Chemical composition of the small coastal lagoons of the Mediterranean Spanish littoral

About sixty small water bodies (coastal lagoons, marshes, salt pans, channels, springs, etc.) of the Spanish Mediterranean coast were sampled seasonally for one year (1979-1980), in order to study different aspects of their chemical composition. The concentrations of major ions (alkalinity, Cl-, Ca2+, Mg2+, Na+, and K+), nutrients (N.NO-3, N.NO2-, TRP and Si), oxygen and pH were determined for this purpose. The salt concentrations measured range between 0.4 and 361.3 g l-1. The samples have been divided into four classes of salinity (in g l-1): Cl, S < 5; C2, 5 40. Within these classes, the pattern of ionic dominance recorded is remarkably constant and similar to that found in most coastal lagoons (Cl- > So42- > Alk., for the anions, and Na+ > Mg2+ > Ca2+ > K+, for the cations), although other models occur especially in the first class. The dominance of Na+ and Cl-, as well as the molar ratios Mg2+/Ca2+ and Cl- / SO42- ,clearly increase from class Cl to class C4. The hyperhaline waters include different subtypes of the major brine type"c",, of EUGSTER & HARDIE (1978), the Na+ - (Mg2+) - Cl- - (SO42-) being the most frequent. Nutrient concentrations fall within a wide range (N.NO3 from 0.1 to 1100 mg-at 1-1; PRT from 0.01 to 23.56 mg-at l-1 and Si from 1.0 to 502.0 mg-at l-1). The oxygen values are very variable too, ranging between 0 and 14.4 ml l-1. Four different patterns of nutrient distribution have been distinguished based on the mean concentrations of N.NO3-, and TRP (mean values in mg-at l-1): A, N.NO3- < 10, TRP > l ; B, N.NO3- > 100, TRP < 1; C, 10 < N.NO3- < 100, TRP < 1; C, D, N.NO3- < 10, TRP < 1. As a rule, lagoons of low salinity (C1 and C2 classes) display the nutrient pattern C, and lagoons of high salinity (C3 and C4) show the nutrient pattern D. Model A only appears in waters of very low salinity, whereas model B does not seem to be related to salinity.

