High incidence of clinical fragility fractures in postmenopausal women with rheumatoid arthritis. A case-control study.

OBJECTIVES: To estimate the incidence of clinical fragility fractures in postmenopausal women with rheumatoid arthritis (RA) and analyze risk factors for fracture. METHODS: Incidence of clinical fragility fractures in 330 postmenopausal women with RA was compared to that of a control population of 660 age-matched postmenopausal Spanish women. Clinical fractures during the previous five years were recorded. We analyzed associations with risk factors for fracture in both populations and with disease-related variables in RA patients. RESULTS: Median age of RA patients was 64 years; median RA duration was eight years. Sixty-nine percent were in remission or on low activity. Eighty-five percent had received glucocorticoids (GCs); 85 %, methotrexate; and 40 %, ≥1 biologic DMARD. Fifty-four patients and 47 controls had ≥1 major osteoporotic fracture (MOF). Incidence of MOFs was 3.55 per 100 patient-year in patients and 0.72 in controls (HR: 2.6). Risk factors for MOFs in RA patients were age, previous fracture, parental hip fracture, years since menopause, BMD, erosions, disease activity and disability, and cumulative dose of GCs. Previous fracture in RA patients was a strong risk for MOFs (HR: 10.37). CONCLUSION: Of every 100 postmenopausal Spanish women with RA, 3-4 have a MOF per year. This is more than double that of the general population. A previous fracture poses a high risk for a new fracture. Other classic risk factors for fracture, RA disease activity and disability, and the cumulative dose of GCs are associated with fracture development.

PrsQ2, a small periplasmic protein involved in increased uranium resistance in the bacterium Cupriavidus metallidurans.

Uranium contamination is a widespread problem caused by natural and anthropogenic activities. Although microorganisms thrive in uranium-contaminated environments, little is known about the actual molecular mechanisms mediating uranium resistance. Here, we investigated the resistance mechanisms driving the adaptation of Cupriavidus metallidurans NA4 to toxic uranium concentrations. We selected a spontaneous mutant able to grow in the presence of 1 mM uranyl nitrate compared to 250 µM for the parental strain. The increased uranium resistance was acquired via the formation of periplasmic uranium-phosphate precipitates facilitated by the increased expression of a genus-specific small periplasmic protein, PrsQ2, regulated as non-cognate target of the CzcS2-CzcR2 two-component system. This study shows that bacteria can adapt to toxic uranium concentrations and explicates the complete genetic circuit behind the adaptation.

Eng2, a new player involved in feedback loop regulation of Cdc42 activity in fission yeast.

Cell polarity and morphogenesis are regulated by the small GTPase Cdc42. Even though major advances have been done in the field during the last years, the molecular details leading to its activation in particular cellular contexts are not completely understood. In fission yeast, the ß(1,3)-glucanase Eng2 is a "moonlighting protein" with a dual function, acting as a hydrolase during spore dehiscence, and as component of the endocytic machinery in vegetative cells. Here, we report that Eng2 plays a role in Cdc42 activation during polarized growth through its interaction with the scaffold protein Scd2, which brings Cdc42 together with its guanine nucleotide exchange factor (GEF) Scd1. eng2Δ mutant cells have defects in activation of the bipolar growth (NETO), remaining monopolar during all the cell cycle. In the absence of Eng2 the accumulation of Scd1 and Scd2 at the poles is reduced, the levels of Cdc42 activation decrease, and the Cdc42 oscillatory behavior, associated with bipolar growth in wild type cells, is altered. Furthermore, overexpression of Eng2 partially rescues the growth and polarity defects of a cdc42-L160S mutant. Altogether, our work unveils a new factor regulating the activity of Cdc42, which could potentially link the polarity and endocytic machineries.

Differential associations between impaired autobiographical memory recall and future thinking in people with and without schizophrenia.

