Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis

Background: In the SOD1G93A mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS. Methods: The cellular effects of pharmacological inhibition of tyrosine kinases with masitinib were analyzed in cell cultures of microglia isolated from aged symptomatic SOD1G93A rats. To determine whether masitinib prevented the appearance of aberrant glial cells or modified post-paralysis survival, the drug was orally administered at 30 mg/kg/day starting after paralysis onset. Results: We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations. In microglia cultures from symptomatic SOD1G93A spinal cords, masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of masitinib to SOD1G93A rats starting after paralysis onset decreased the number of aberrant glial cells, microgliosis, and motor neuron pathology in the degenerating spinal cord, relative to vehicle-treated rats. Masitinib treatment initiated 7 days after paralysis onset prolonged post-paralysis survival by 40 %. Conclusions: These data show that masitinib is capable of controlling microgliosis and the emergence/expansion of aberrant glial cells, thus providing a strong biological rationale for its use to control neuroinflammation in ALS. Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS.Agencia Nacional de Investigación e Innovació

Composite Bulges -- III. A Study of Nuclear Star Clusters in Nearby Spiral Galaxies

We present photometric and morphological analyses of nuclear star clusters (NSCs) -- very dense, massive star clusters present in the central regions of most galaxies -- in a sample of 33 massive disk galaxies within 20 Mpc, part of the "Composite Bulges Survey." We use data from the Hubble Space Telescope including optical (F475W and F814W) and near-IR (F160W) images from the Wide Field Camera 3. We fit the images in 2D to take into account the full complexity of the inner regions of these galaxies (including the contributions of nuclear disks and bars), isolating the nuclear star cluster and bulge components. We derive NSC radii and magnitudes in all 3 bands, which we then use to estimate NSC masses. Our sample significantly expands the sample of massive late-type galaxies with measured NSC properties. We clearly identify nuclear star clusters in nearly 80% of our galaxies, putting a lower limit on the nucleation fraction in these galaxies that is higher than previous estimates. We find that the NSCs in our massive disk galaxies are consistent with previous NSC mass-NSC radius and Galaxy Mass-NSC Mass relations. However, we also find a large spread in NSC masses, with a handful of galaxies hosting very low-mass, compact clusters. Our NSCs are aligned in PA with their host galaxy disks but are less flattened. They show no correlations with bar or bulge properties. Finally, we find the ratio of NSC to BH mass in our massive disk galaxy sample spans a factor of $\sim$300.Comment: Accepted to The Astrophysical Journa

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Composite Bulges – II. Classical Bulges and Nuclear Discs in Barred Galaxies: The Contrasting Cases of NGC 4608 and NGC 4643

Abstract We present detailed morphological, photometric, and stellar-kinematic analyses of the central regions of two massive, early-type barred galaxies with nearly identical large-scale morphologies. Both have large, strong bars with prominent inner photometric excesses that we associate with boxy/peanut-shaped (B/P) bulges; the latter constitute ∼30% of the galaxy light. Inside its B/P bulge, NGC 4608 has a compact, almost circular structure (half-light radius Re ≈ 310 pc, Sérsic n = 2.2) we identify as a classical bulge, amounting to 12.1% of the total light, along with a nuclear star cluster (Re ∼ 4 pc). NGC 4643, in contrast, has a nuclear disc with an unusual broken-exponential surface-brightness profile (13.2% of the light), and a very small spheroidal component (Re ≈ 35 pc, n = 1.6; 0.5% of the light). IFU stellar kinematics support this picture, with NGC 4608’s classical bulge slowly rotating and dominated by high velocity dispersion, while NGC 4643’s nuclear disc shows a drop to lower dispersion, rapid rotation, V-h3 anticorrelation, and elevated h4. Both galaxies show at least some evidence for V-h3correlation in the bar (outside the respective classical bulge and nuclear disc), in agreement with model predictions. Standard 2-component (bulge/disc) decompositions yield B/T ∼ 0.5–0.7 (and bulge n > 2) for both galaxies. This overestimates the true “spheroid” components by factors of four (NGC 4608) and over 100 (NGC 4643), illustrating the perils of naive bulge-disc decompositions applied to massive barred galaxies

Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis

Background: In the SOD1^G93A mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS. Methods: The cellular effects of pharmacological inhibition of tyrosine kinases with masitinib were analyzed in cell cultures of microglia isolated from aged symptomatic SOD1^G93A rats. To determine whether masitinib prevented the appearance of aberrant glial cells or modified post-paralysis survival, the drug was orally administered at 30 mg/kg/day starting after paralysis onset. Results: We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations. In microglia cultures from symptomatic SOD1^G93A spinal cords, masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of masitinib to SOD1^G93A rats starting after paralysis onset decreased the number of aberrant glial cells, microgliosis, and motor neuron pathology in the degenerating spinal cord, relative to vehicle-treated rats. Masitinib treatment initiated 7 days after paralysis onset prolonged post-paralysis survival by 40 %. Conclusions: These data show that masitinib is capable of controlling microgliosis and the emergence/expansion of aberrant glial cells, thus providing a strong biological rationale for its use to control neuroinflammation in ALS. Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS.Keywords: M-CSF, Neurodegeneration, ALS, Aberrant glial cells, MasitinibKeywords: M-CSF, Neurodegeneration, ALS, Aberrant glial cells, Masitini

Agenda-setting revisited: When and how do primary-care physicians solicit patients’ additional concerns?

Objective: Soliciting patients’ complete agendas of concerns (aka. ‘agenda setting’) can improve patients’ health outcomes and satisfaction, and physicians’ time management. We assess the distribution, content, and effectiveness of physicians’ post-chief-complaint, agenda-setting questions. Methods: We coded videotapes/transcripts of 407 primary-, acute-care visits between adults and 85 general-practice physicians operating in 46 community-based clinics in two states representing urban and rural care. Measures are the incidence of physicians’ questions, their linguistic format, position within visits, likelihood of being responded to, and the nature of such responses. Results: Physicians’ questions designed to solicit concerns additional to chief concerns occurred in only 32% of visits (p \u3c .001). Compared to questions whose communication format explicitly solicited ‘questions’ (e.g., “Do you have any questions?”), those that were formatted so as to allow for ‘concerns’ (e.g., “Any other concerns?”) were significantly more likely to generate some type of agenda item (Chi2 (1, N = 131) = 11.96, p = .001), and to do so more frequently when positioned ‘early’ vs. ‘late’ during visits (Chi2 (1, N = 73) = 4.99, p = .025). Conclusions: Agenda setting is comparatively infrequent. The communication format and position of physicians’ questions affects patients’ provision of additional concerns/questions. Practice implications: Physicians should increase use of optimized forms of agenda setting

Schädliche Mißbräuche Und Vnordnungen Bey den heutigen fast immerwehrenden ärgerlichen und kostbaren Processen : Wobey Deren Quell und Ursprung gründlich entdeckt/ die Mißbräuche nachtrücklich vorgestellt ... umb die lengst desiderirte Verbesserung ... zu erhalten ...

Außgefertiget von Theodoro Matthia Beckman Dr. Cons. Essend.Vorlageform des Erscheinungsvermerks: Druckts Johann Friderich Rüh

Introduction of car sharing into existing car fleets in microscopic travel demand modelling

Microscopic travel demand models take the characteristics of every individual person of the modelled population into account for computing the travel demand for the modelled region. Car sharing is an old concept, but the combination of a car sharing fleet parked in public space with smartphone services to find available cars nearby offers a new mobility service. It enables people to use a fleet operators cars by providing individual mobility on demand. However, integrating this mobility option into microscopic travel demand models still is a difficult task due to a lack of data. This paper shows an integrated approach to model car sharing as a new mode for transport within a travel demand model using disaggregated car fleets with car specific attributes. The necessary parameters for mode choice are estimated from various surveys and integrated into an existing multi nominal logit model. The proposed work is used to simulate the travel demand of a synthetic population for the German capital of Berlin. A comparison with the survey results shows that the proposed integration of car sharing meets the real-world data. Furthermore, it is shown that the mode choice reacts well for access restrictions for specific car segments and local accessibility influencing the trip lengths