significantly higher in group B (mean 119.9 min.) than in group A (mean 99.6 min., p <0.000). Conclusion: Our study showed consistent significant improvement of postoperative frontal alignment in TKA by computer assisted navigation (CAS) compared to standard methods, even in the hands of a surgeon well experienced in standard TKA implantation. However, the follow-up time of this study was not long enough to judge differences in clinical outcome. Thus, the relevance of computer navigation for clinical outcome and survival of TKA remains to be proved in long term studies to justify the longer operation time. References 1 Stulberg SD. Clin Orth Rel Res. 2003;(416):177-84. 2 Chauhan SK. JBJS Br. 2004;86(3):372-7. 3 Bäthis H, et al. Orthopäde. 2006;35(10):1056-65.

Three essays on the psychology of investment and financial markets

Préface My thesis consists of three essays where I consider equilibrium asset prices and investment strategies when the market is likely to experience crashes and possibly sharp windfalls. Although each part is written as an independent and self contained article, the papers share a common behavioral approach in representing investors preferences regarding to extremal returns. Investors utility is defined over their relative performance rather than over their final wealth position, a method first proposed by Markowitz (1952b) and by Kahneman and Tversky (1979), that I extend to incorporate preferences over extremal outcomes. With the failure of the traditional expected utility models in reproducing the observed stylized features of financial markets, the Prospect theory of Kahneman and Tversky (1979) offered the first significant alternative to the expected utility paradigm by considering that people focus on gains and losses rather than on final positions. Under this setting, Barberis, Huang, and Santos (2000) and McQueen and Vorkink (2004) were able to build a representative agent optimization model which solution reproduced some of the observed risk premium and excess volatility. The research in behavioral finance is relatively new and its potential still to explore. The three essays composing my thesis propose to use and extend this setting to study investors behavior and investment strategies in a market where crashes and sharp windfalls are likely to occur. In the first paper, the preferences of a representative agent, relative to time varying positive and negative extremal thresholds are modelled and estimated. A new utility function that conciliates between expected utility maximization and tail-related performance measures is proposed. The model estimation shows that the representative agent preferences reveals a significant level of crash aversion and lottery-pursuit. Assuming a single risky asset economy the proposed specification is able to reproduce some of the distributional features exhibited by financial return series. The second part proposes and illustrates a preference-based asset allocation model taking into account investors crash aversion. Using the skewed t distribution, optimal allocations are characterized as a resulting tradeoff between the distribution four moments. The specification highlights the preference for odd moments and the aversion for even moments. Qualitatively, optimal portfolios are analyzed in terms of firm characteristics and in a setting that reflects real-time asset allocation, a systematic over-performance is obtained compared to the aggregate stock market. Finally, in my third article, dynamic option-based investment strategies are derived and illustrated for investors presenting downside loss aversion. The problem is solved in closed form when the stock market exhibits stochastic volatility and jumps. The specification of downside loss averse utility functions allows corresponding terminal wealth profiles to be expressed as options on the stochastic discount factor contingent on the loss aversion level. Therefore dynamic strategies reduce to the replicating portfolio using exchange traded and well selected options, and the risky stock.

Validation of an analytical method for nitrous oxide (N2O) laughing gas by headspace gas chromatography coupled to mass spectrometry (HS-GC-MS): Forensic application to a lethal intoxication.

Drug abuse is a widespread problem affecting both teenagers and adults. Nitrous oxide is becoming increasingly popular as an inhalation drug, causing harmful neurological and hematological effects. Some gas chromatography-mass spectrometry (GC-MS) methods for nitrous oxide measurement have been previously described. The main drawbacks of these methods include a lack of sensitivity for forensic applications; including an inability to quantitatively determine the concentration of gas present. The following study provides a validated method using HS-GC-MS which incorporates hydrogen sulfide as a suitable internal standard allowing the quantification of nitrous oxide. Upon analysis, sample and internal standard have similar retention times and are eluted quickly from the molecular sieve 5Å PLOT capillary column and the Porabond Q column therefore providing rapid data collection whilst preserving well defined peaks. After validation, the method has been applied to a real case of N2O intoxication indicating concentrations in a mono-intoxication.

