A dynamical measure of the black hole mass in a quasar 11 billion years ago.

Tight relationships exist in the local Universe between the central stellar properties of galaxies and the mass of their supermassive black hole (SMBH)1-3. These suggest that galaxies and black holes co-evolve, with the main regulation mechanism being energetic feedback from accretion onto the black hole during its quasar phase4-6. A crucial question is how the relationship between black holes and galaxies evolves with time; a key epoch to examine this relationship is at the peaks of star formation and black hole growth 8-12 billion years ago (redshifts 1-3)7. Here we report a dynamical measurement of the mass of the black hole in a luminous quasar at a redshift of 2, with a look back in time of 11 billion years, by spatially resolving the broad-line region (BLR). We detect a 40-µas (0.31-pc) spatial offset between the red and blue photocentres of the Hα line that traces the velocity gradient of a rotating BLR. The flux and differential phase spectra are well reproduced by a thick, moderately inclined disk of gas clouds within the sphere of influence of a central black hole with a mass of 3.2 × 108 solar masses. Molecular gas data reveal a dynamical mass for the host galaxy of 6 × 1011 solar masses, which indicates an undermassive black hole accreting at a super-Eddington rate. This suggests a host galaxy that grew faster than the SMBH, indicating a delay between galaxy and black hole formation for some systems.

Disability, support and long-term social care of an elderly Spanish population, 2008-2009: an epidemiologic analysis.

BACKGROUND: Though poorly known, relationships between disability, need of help (dependency) and use of social services are crucial aspects of public health. The objective of this study was to describe the links between disability, officially assessed dependency, and social service use by an industrial population, and identify areas of inequity. METHODS: We took advantage of a door-to-door survey conducted in the Cinco Villas district, Spain, in 2008-2009, which provided data on disability, morbidity, and service use among 1216 residents aged ≥50 years, and officially assessed dependency under the 2006 Dependency Act (OAD). Using logistic regression, we combined data collected at homes/residences on 625 disability screened-positive participants, and administrative information on degree of OAD and benefits at date of visit. RESULTS: Based on 163 disabled persons, the prevalence of residential/community-care users was 13.4% overall, with 6.0% being market-provided, 2.5% supported by the 2006 Act, and 4.9% supported by other public funds. Of 111 OAD applicants, 30 had been assigned an OAD degree; in 29 cases this was the highest OAD degree, with 12 receiving direct support for residential care and 17 receiving home care. Compared to unassessed dependency, the highest OAD degree was linked to residential care (OR and 95% CI) 12.13 (3.86-38.16), declared non-professional care 10.99 (1.28-94.53), and publicly-funded, non-professional care 26.30 (3.36-205.88). In contrast, 43 persons, 58% of the severely/extremely disabled, community-dwelling sample population, 81% of whom were homebound, including 10 persons with OAD but no implemented service plan, made no use of any service, and of these, 40% lacked a non-professional carer. CONCLUSIONS: Formal service use in the Cinco Villas district attained ratios observed for established welfare systems but the publicly-funded proportion was lower. The 2006 Act had a modest, albeit significant, impact on support for non-professional carers and residential care, coexisting with a high prevalence of non-use of social services by severely disabled persons.

Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells.

Tamoxifen is a standard endocrine therapy for estrogen receptor positive breast cancer patients. Despite its success, development of resistance mechanisms is still a serious clinical problem. Deregulation of survival signaling pathways play a key role in tamoxifen resistance, being upregulation of Rac1-PAK1 signaling pathway one of the most important. Here, we report the development of the breast cancer cell model MCF7::C1199 having Rac1 enhanced activity with the aim of evaluating the role of Rac1 in acquired endocrine resistance. These cells not only showed distinctive features of Rac1-regulated process as increased migration and proliferation rates, but also showed that upregulation of Rac1 activity triggered a hormonal-independent and tamoxifen resistant phenotype. We also demonstrated that PAK1 activity increases in response to Tamoxifen, increasing phosphorylation levels of estrogen receptor at Ser305, a key phosphorylation site involved in tamoxifen resistance. Finally, we evaluated the effect of 1A-116, a specific Rac1 inhibitor developed by our group, in tamoxifen-resistant cells. 1A-116 effectively restored tamoxifen anti-proliferative effects, switched off PAK1 activity and decreased estrogen receptor phospho-Ser305 levels. Since combination schemes of novel targeted agents with endocrine therapy could be potential new strategies to restore tamoxifen sensibility, these results show that inhibition of Rac1-PAK1 signaling pathway may provides benefits to revert resistance mechanisms in endocrine therapies.

Analysis of disability using WHODAS 2.0 among the middle-aged and elderly in Cinco Villas, Spain.