Looking for factors involved in the light-dependent degradation of phytochrome A

SUMMARY : Phytochromes constitute a family of red/far-red photoreceptors regulating all the major transitions during the life cycle of plants. In Arabidopsis, five members: phyA,_ B, C, D and E, were identified. Phytochromes are synthesized in their inactive red-light absorbing form called Pr. Upon light absorbance they convert to the far-red light absorbing Pfr form. The Pfr form is the active conformer which converts back to the Pr form either rapidly upon far-red perception or in a slower process called dark reversion. ph~A represents an exception, in that it does not significantly dark-revert and two specific processes have been developed by the plants to decrease the amount of biologically active phyA. The first one is alight-dependent repression of the PHYA gene expression and the second one is alight-dependent degradation of the phyA protein. The latter is the most efficient process to rapidly decrease the level of active phyA. The ability of plants to regulate the amount of active phyA is critical in a far-red rich environment, a situation observed under a canopy. In these conditions, phyA is essential to induce the germination and the deetiolation of the young seedling. Later in the development the ability of phyA to repress growth counteracts the shade avoidance response. Therefore decreasing the amount of phyA allows stem growth and to compete with neighbours for the light. In this thesis, I investigate the light-dependent degradation of phyA. I developed a reverse genetic approach based on the systematic analysis of the light-dependent accumulation of phyA in the different cullin mutant cull, cul3a; cul3b and cul4. This analysis allowed me to show that CUL1 and CUL3A-based E3 ligase complexes are involved in the regulation of phyA degradation. Surprisingly, our results also demonstrate that cu14 is not affected in the degradation of phyA whereas constitutive Photomorphogenic 1 (COP1) a subunit of one CUL4based E3 complex was reported to be involved. Further investigations showed that the phenotype of cop1 is conditional, the mutant being defective in phyA degradation only in the presence of metabolisable sugars. I also showed that phyA is degraded by a proteasome-dependent mechanism both in the cytoplasm and in the nucleus using mutants and transgenic lines affected in the localization of phyA. Interestingly, I observed that phyA degradation was faster in the nucleus than in the cytosol and that rapid degradation of Pr also occurred in the nucleus suggesting that cytosolic accumulation of phyA in the dark is a way to regulate its proteolysis. Finally, we identify a short region similar to a PEST sequence required for phyA stability and we developed a unbiased genetic screen to identify new components involved in the regulation of the light-dependent degradation of phyA. The significance of these results are discussed. RESUME : Les phytochromes (phy) constituent une famille de photorécepteurs absorbant la lumière rouge et rouge lointaine et régulant toutes les étapes de transitions majeures dans la vie des plantes. Chez Arabidopsis, cinq membres : phyA, B, C, D et E ont été identifiés. Les phytochromes sont synthétisés sous une forme inactive appelée Pr absorbant la lumière rouge. Après perception de lumière ils passent sous une forme active Pfr absorbant dans le rouge lointain. La forme Pfr peut retourner sous la forme Pr après absorption de lumiëre rouge lointaine ou dans un processus lent appelé «réversion à l'obscurité ». phyA représente une exception à cette règle car il ne retoune pas significativement sous sa forme inactive dans le noir. Deux processus spécifiques ont donc été développés pour diminuer le taux de phyA actif. Le premier consiste en la répression du gène PHYA en condition de lumière et le second en une dégradation induite par la lumière de la protéine phyA. Ce dernier processus est le plus efficace pour diminuer rapidement le niveau de phyA. La capacité des plantes à réguler le taux de phyA actifs est critique dans un environnement riche en lumière rouge lointaine, une situation observée sous une canopée. Sous une canopée, phyA est essentiel pour induire la germination et la dé-étiolation de la jeune pousse. Plus tard dans le développement la capacité de phyA de réprimer la croissance freine la «réponse à l'évitement de l'ombre ». Par conséquent diminuer le taux de phyA permet la croissance de la tige et donc de rentrer en compétition pour la lumière avec les plantes avoisinantes. Dans cette thèse, j'ai étudié la dégradation de phyA. J'ai développé une approche génétique inverse basée sur l'analyse systématique de l'accumulation de phyA en condition de lumière dans les différents mutants cullin, cul1, cul3a, cul3b et cul4. Ces analyses nous ont permis d'identifier qu'un complexe E3 ligase CUL1 et un complexe E3 ligase CUL3A sont impliqués dans la régulation de la dégradation de phyA. Mes résultats démontrent aussi que le mutant cul4 n'est pas affecté dans la dégradation de phyA alors que Çonstitutive Photomorphogenic 1 (COPI) une sous unité d'un complexe CUL4 à été identifier dans la régulation de cette dégradation. Des analyses supplémentaires suggèrent que l'effet de la mutation cop1 est dépendante dë la présence de sucres métabolisables. J'ai aussi montré que phyA est dégradé dans le noyau et dans le cytoplasme par un mécanisme dépendant du protéasome et que la dégradation dans le.noyau est non seulement aspécifique de la forme Pr ou Pfr mais aussi est plus rapide que dans le cytoplasme. Ceci suggère que l'accumulation de phyA dans le cytoplasme permet son accumulation à des niveaux élevés à l'obscurité. Enfin j'ai identifié une région similaire à un motif PEST requise pour la stabilité de phyA et j'ai aussi développé un criblage génétique non biaisé pour identifier de nouveaux composants impliqués dans la régulation de la dégradation de phyA. L'importance de ces résultats est discutée dans le dernier chapitre de cette thèse.