Nest distribution varies with dispersal method and familiarity-mediated aggression for two sympatric ants

Dispersal mechanisms and competition together play a key role in the spatial distribution of a population. Species that disperse via fission are likely to experience high levels of localized competitive pressure from conspecifics relative to species that disperse in other ways. Although fission dispersal occurs in many species, its ecological and behavioural effects remain unclear. We compared foraging effort, nest spatial distribution and aggression of two sympatric ant species that differ in reproductive dispersal: Streblognathus peetersi, which disperse by group fission, and Plectroctena mandibularis, which disperse by solitary wingless queens. We found that although both species share space and have similar foraging strategies, they differ in nest distribution and aggressive behaviour. The spatial distribution of S. peetersi nests was extremely aggregated, and workers were less aggressive towards conspecifics from nearby nests than towards distant conspecifics and all heterospecific workers. By contrast, the spatial distribution of P. mandibularis nests was overdispersed, and workers were equally aggressive towards conspecific and heterospecific competitors regardless of nest distance. Finally, laboratory experiments showed that familiarity led to the positive relationship between aggression and nest distance in S. peetersi. While unfamiliar individuals were initially aggressive, the level of aggression decreased within 1 h of contact, and continued to decrease over 24 h. Furthermore, individuals from near nests that were not aggressive could be induced to aggression after prolonged isolation. Overall, these results suggest that low aggression mediated by familiarity could provide benefits for a species with fission reproduction and an aggregated spatial distribution.

Le Q-sort, un outil pour la recherche en soins le cas des représentations chez les infirmiers en psychiatrie de l'âge avancé [Q-sort, a useful research method in care in cases of psychiatric nursing of the aged]

Q-sort is a research method which allows defining profiles of attitudes toward a set of statements, ordered in relation to each other. Pertaining to the Q Methodology, the qualitative analysis of the Q-sorts is based on quantitative techniques. This method is of particular interest for research in health professions, a field in which attitudes of patients and professionals are very important. The method is presented in this article, along with an example of application in nursing in old age psychiatry.

I have faith in my thing, you know what I mean? Mixed method elements on individual investments on religious markets.

In contemporary society, religious signification and secular systems mix and influence each other. Holistic conceptions of a world in which man is integrated harmoniously with nature meet representations of a world run by an immanent God. On the market of the various systems, the individual goes from one system to another, following his immediate needs and expectations without necessarily leaving any marks in a meaningful long term system. This article presents the first results of an ongoing research in Switzerland on contemporary religion focusing on (new) paths of socialization of modern that individuals and the various (non-) belief systems that they simultaneously develop

Innovative method for carbon dioxide determination in human postmortem cardiac gas samples using headspace-gas chromatography-mass spectrometry and stable labeled isotope as internal standard.

A novel approach to measure carbon dioxide (CO2) in gaseous samples, based on a precise and accurate quantification by (13)CO2 internal standard generated in situ is presented. The main goal of this study was to provide an innovative headspace-gas chromatography-mass spectrometry (HS-GC-MS) method applicable in the routine determination of CO2. The main drawback of the GC methods discussed in the literature for CO2 measurement is the lack of a specific internal standard necessary to perform quantification. CO2 measurement is still quantified by external calibration without taking into account analytical problems which can often occur considering gaseous samples. To avoid the manipulation of a stable isotope-labeled gas, we have chosen to generate in situ an internal labeled standard gas ((13)CO2) on the basis of the stoichiometric formation of CO2 by the reaction of hydrochloric acid (HCl) with sodium hydrogen carbonate (NaH(13)CO3). This method allows a precise measurement of CO2 concentration and was validated on various human postmortem gas samples in order to study its efficiency.

Modified 'dumbbell' technique: a simple and intuitive method to position balloon-expandable stent valves.