OBJECTIVES: The ability to think about future events serves a range of important functions. People with schizophrenia show impairments in future thinking. However, whether these impairments are specific to positive or negative events and to what extent they are associated with impairments in verbal fluency and autobiographical memory remains poorly understood. METHODS: People with schizophrenia (n = 93) and people without psychiatric diagnoses (n = 111) were asked to generate future events and retrieve past autobiographical events and they also completed a test of verbal fluency. Participants also completed questionnaire measures of the positive and negative dimensions of schizophrenia and depression symptoms. RESULTS: People with schizophrenia generated significantly fewer positive and negative future events than controls. In a linear regression, the interaction between diagnosis and autobiographical memory retrieval explained a significant amount of variance in the number of future events that participants generated even when accounting for symptoms and verbal fluency. Past and future thinking abilities were correlated in controls but not in people with schizophrenia. CONCLUSIONS: People with schizophrenia may not rely on autobiographical content to imagine the future and may rely instead on semantic processes. Interventions that improve past and future thinking amongst people with schizophrenia are warranted. PRACTITIONER POINTS: Compared to control participants, people with schizophrenia have marked difficulty generating possible, positive and negative, future events. Unlike controls, for people with schizophrenia there is no relation between their ability to remember past events and their ability to think about the future. People with schizophrenia may have difficulty using their memories for their past to imagine and simulate possible future events.

A new toolkit for gene tagging in Candida albicans containing recyclable markers.

Gene manipulation and epitope tagging are essential tools for understanding the molecular function of specific genes. The opportunistic human pathogen Candida albicans is a diploid fungus that utilizes a non-canonical genetic code. Since selection markers available in this organism are scarce, several tools based on recyclable markers have been developed for gene disruption, such as the Clox system. This system relies on the Cre recombinase, which recycles selection markers flanked by loxP sites with high efficiency, facilitating single marker or multi-marker recycling. However, PCR-based modules for epitope tagging, such the pFA-modules, mainly use limited non-recyclable auxotrophic markers. To solve this problem, we have used a Gibson assembly strategy to construct a set of new plasmids where the auxotrophic markers of the pFA vectors were swapped with five recyclable marker modules of the Clox system, enhancing the versatility of the pFA plasmids. This new toolkit, named pFA-Clox, is composed of 36 new vectors for gene disruption and epitope tagging (GFP, 3xGFP, mCherry, 3xHA, 5xmyc and TAP). These plasmids contain the dominant NAT1 marker, as well as URA3, HIS1 and ARG4 cassettes, thereby permitting functional analysis of laboratory strains as well as clinical isolates of C. albicans. In summary, we have adapted the Clox system to the pFA-backbone vectors. Thus, the set of primers used for the amplification of previously published pFA modules can also be utilized in this new pFA-Clox system. Therefore, this new toolkit harbors the advantages of both systems, allowing accelerated gene modification strategies that could reduce time and costs in strain construction for C. albicans.

Valence-related impairments in the retrieval of specific autobiographical memories amongst patients with schizophrenia.

OBJECTIVES: People with schizophrenia have difficulty recalling specific autobiographical events from their past. However, the nature of this difficulty (e.g., whether these problems are only for memories that are negative or positive) and the mechanisms associated with it remain poorly understood. METHODS: The present investigation asked patients with schizophrenia (n = 91) and healthy controls (n = 109) to recall memories related to several positive and negative cue words. Participants also completed self-report measures of rumination and depressive symptoms and a measure of verbal fluency to assess executive functioning. Participants' memories were coded for specificity (whether or not they referred to a specific event lasting <24 hr) and valence (positive vs. negative). RESULTS: Patients recalled fewer specific memories than controls and they showed particular difficulty recalling specific negative memories cued by negative words. For healthy controls, impoverished verbal fluency was associated with recall of fewer specific memories and particularly recall of fewer positive specific memories. These variables were unrelated to specificity amongst patients. Rumination was not associated with specificity in either group. CONCLUSIONS: These findings are discussed with reference to other mechanisms that might contribute towards reduced specificity in schizophrenia, such as the tendency to avoid negative affect, and the implications of this for interventions for schizophrenia and memory specificity problems. PRACTITIONER POINTS: The experience of schizophrenia is associated with problems recalling specific events from one's past. In particular, patients have difficulty recalling specific negative memories from their past. These memory problems are independent of executive functioning difficulties, ruminative tendencies, and also depression symptoms. Interventions for memory problems in schizophrenia must target the difficulty people have in recalling specific negative events.