The structure of nervous tissue and of Gram-positive bacteria studied by cryo-electron microscopy of vitreous sections

Résumé La structure, ou l'architecture, des êtres vivants définit le cadre dans lequel la physique de la vie s'accomplit. La connaissance de cette structure dans ses moindres détails est un but essentiel de la biologie. Son étude est toutefois entravée par des limitations techniques. Malgré son potentiel théorique, la microscopie électronique n'atteint pas une résolution atomique lorsqu'elle est appliquée ä la matièxe biologique. Cela est dû en grande partie au fait qu'elle contient beaucoup d'eau qui ne résiste pas au vide du microscope. Elle doit donc être déshydratée avant d'être introduite dans un microscope conventionnel. Des artéfacts d'agrégation en découlent inévitablement. La cryo-microscopie électronique des sections vitreuses (CEMOVIS) a ëté développée afin de résoudre cela. Les spécimens sont vitrifiés, c.-à-d. que leur eau est immobilisée sans cristalliser par le froid. Ils sont ensuite coupés en sections ultrafines et celles-ci sont observées à basse température. Les spécimens sont donc observés sous forme hydratée et non fixée; ils sont proches de leur état natif. Durant longtemps, CEMOVIS était très difficile à exécuter mais ce n'est plus le cas. Durant cette thèse, CEMOVIS a été appliqué à différents spécimens. La synapse du système nerveux central a été étudiée. La présence dans la fente synaptique d'une forte densité de molécules organisées de manière périodique a été démontrée. Des particules luminales ont été trouvées dans Ies microtubules cérébraux. Les microtubules ont servi d'objets-test et ont permis de démontrer que des détails moléculaires de l'ordre du nm sont préservés. La compréhension de la structure de l'enveloppe cellulaire des bactéries Grampositives aété améliorée. Nos observations ont abouti à l'élaboration d'un nouveau modèle hypothétique de la synthèse de la paroi. Nous avons aussi focalisé notre attention sur le nucléoïde bactérien et cela a suscité un modèle de la fonction des différents états structuraux du nucléoïde. En conclusion, cette thèse a démontré que CEMOVIS est une excellente méthode poux étudier la structure d'échantillons biologiques à haute résolution. L'étude de la structure de divers aspects des êtres vivants a évoqué des hypothèses quant à la compréhension de leur fonctionnement. Summary The structure, or the architecture, of living beings defines the framework in which the physics of life takes place. Understanding it in its finest details is an essential goal of biology. Its study is however hampered by technical limitations. Despite its theoretical potential, electron microscopy cannot resolve individual atoms in biological matter. This is in great part due to the fact. that it contains a lot of water that cannot stand the vacuum of the microscope. It must therefore be dehydrated before being introduced in a conventional mìcroscope. Aggregation artefacts unavoidably happen. Cryo-electron microscopy of vitreous sections (CEMOVIS) has been developed to solve this problem. Specimens are vitrified, i.e. they are rapidly cooled and their water is immobilised without crystallising by the cold. They are then. sectioned in ultrathin slices, which are observed at low temperatures. Specimens are therefore observed in hydrated and unfixed form; they are close to their native state. For a long time, CEMOVIS was extremely tedious but this is not the case anymore. During this thesis, CEMOVIS was applied to different specimens. Synapse of central nervous system was studied. A high density of periodically-organised molecules was shown in the synaptic cleft. Luminal particles were found in brain microtubules. Microtubules, used as test specimen, permitted to demonstrate that molecular details of the order of nm .are preserved. The understanding of the structure of cell envelope of Gram-positive bacteria was improved. Our observations led to the elaboration of a new hypothetic model of cell wall synthesis. We also focused our attention on bacterial nucleoids and this also gave rise to a functional model of nucleoid structural states. In conclusion, this thesis demonstrated that CEMOVIS is an excellent method for studying the structure of bìologìcal specimens at high resolution. The study of the structure of various aspects of living beings evoked hypothesis for their functioning.

Variation in thermal performance and reaction norms among populations of Drosophila melanogaster.

The major goal of evolutionary thermal biology is to understand how variation in temperature shapes phenotypic evolution. Comparing thermal reaction norms among populations from different thermal environments allows us to gain insights into the evolutionary mechanisms underlying thermal adaptation. Here, we have examined thermal adaptation in six wild populations of the fruit fly (Drosophila melanogaster) from markedly different natural environments by analyzing thermal reaction norms for fecundity, thorax length, wing area, and ovariole number under ecologically realistic fluctuating temperature regimes in the laboratory. Contrary to expectation, we found only minor differences in the thermal optima for fecundity among populations. Differentiation among populations was mainly due to differences in absolute (and partly also relative) thermal fecundity performance. Despite significant variation among populations in the absolute values of morphological traits, we observed only minor differentiation in their reaction norms. Overall, the thermal reaction norms for all traits examined were remarkably similar among different populations. Our results therefore suggest that thermal adaptation in D. melanogaster predominantly involves evolutionary changes in absolute trait values rather than in aspects of thermal reaction norms.