Intraoperative cardiac imaging plays a key role during transcatheter aortic valve replacement. In recent years, new techniques and new tools for improved image quality and virtual navigation have been proposed, in order to simplify and standardize stent valve positioning and implantation. But routine performance of the new techniques may require major economic investments or specific knowledge and skills and, for this reason, they may not be accessible to the majority of cardiac centres involved in transcatheter valve replacement projects. Additionally, they still require injections of contrast medium to obtain computed images. Therefore, we have developed and describe here a very simple and intuitive method of positioning balloon-expandable stent valves, which represents the evolution of the 'dumbbell' technique for echocardiography-guided transcatheter valve replacement without angiography. This method, based on the partial inflation of the balloon catheter during positioning, traps the crimped valve in the aortic valve orifice and, consequently, very near to the ideal landing zone. It does not require specific echocardiographic knowledge; it does not require angiographies that increase the risk of postoperative kidney failure in elderly patients, and it can be also performed in centres not equipped with a hybrid operating room.

Validation and long-term evaluation of a modified on-line chiral analytical method for therapeutic drug monitoring of (R,S)-methadone in clinical samples.

Matrix effects, which represent an important issue in liquid chromatography coupled to mass spectrometry or tandem mass spectrometry detection, should be closely assessed during method development. In the case of quantitative analysis, the use of stable isotope-labelled internal standard with physico-chemical properties and ionization behaviour similar to the analyte is recommended. In this paper, an example of the choice of a co-eluting deuterated internal standard to compensate for short-term and long-term matrix effect in the case of chiral (R,S)-methadone plasma quantification is reported. The method was fully validated over a concentration range of 5-800 ng/mL for each methadone enantiomer with satisfactory relative bias (-1.0 to 1.0%), repeatability (0.9-4.9%) and intermediate precision (1.4-12.0%). From the results obtained during validation, a control chart process during 52 series of routine analysis was established using both intermediate precision standard deviation and FDA acceptance criteria. The results of routine quality control samples were generally included in the +/-15% variability around the target value and mainly in the two standard deviation interval illustrating the long-term stability of the method. The intermediate precision variability estimated in method validation was found to be coherent with the routine use of the method. During this period, 257 trough concentration and 54 peak concentration plasma samples of patients undergoing (R,S)-methadone treatment were successfully analysed for routine therapeutic drug monitoring.

The management of iron deficiency in inflammatory bowel disease--an online tool developed by the RAND/UCLA appropriateness method.

BACKGROUND: Iron deficiency is a common and undertreated problem in inflammatory bowel disease (IBD). AIM: To develop an online tool to support treatment choice at the patient-specific level. METHODS: Using the RAND/UCLA Appropriateness Method (RUAM), a European expert panel assessed the appropriateness of treatment regimens for a variety of clinical scenarios in patients with non-anaemic iron deficiency (NAID) and iron deficiency anaemia (IDA). Treatment options included adjustment of IBD medication only, oral iron supplementation, high-/low-dose intravenous (IV) regimens, IV iron plus erythropoietin-stimulating agent (ESA), and blood transfusion. The panel process consisted of two individual rating rounds (1148 treatment indications; 9-point scale) and three plenary discussion meetings. RESULTS: The panel reached agreement on 71% of treatment indications. 'No treatment' was never considered appropriate, and repeat treatment after previous failure was generally discouraged. For 98% of scenarios, at least one treatment was appropriate. Adjustment of IBD medication was deemed appropriate in all patients with active disease. Use of oral iron was mainly considered an option in NAID and mildly anaemic patients without disease activity. IV regimens were often judged appropriate, with high-dose IV iron being the preferred option in 77% of IDA scenarios. Blood transfusion and IV+ESA were indicated in exceptional cases only. CONCLUSIONS: The RUAM revealed high agreement amongst experts on the management of iron deficiency in patients with IBD. High-dose IV iron was more often considered appropriate than other options. To facilitate dissemination of the recommendations, panel outcomes were embedded in an online tool, accessible via http://ferroscope.com/.