Epidemiología de las fracturas osteoporóticas en Andalucía en el período 2000-2010 / Epidemiology of osteoporotic fractures in Andalusia, Spain, from 2000-2010

Fundamento y objetivo: El objetivo de este estudio es conocer diferentes datos epidemiológicos de las fracturas osteoporóticas en Andalucía en el período 2000-2010. Ante la falta de estudios epidemiológicos de fracturas en Andalucía nos propusimos conocer el número y tasas de incidencia de las fracturas osteoporóticas, su distribución por sexo y edad, localización, estacionalidad y tendencia secular. Métodos: Estudio de cohorte observada durante un periodo de 11 años analizando los datos suministrados por el registro del Conjunto Mínimo Básico de Datos durante el período 2000-2010. Resultados: El total de fracturas osteoporóticas fueron 96.458 con una tasa de incidencia bruta de 374,18 fracturas por 100.000 habitantes. Las fracturas aumentaron en este período un 27% (p<0,01, IC 95%, 0,71; 0,73). Hemos encontrado un cambio de tendencia en la relación mujer/hombre pasando de 3,4 a 3,2 y en la disminución de fracturas en los dos últimos años, sobre todo en el último, con una disminución del 11,2% en las fracturas de cadera (p<0,001, IC 95%, 0,88; 0,895). Conclusiones: En este periodo se ha producido un aumento de fracturas por el envejecimiento de la población pero también un cambio de tendencia con la disminución de fracturas en algunos grupos de edad. La tasa de incidencia de fracturas es variable entre los diferentes países y regiones de España y entre las diferentes provincias de Andalucía

Background and objective: The aim of this study was to examine the epidemiological data on osteoporotic fractures in Andalusia in the period 2000-2010. In view of the lack of epidemiological studies of fractures in Andalusia, we set out to ascertain the number and incidence rates of osteoporotic fractures and their distribution by gender and age, location, comorbidity, seasonality and secular trend. Methods: Cohort study observed over a period of 11 years analysing the data provided by the Minimum Basic Data Set register for the period 2000-2010. Results: There were a total of 96,458 osteoporotic fractures, with a crude incidence rate of 374.18 fractures per 100,000 population. Fractures increased in this period by 27% (p<.01, IC 95%, 0.71; 0.73). We found a trend change in female/male ratio, from 3.4 to 3.2, and in the reduction in fractures in the last two years, especially in the past year, with a decrease of 11.2% in hip fractures (p<.001, IC 95%, 0.88; 0.895). Conclusions: In this period, there has been an increase in fractures as a consequence of the ageing of the population, but also a change in trend, with fractures decreasing in some age groups. The incidence rate of fractures varies between different countries and regions of Spain, and between different provinces of Andalusia

The anillin-related Int1 protein and the Sep7 septin collaborate to maintain cellular ploidy in Candida albicans.

Variation in cell ploidy is a common feature of Candida albicans clinical isolates that are resistant to the antifungal drug fluconazole. Here, we report that the anillin-related protein Int1 interacts with septins for coupling cytokinesis with nuclear segregation. Loss of Int1 results in a rapid disassembly of duplicated septin rings from the bud neck at the onset of actomyosin ring contraction. Strikingly, this has no major impact on cytokinesis and septum formation. However, Int1 genetically interacts with the Sep7 septin, maintaining the diffusion barrier at the bud neck and guarantying a faithful nuclear segregation. Indeed, int1ΔΔ sep7ΔΔ mutant cells, in contrast to int1ΔΔ cdc10ΔΔ, undergo a premature activation of mitotic exit prior to the alignment of the mitotic spindle with the division axis, producing large multinucleated cells. Some of these multinucleated cells arise from trimeras similar to those observed upon fluconazole exposure. Finally, the defects in nuclear segregation could be in part due to the inability to maintain the Lte1 mitotic exit activator at the cortex of the daughter cell. These results suggest that Int1 and Sep7 play a role in maintaining genome stability by acting as a diffusion barrier for Lte1.