Association of T-zone reticular networks and conduits with ectopic lymphoid tissues in mice and humans.

Ectopic or tertiary lymphoid tissues (TLTs) are often induced at sites of chronic inflammation. They typically contain various hematopoietic cell types, high endothelial venules, and follicular dendritic cells; and are organized in lymph node-like structures. Although fibroblastic stromal cells may play a role in TLT induction and persistence, they have remained poorly defined. Herein, we report that TLTs arising during inflammation in mice and humans in a variety of tissues (eg, pancreas, kidney, liver, and salivary gland) contain stromal cell networks consisting of podoplanin(+) T-zone fibroblastic reticular cells (TRCs), distinct from follicular dendritic cells. Similar to lymph nodes, TRCs were present throughout T-cell-rich areas and had dendritic cells associated with them. They expressed lymphotoxin (LT) β receptor (LTβR), produced CCL21, and formed a functional conduit system. In rat insulin promoter-CXCL13-transgenic pancreas, the maintenance of TRC networks and conduits was partially dependent on LTβR and on lymphoid tissue inducer cells expressing LTβR ligands. In conclusion, TRCs and conduits are hallmarks of secondary lymphoid organs and of well-developed TLTs, in both mice and humans, and are likely to act as important scaffold and organizer cells of the T-cell-rich zone.

Resposta do tomateiro à fertirrigação potássica e cobertura plástica do solo

O objetivo do presente estudo foi determinar os efeitos da fertirrigação potássica e da cobertura do solo em película de plástico preto, na cultura do tomate. O experimento foi realizado na Universidade Federal de Viçosa, em solo Podzólico Vermelho-Amarelo câmbico. Os tratamentos, em cinco repetições, no delineamento em blocos casualizados, corresponderam a: (A) aplicação manual de 40% da dose recomendada de K no sulco de transplante e 60% aplicados manualmente, em cobertura; (B) aplicação manual de 40% da dose de K no sulco de transplante, e 60% aplicados por fertirrigação; (C) procedimento idêntico ao anterior, porém com o solo coberto por plástico preto; (D) aplicação de 100% da dose de K por fertirrigação e (E) procedimento idêntico ao anterior, porém com o solo coberto por plástico preto. Os tratamentos B, C, D e E foram irrigados por gotejamento. Maiores produções de tomates foram obtidas com a aplicação do K por fertirrigação do que com a aplicação manual. Estas produções, entretanto, não foram influenciadas pela aplicação total ou parcial de K por fertirrigação, nem pela presença de cobertura plástica do solo. Os teores de N-NO3-, N-orgânico, K, Ca e Mg no pecíolo do tomateiro não foram influenciados pelos tratamentos.

Forgoing dental care for economic reasons in Switzerland: a six-year cross-sectional population-based study

BACKGROUND: While oral health is part of general health and well-being, oral health disparities nevertheless persist. Potential mechanisms include socioeconomic factors that may influence access to dental care in the absence of universal dental care insurance coverage. We investigated the evolution, prevalence and determinants (including socioeconomic) of forgoing of dental care for economic reasons in a Swiss region, over the course of six years. METHODS: Repeated population-based surveys (2007-2012) of a representative sample of the adult population of the Canton of Geneva, Switzerland. Forgone dental care, socioeconomic and insurance status, marital status, and presence of dependent children were assessed using standardized methods. RESULTS: A total of 4313 subjects were included, 10.6% (457/4313) of whom reported having forgone dental care for economic reasons in the previous 12 months. The crude percentage varied from 2.4% in the wealthiest group (monthly income ≥ 13,000 CHF, 1 CHF ≈ 1$) to 23.5% among participants with the lowest income (<3,000 CHF). Since 2007/8, forgoing dental care remained stable overall, but in subjects with a monthly income of <3,000 CHF, the adjusted percentage increased from 16.3% in 2007/8 to 20.6% in 2012 (P trend = 0.002). Forgoing dental care for economic reasons was independently associated with lower income, younger age, female gender, current smoking, having dependent children, divorced status and not living with a partner, not having a supplementary health insurance, and receipt of a health insurance premium cost-subsidy. CONCLUSIONS: In a Swiss region without universal dental care insurance coverage, prevalence of forgoing dental care for economic reasons was high and highly dependent on income. Efforts should be made to prevent high-risk populations from forgoing dental care.