BACKGROUND: The prevalence of disability, as defined by the International Classification of Functioning, Disability and Health (ICF), among the middle-aged and elderly population is poorly known. OBJECTIVE: To determine disability prevalence in a resident population sample aged ≥50 years, in the Cinco Villas district, Spain, from June 2008 through June 2009. METHODS: We used the WHODAS 2.0 36-item questionnaire to quantify the prevalence of disability, globally and by domain, together with a 13-item combined measure of three domains, Getting around, Self-care and Life activities, claimed to reflect the need of integrated services. In addition, we performed exploratory analyses of the relationship between disability and different variables using ordinal logistic regression. RESULTS: Disability was detected by global WHODAS score in 604 of a total of 1214 persons, i.e., a prevalence of 49.8% 95% CI (46.9-52.5), with the corresponding figures for mild, moderate, severe, and extreme disability being 26.8%, 16.0%, 7.6% and 0.1%, respectively. Disability increased with age, was higher among women, and for specific domains. Prevalence of severe/extreme disability among women vs. men was as follows: Getting around, 26.8% vs. 12.1%; Life activities, 25.2% vs. 6.8%; and Self-care, 9.5% vs. 6.0%. Disability was more frequent among subjects diagnosed with dementia, chronic liver disease, severe mental disease, and stroke. The abovementioned 13-item measure yielded prevalence figures for disability levels quite similar to those obtained using 36-item scores. CONCLUSIONS: For the first time, this study furnishes detailed disability prevalence figures and data on associated variables in a middle-aged and elderly Western population.

Evaluation of the antiviral activity of natural sulfated polyhydroxysteroids and their synthetic derivatives and analogs.

Disodium 3beta,21-dihydroxypregn-5-en-20-one disulfate (2), sodium 3beta,21-dihydroxypregn-5-en-20-one 3-sulfate (3), sodium 3beta,21-dihydroxypregn-5-en-20-one 21-sulfate (4), and disodium 3beta,6alpha-dihydroxy-5alpha-pregnan-20-one disulfate (6) have been synthesized and completely characterized for the first time from readily available materials. Sulfation was performed using triethylamine-sulfur trioxide complex in dimethylformamide as the sulfating agent. Selective sulfation of 3beta,21-dihydroxypregn-5-en-20-one rendered sodium 3beta,21-dihydroxypregn-5-en-20-one 3-sulfate (3) as the major compound. The synthetic sulfated steroids as well as natural disulfated polyhydroxysteroids (7-9) isolated by us from the antarctic ophiuroid Astrotoma agassizii and the synthetic derivatives disodium 2beta,3alpha,21-trihydroxy-(20R)-cholesta-5,24-diene 3-acetate, 2,21-disulfate (7a) and 2beta,3alpha,21-trihydroxy-(20R)-cholesta-5,24-diene (7b) were comparatively evaluated for their inhibitory effect on the replication of one DNA (HSV-2) and two RNA (PV-3, JV) viruses. In general, steroids with sulfate groups at C-21 and C-2 or C-3 were the most effective in their inhibitory action against HSV-2 and also proved to be active against PV-3 and JV.

Clinical experiences with the use of indole-3-pyruvic acid.

In the last few years, Indol-3-pyruvic acid (IPA) has been subjected to 5 pilot clinical trials in volunteers and a phase II study on patients affected by anxiety, with or without sleep problems. Overall, results indicated a very good safety profile, relief from anxiety and a better quality of sleep in patients treated with IPA. Moreover, the drug showed no withdrawal signs, but positive effects on mood, improving feelings of relaxation, calmness and happiness. The mechanism of action of IPA, depending on increased turnover of some indoles in the CNS, appears clearly distinct from that of benzodiazepines, suggesting that the drug might be used in the treatment of symptoms of mild anxiety and stress experienced by busy and anxious people.

Synthesis of C-5'-nor-dideoxycarbanucleosides structurally related to neplanocin C.

Purine carbanucleosides built on a 6-oxabicyclo[3.1.0]hexane template were synthesized from readily available 2-cyclopentenone employing a Mitsunobu reaction to incorporate the base onto the carbocyclic ring. Both adenosine and guanosine analogues exhibited moderate antiviral activity.

Load transmission through the callus site with external fixation systems: theoretical and experimental analysis.

The fracture callus contribution to the total rigidity of external fixator-fractured bone element was analysed. This study was achieved from both theoretical and experimental perspectives. The theoretical study was done using the finite element method with a three-dimensional model. In this model, both the callus and the development of its elastic characteristics were considered. A series of 38 New Zealand-California white rabbits with tibial fractures treated with some external fixation system was used in this study. Such devices could reproduce either rigid or elastic features. The frame dynamization can be obtained at different fracture healing stages. Animals were classified into four series: (1) rigid fixators, (2) dynamized fixators two weeks after surgery, (3) three weeks after surgery and (4) four weeks after surgery. Tension tests were performed to evaluate callus strength. Theoretical results showed significant levels of callus load transmission (85.5%) when the callus elastic modulus is 1/100 of the elastic modulus of intact bone in an external fixator with rigid features. Experimental analysis of the callus obtained with different external fixator systems did not show differences among them. This fact implies that the immature callus theoretically modelled (E = 100 N mm-2) appears early in the rabbit fracture model (before two weeks, when first dynamization was made), for this reason no differences were found between the two types of treatment (rigid and dynamized systems). This fact questions the reliability of the dynamization process in external fixation of fractures and it implies accurate investigations in the clinical field.

Design and development of a new general purpose stereotaxic device.

This paper describes the design and development of a new device which allows the surgeon to locate an internal point following two X-ray views with an image intensifier. Three dimensional coordinates of the target point are directly estimated by means of two ring-and-bead sights and no computer calculations are necessary. After the location of the target point it is possible to choose any track to it by means of the rotation of an arc and the circumferential sliding of the arc. The system reduces radiation doses and it can be used for many purposes such as percutaneous discectomies and chemonucleolysis, biopsies and screw insertion of interlocking nails.