Epidemiology of osteoporotic fractures in Andalusia, Spain, from 2000-2010. / Epidemiología de las fracturas osteoporóticas en Andalucía en el período 2000-2010.

BACKGROUND AND OBJECTIVE: The aim of this study was to examine the epidemiological data on osteoporotic fractures in Andalusia in the period 2000-2010. In view of the lack of epidemiological studies of fractures in Andalusia, we set out to ascertain the number and incidence rates of osteoporotic fractures and their distribution by gender and age, location, comorbidity, seasonality and secular trend. METHODS: Cohort study observed over a period of 11 years analysing the data provided by the Minimum Basic Data Set register for the period 2000-2010. RESULTS: There were a total of 96,458 osteoporotic fractures, with a crude incidence rate of 374.18 fractures per 100,000 population. Fractures increased in this period by 27% (p<.01, IC 95%, 0.71; 0.73). We found a trend change in female/male ratio, from 3.4 to 3.2, and in the reduction in fractures in the last two years, especially in the past year, with a decrease of 11.2% in hip fractures (p<.001, IC 95%, 0.88; 0.895). CONCLUSIONS: In this period, there has been an increase in fractures as a consequence of the ageing of the population, but also a change in trend, with fractures decreasing in some age groups. The incidence rate of fractures varies between different countries and regions of Spain, and between different provinces of Andalusia.

Editorial: Deficiencia de vitamina D. Consecuencias para la salud / No disponible

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Introducción: Deficiencia de vitamina D. Consecuencias para la salud / No disponible

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Utilización de la vitamina D en la práctica clínica / No disponible

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Efecto del bloqueo del factor de necrosis tumoral α sobre el metabolismo óseo en las enfermedades inflamatorias articulares crónicas / Effect of tumour necrosis factor α blockade on bone metabolism in chronic inflammatory joint diseases

Fundamento y objetivo: Evaluar el efecto de los tratamientos anti-TNF sobre la densidad mineral ósea (DMO), los marcadores de remodelado óseo (MRO) y la ratio receptor activator for nuclear factor κB ligand (RANKL, «ligando del receptor activador del factor nuclear κB»)/osteoprotegerina (OPG) en los pacientes con enfermedades inflamatorias articulares crónicas. Métodos: Estudio longitudinal prospectivo en condiciones de práctica clínica sobre 31 pacientes diagnosticados de artritis reumatoide, artropatía psoriásica y espondilitis anquilosante que estuvieron durante un año en tratamiento con fármacos anti-TNF alfa. Al inicio y al final del estudio se evaluaron la DMO, la OPG y la forma soluble de RANKL (sRANKL), y durante el estudio (0, 3, 6, 9 y 12 meses), la actividad de la enfermedad (SDAI, BASDAI y PCR), la capacidad funcional (HAQ, BASFI), los MRO y la vitamina D. Resultados: La DMO no se modificó después de un año de tratamiento. Los pacientes que consumieron corticoides tuvieron una pérdida media de masa ósea del 3% en el raquis lumbar (± 1,6, p = 0,02). En cuanto a los MRO, no experimentaron cambios significativos a lo largo del estudio. Disminuyó la actividad de la enfermedad, tanto SDAI (p = 0,002) como BASDAI (p = 0,002). La OPG se mantuvo sin cambios durante el año de tratamiento, mientras que disminuyeron significativamente tanto el sRANKL (0,28 ± 0,22, p = 0,013) como la ratio sRANKL/OPG (0,04 ± 0,03, p = 0,031). Conclusión: Los pacientes en tratamiento con anti-TNF no presentaron una pérdida de DMO significativa durante el seguimiento (un año), a la vez que experimentaron una mejora de la actividad de la enfermedad. Estos resultados han sido más evidentes en los pacientes respondedores (AU)