Cytokines and T-cell homeostasis.

Homeostasis of T cells can be defined as the ability of the immune system to maintain normal T-cell counts and to restore T-cell numbers following T-cell depletion or expansion. These processes are governed by extrinsic signals, most notably cytokines. Two members of the common gamma chain family of cytokines, interleukin (IL)-7 and IL-15, are central to homeostatic proliferation and survival of mature CD4(+) and CD8(+) T cells. Recent evidence suggests that other cytokines, including IL-2, IL-10, IL-12, interferons and TGF-beta, as well as the transcription factors T-bet and eomesodermin all play important but different roles at distinct stages of T-cell homeostasis.

The relationship between cognitive errors and interpersonal patterns in depressed women.

Individuals with depression process information in an overly negative or biased way (e.g., Henriques & Leitenberg, 2002) and demonstrate significant interpersonal dysfunction (e.g., Zlotnick, Kohn, Keitner, & Della Grotta, 2000). This study examined the relationship between cognitive errors (CEs) and interpersonal interactions in early psychotherapy sessions of 25 female patients with major depression. Transcripts were rated for CEs using the Cognitive Error Rating Scale (Drapeau, Perry, & Dunkley, 2008). Interpersonal patterns were assessed using the Structural Analysis of Social Behavior (Benjamin, 1974). Significant associations were found between CEs and markers of interpersonal functioning in selected contexts. The implications of these findings in bridging the gap between research and practice, enhancing treatment outcome, and improving therapist training are discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

Initial and Extended Use of Femoral Versus Nonfemoral Double-Lumen Vascular Catheters and Catheter-Related Infection During Continuous Renal Replacement Therapy.

BACKGROUND: The risk of catheter-related infection or bacteremia, with initial and extended use of femoral versus nonfemoral sites for double-lumen vascular catheters (DLVCs) during continuous renal replacement therapy (CRRT), is unclear. STUDY DESIGN: Retrospective observational cohort study. SETTING & PARTICIPANTS: Critically ill patients on CRRT in a combined intensive care unit of a tertiary institution. FACTOR: Femoral versus nonfemoral venous DLVC placement. OUTCOMES: Catheter-related colonization (CRCOL) and bloodstream infection (CRBSI). MEASUREMENTS: CRCOL/CRBSI rates expressed per 1,000 catheter-days. RESULTS: We studied 458 patients (median age, 65 years; 60% males) and 647 DLVCs. Of 405 single-site only DLVC users, 82% versus 18% received exclusively 419 femoral versus 82 jugular or subclavian DLVCs, respectively. The corresponding DLVC indwelling duration was 6±4 versus 7±5 days (P=0.03). Corresponding CRCOL and CRBSI rates (per 1,000 catheter-days) were 9.7 versus 8.8 events (P=0.8) and 1.2 versus 3.5 events (P=0.3), respectively. Overall, 96 patients with extended CRRT received femoral-site insertion first with subsequent site change, including 53 femoral guidewire exchanges, 53 new femoral venipunctures, and 47 new jugular/subclavian sites. CRCOL and CRBSI rates were similar for all such approaches (P=0.7 and P=0.9, respectively). On multivariate analysis, CRCOL risk was higher in patients older than 65 years and weighing >90kg (ORs of 2.1 and 2.2, respectively; P<0.05). This association between higher weight and greater CRCOL risk was significant for femoral DLVCs, but not for nonfemoral sites. Other covariates, including initial or specific DLVC site, guidewire exchange versus new venipuncture, and primary versus secondary DLVC placement, did not significantly affect CRCOL rates. LIMITATIONS: Nonrandomized retrospective design and single-center evaluation. CONCLUSIONS: CRCOL and CRBSI rates in patients on CRRT are low and not influenced significantly by initial or serial femoral catheterizations with guidewire exchange or new venipuncture. CRCOL risk is higher in older and heavier patients, the latter especially so with femoral sites.

High prevalence of the metabolic syndrome in HIV-infected patients: impact of different definitions of the metabolic syndrome.

INTRODUCTION: This study describes the characteristics of the metabolic syndrome in HIV-positive patients in the Data Collection on Adverse Events of Anti-HIV Drugs study and discusses the impact of different methodological approaches on estimates of the prevalence of metabolic syndrome over time. METHODS: We described the prevalence of the metabolic syndrome in patients under follow-up at the end of six calendar periods from 2000 to 2007. The definition that was used for the metabolic syndrome was modified to take account of the use of lipid-lowering and antihypertensive medication, measurement variability and missing values, and assessed the impact of these modifications on the estimated prevalence. RESULTS: For all definitions considered, there was an increasing prevalence of the metabolic syndrome over time, although the prevalence estimates themselves varied widely. Using our primary definition, we found an increase in prevalence from 19.4% in 2000/2001 to 41.6% in 2006/2007. Modification of the definition to incorporate antihypertensive and lipid-lowering medication had relatively little impact on the prevalence estimates, as did modification to allow for missing data. In contrast, modification to allow the metabolic syndrome to be reversible and to allow for measurement variability lowered prevalence estimates substantially. DISCUSSION: The prevalence of the metabolic syndrome in cohort studies is largely based on the use of nonstandardized measurements as they are captured in daily clinical care. As a result, bias is easily introduced, particularly when measurements are both highly variable and may be missing. We suggest that the prevalence of the metabolic syndrome in cohort studies should be based on two consecutive measurements of the laboratory components in the syndrome definition.

The ArgR regulatory protein, a helper to the anaerobic regulator ANR during transcriptional activation of the arcD promoter in Pseudomonas aeruginosa.

Pseudomonas aeruginosa, when deprived of oxygen, generates ATP from arginine catabolism by enzymes of the arginine deiminase pathway, encoded by the arcDABC operon. Under conditions of low oxygen tension, the transcriptional activator ANR binds to a site centered 41.5 bp upstream of the arcD transcriptional start. ANR-mediated anaerobic induction was enhanced two- to threefold by extracellular arginine. This arginine effect depended, in trans, on the transcriptional regulator ArgR and, in cis, on an ArgR binding site centered at -73.5 bp in the arcD promoter. Binding of purified ArgR protein to this site was demonstrated by electrophoretic mobility shift assays and DNase I footprinting. This ArgR recognition site contained a sequence, 5'-TGACGC-3', which deviated in only 1 base from the common sequence motif 5'-TGTCGC-3' found in other ArgR binding sites of P. aeruginosa. Furthermore, an alignment of all known ArgR binding sites confirmed that they consist of two directly repeated half-sites. In the absence of ANR, arginine did not induce the arc operon, suggesting that ArgR alone does not activate the arcD promoter. According to a model proposed, ArgR makes physical contact with ANR and thereby facilitates initiation of arc transcription.

Long diagnostic delay in Crohn's disease is associated with complicated disease course and increased operation rate