Background and objective: To evaluate the effect of anti-TNF treatments on bone mineral density (BMD), bone remodelling markers (BRM) and receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) in patients with chronic inflammatory joint diseases. Methods: A longitudinal prospective study was performed under clinical practice conditions on 31 patients diagnosed of rheumatoid arthritis, psoriatic arthropathy and ankylosing spondylitis who had received treatment with anti-TNF alpha drugs for one year. BMD, OPG and RANKL soluble form (sRANKL) were studied at the onset and end of the study. During the study (0, 3, 6, 9 and 12 month), disease activity (SDAI, BASDAI and CRP), functional capacity (HAQ, BASFI), BRM and vitamin D were studied. Results: BMD was not modified after one year of treatment. The patients who took corticosteroids had a mean bone mass loss of 3% in the lumbar spine (± 1.6, P = .02). In regards to the BRM, did not experience significant changes over the course of the study. Disease activity, both SDAI (P = .002) and BASDAI (P = .002), decreased. OPG was maintained without changes during the year of treatment while both the sRANKL (0.28 ± 0.22, P = .013) and sRANKL/OPG ratio significantly decreased (0.04 ± 0.03,P = .031). Conclusion: The patients being treated with anti-TNF did not present with a significant loss of DMO during the study (one year), at the same time experiencing an improvement in disease activity. This protection has been clearer in the responding patients (AU)

[Effect of tumour necrosis factor α blockade on bone metabolism in chronic inflammatory joint diseases]. / Efecto del bloqueo del factor de necrosis tumoral α sobre el metabolismo óseo en las enfermedades inflamatorias articulares crónicas.

BACKGROUND AND OBJECTIVE: To evaluate the effect of anti-TNF treatments on bone mineral density (BMD), bone remodelling markers (BRM) and receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) in patients with chronic inflammatory joint diseases. METHODS: A longitudinal prospective study was performed under clinical practice conditions on 31 patients diagnosed of rheumatoid arthritis, psoriatic arthropathy and ankylosing spondylitis who had received treatment with anti-TNF alpha drugs for one year. BMD, OPG and RANKL soluble form (sRANKL) were studied at the onset and end of the study. During the study (0, 3, 6, 9 and 12 month), disease activity (SDAI, BASDAI and CRP), functional capacity (HAQ, BASFI), BRM and vitamin D were studied. RESULTS: BMD was not modified after one year of treatment. The patients who took corticosteroids had a mean bone mass loss of 3% in the lumbar spine (±1.6, P=.02). In regards to the BRM, did not experience significant changes over the course of the study. Disease activity, both SDAI (P=.002) and BASDAI (P=.002), decreased. OPG was maintained without changes during the year of treatment while both the sRANKL (0.28±0.22, P=.013) and sRANKL/OPG ratio significantly decreased (0.04±0.03, P=.031). CONCLUSION: The patients being treated with anti-TNF did not present with a significant loss of DMO during the study (one year), at the same time experiencing an improvement in disease activity. This protection has been clearer in the responding patients.

Regulation of Ace2-dependent genes requires components of the PBF complex in Schizosaccharomyces pombe.

The division cycle of unicellular yeasts is completed with the activation of a cell separation program that results in the dissolution of the septum assembled during cytokinesis between the 2 daughter cells, allowing them to become independent entities. Expression of the eng1(+) and agn1(+) genes, encoding the hydrolytic enzymes responsible for septum degradation, is activated at the end of each cell cycle by the transcription factor Ace2. Periodic ace2(+) expression is regulated by the transcriptional complex PBF (PCB Binding Factor), composed of the forkhead-like proteins Sep1 and Fkh2 and the MADS box-like protein Mbx1. In this report, we show that Ace2-dependent genes contain several combinations of motifs for Ace2 and PBF binding in their promoters. Thus, Ace2, Fkh2 and Sep1 were found to bind in vivo to the eng1(+) promoter. Ace2 binding was coincident with maximum level of eng1(+) expression, whereas Fkh2 binding was maximal when mRNA levels were low, supporting the notion that they play opposing roles. In addition, we found that the expression of eng1(+) and agn1(+) was differentially affected by mutations in PBF components. Interestingly, agn1(+) was a major target of Mbx1, since its ectopic expression resulted in the suppression of Mbx1 deletion phenotypes. Our results reveal a complex regulation system through which the transcription factors Ace2, Fkh2, Sep1 and Mbx1 in combination control the expression of the genes involved in separation at the end of the cell division cycle.

A single nucleotide polymorphism uncovers a novel function for the transcription factor Ace2 during Candida albicans hyphal development.

Candida albicans is a major invasive fungal pathogen in humans. An important virulence factor is its ability to switch between the yeast and hyphal forms, and these filamentous forms are important in tissue penetration and invasion. A common feature for filamentous growth is the ability to inhibit cell separation after cytokinesis, although it is poorly understood how this process is regulated developmentally. In C. albicans, the formation of filaments during hyphal growth requires changes in septin ring dynamics. In this work, we studied the functional relationship between septins and the transcription factor Ace2, which controls the expression of enzymes that catalyze septum degradation. We found that alternative translation initiation produces two Ace2 isoforms. While full-length Ace2, Ace2L, influences septin dynamics in a transcription-independent manner in hyphal cells but not in yeast cells, the use of methionine-55 as the initiation codon gives rise to Ace2S, which functions as the nuclear transcription factor required for the expression of cell separation genes. Genetic evidence indicates that Ace2L influences the incorporation of the Sep7 septin to hyphal septin rings in order to avoid inappropriate activation of cell separation during filamentous growth. Interestingly, a natural single nucleotide polymorphism (SNP) present in the C. albicans WO-1 background and other C. albicans commensal and clinical isolates generates a stop codon in the ninth codon of Ace2L that mimics the phenotype of cells lacking Ace2L. Finally, we report that Ace2L and Ace2S interact with the NDR kinase Cbk1 and that impairing activity of this kinase results in a defect in septin dynamics similar to that of hyphal cells lacking Ace2L. Together, our findings identify Ace2L and the NDR kinase Cbk1 as new elements of the signaling system that modify septin ring dynamics in hyphae to allow cell-chain formation, a feature that appears to have evolved in specific C. albicans lineages.

Eng2 is a component of a dynamic protein complex required for endocytic uptake in fission yeast.

Eng2 is a glucanase required for spore release, although it is also expressed during vegetative growth, suggesting that it might play other cellular functions. Its homology to the Saccharomyces cerevisiae Acf2 protein, previously shown to promote actin polymerization at endocytic sites in vitro, prompted us to investigate its role in endocytosis. Interestingly, depletion of Eng2 caused profound defects in endocytic uptake, which were not due to the absence of its glucanase activity. Analysis of the dynamics of endocytic proteins by fluorescence microscopy in the eng2Δ strain unveiled a previously undescribed phenotype, in which assembly of the Arp2/3 complex appeared uncoupled from the internalization of the endocytic coat and resulted in a fission defect. Strikingly also, we found that Eng2-GFP dynamics did not match the pattern of other endocytic proteins. Eng2-GFP localized to bright cytosolic spots that moved around the cellular poles and occasionally contacted assembling endocytic patches just before recruitment of Wsp1, the Schizosaccharomyces pombe WASP. Interestingly, Csh3-YFP, a WASP-interacting protein, interacted with Eng2 by co-immunoprecipitation and was recruited to Eng2 in bright cytosolic spots. Altogether, our work defines a novel endocytic functional module, which probably couples the endocytic coat to the actin module.

Protocolo de tratamiento de la deficiencia de vitamina D / Protocol of treatment of vitamin D deficiency

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