Background and Aims: The impact of d iagnostic delay ( a period from appearance of f irst s ymptoms t o diagnosis) o n the clinical c ourse o f Crohn's disease (CD) i s unknown. W e examined whether length of d iagnostic delay a ffects d isease outcome. Methods: Data from the Swiss IBD cohort study were analyzed. T he frequencies of o ccurrence of b owel s tenoses, internal fistulas, perianal f istulas, and CD-related surgery at distinct i ntervals a fter C D diagnosis (0 - < 2 , 2 - < 6,  6 years) were c ompared f or g roups o f patients w ith different length of d iagnostic delay. Results: T he data from a g roup o f 200 CD patients with long diagnostic delay (> 24 months, 76th - 100th p ercentile) were c ompared to t hose from a group of 4 61 patients with a short diagnostic delay ( within 9 months, 1st - 50th p ercentile). T reatment r egimens d id n ot d iffer between t he two groups. Two years following diagnosis, p atients with long diagnostic delay presented more frequently with bowel stenoses (25% vs. 13.1%, p = 0.044), internal fistulas (10% vs. 2%, p = 0.018), perianal f istulas ( 20% vs. 8 .1%, p = 0.023) a nd more frequently underwent intestinal surgery (15% vs. 5 .1%, p = 0.024) t han patients with short diagnostic delay. Intestinal surgery was a lso m ore frequently p erformed  6 y ears after diagnosis in t he group with long d iagnostic delay ( 56.2% vs. 42.3%, p = 0.005) w hen compared to t he g roup with short diagnostic delay. Conclusions: L ong diagnostic delay i s associated with worse o utcome c haracterized by t he development o f increased bowel damage, n ecessitating more frequently operations in t he years following CD d iagnosis. Efforts should be undertaken to shorten the diagnostic delay.

Modelling Bone Mineral Density in Swiss Breast Cancer Patients Treated with Letrozole, Tamoxifen and Sequences of Letrozole and Tamoxifen in the BIG 1-98 Study (SAKK 21/07).

Background: Bone health is a concern when treating early stage breast cancer patients with adjuvant aromatase inhibitors. Early detection of patients (pts) at risk of osteoporosis and fractures may be helpful for starting preventive therapies and selecting the most appropriate endocrine therapy schedule. We present statistical models describing the evolution of lumbar and hip bone mineral density (BMD) in pts treated with tamoxifen (T), letrozole (L) and sequences of T and L. Methods: Available dual-energy x-ray absorptiometry exams (DXA) of pts treated in trial BIG 1-98 were retrospectively collected from Swiss centers. Treatment arms: A) T for 5 years, B) L for 5 years, C) 2 years of T followed by 3 years of L and, D) 2 years of L followed by 3 years of T. Pts without DXA were used as a control for detecting selection biases. Patients randomized to arm A were subsequently allowed an unplanned switch from T to L. Allowing for variations between DXA machines and centres, two repeated measures models, using a covariance structure that allow for different times between DXA, were used to estimate changes in hip and lumbar BMD (g/cm2) from trial randomization. Prospectively defined covariates, considered as fixed effects in the multivariable models in an intention to treat analysis, at the time of trial randomization were: age, height, weight, hysterectomy, race, known osteoporosis, tobacco use, prior bone fracture, prior hormone replacement therapy (HRT), bisphosphonate use and previous neo-/adjuvant chemotherapy (ChT). Similarly, the T-scores for lumbar and hip BMD measurements were modeled using a per-protocol approach (allowing for treatment switch in arm A), specifically studying the effect of each therapy upon T-score percentage. Results: A total of 247 out of 546 pts had between 1 and 5 DXA; a total of 576 DXA were collected. Number of DXA measurements per arm were; arm A 133, B 137, C 141 and D 135. The median follow-up time was 5.8 years. Significant factors positively correlated with lumbar and hip BMD in the multivariate analysis were weight, previous HRT use, neo-/adjuvant ChT, hysterectomy and height. Significant negatively correlated factors in the models were osteoporosis, treatment arm (B/C/D vs. A), time since endocrine therapy start, age and smoking (current vs. never).Modeling the T-score percentage, differences from T to L were -4.199% (p = 0.036) and -4.907% (p = 0.025) for the hip and lumbar measurements respectively, before any treatment switch occurred. Conclusions: Our statistical models describe the lumbar and hip BMD evolution for pts treated with L and/or T. The results of both localisations confirm that, contrary to expectation, the sequential schedules do not seem less detrimental for the BMD than L monotherapy. The estimated difference in BMD T-score percent is at least 4% from T to L.

Mutations in the human UBR1 gene and the associated phenotypic spectrum.

Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n = 29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.