132 research outputs found
The Dopamine D3 Receptor Knockout Mouse Mimics Aging-Related Changes in Autonomic Function and Cardiac Fibrosis
Blood pressure increases with age, and dysfunction of the dopamine D3 receptor has been implicated in the pathogenesis of hypertension. To evaluate the role of the D3 receptor in aging-related hypertension, we assessed cardiac structure and function in differently aged (2 mo, 1 yr, 2 yr) wild type (WT) and young (2 mo) D3 receptor knockout mice (D3KO). In WT, systolic and diastolic blood pressures and rate-pressure product (RPP) significantly increased with age, while heart rate significantly decreased. Blood pressure values, heart rate and RPP of young D3KO were significantly elevated over age-matched WT, but similar to those of the 2 yr old WT. Echocardiography revealed that the functional measurements of ejection fraction and fractional shortening decreased significantly with age in WT and that they were significantly smaller in D3KO compared to young WT. Despite this functional change however, cardiac morphology remained similar between the age-matched WT and D3KO. Additional morphometric analyses confirmed an aging-related increase in left ventricle (LV) and myocyte cross-sectional areas in WT, but found no difference between age-matched young WT and D3KO. In contrast, interstitial fibrosis, which increased with age in WT, was significantly elevated in the D3KO over age-matched WT, and similar to 2 yr old WT. Western analyses of myocardial homogenates revealed significantly increased levels of pro- and mature collagen type I in young D3KO. Column zymography revealed that activities of myocardial MMP-2 and MMP-9 increased with age in WTs, but in D3KO, only MMP-9 activity was significantly increased over age-matched WTs. Our data provide evidence that the dopamine D3 receptor has a critical role in the emergence of aging-related cardiac fibrosis, remodeling, and dysfunction
Role of IL-1 Beta in the Development of Human TH17 Cells: Lesson from NLPR3 Mutated Patients
T helper 17 cells (T(H)-17) represent a lineage of effector T cells critical in host defence and autoimmunity. In both mouse and human IL-1ÎČ has been indicated as a key cytokine for the commitment to T(H)-17 cells. Cryopyrin-associated periodic syndromes (CAPS) are a group of inflammatory diseases associated with mutations of the NLRP3 gene encoding the inflammasome component cryopyrin. In this work we asked whether the deregulated secretion of IL-1ÎČ secondary to mutations characterizing these patients could affect the IL-23/IL-17 axis.A total of 11 CAPS, 26 systemic onset juvenile idiopathic arthritis (SoJIA) patients and 20 healthy controls were analyzed. Serum levels of IL-17 and IL-6 serum were assessed by ELISA assay. Frequency of T(H)17 cells was quantified upon staphylococcus enterotoxin B (SEB) stimulation. Secretion of IL-1ÎČ, IL-23 and IL-6 by monocyte derived dendritic cells (MoDCs), were quantified by ELISA assay. A total of 8 CAPS and 11 SoJIA patients were also analysed before and after treatment with IL-1ÎČ blockade. Untreated CAPS patients showed significantly increased IL-17 serum levels as well as a higher frequency of T(H)17 compared to control subjects. On the contrary, SoJIA patients displayed a frequency of T(H)17 similar to normal donors, but were found to have significantly increased serum level of IL-6 when compared to CAPS patients or healthy donors. Remarkably, decreased IL-17 serum levels and T(H)17 frequency were observed in CAPS patients following in vivo IL-1ÎČ blockade. On the same line, MoDCs from CAPS patients exhibited enhanced secretion of IL-1ÎČ and IL-23 upon TLRs stimulation, with a reduction after anti-IL-1 treatment.These findings further support the central role of IL-1ÎČ in the differentiation of T(H)17 in human inflammatory conditions
The Hunt for New Physics at the Large Hadron Collider
The Large Hadron Collider presents an unprecedented opportunity to probe the
realm of new physics in the TeV region and shed light on some of the core
unresolved issues of particle physics. These include the nature of electroweak
symmetry breaking, the origin of mass, the possible constituent of cold dark
matter, new sources of CP violation needed to explain the baryon excess in the
universe, the possible existence of extra gauge groups and extra matter, and
importantly the path Nature chooses to resolve the hierarchy problem - is it
supersymmetry or extra dimensions. Many models of new physics beyond the
standard model contain a hidden sector which can be probed at the LHC.
Additionally, the LHC will be a top factory and accurate measurements of the
properties of the top and its rare decays will provide a window to new physics.
Further, the LHC could shed light on the origin of neutralino masses if the new
physics associated with their generation lies in the TeV region. Finally, the
LHC is also a laboratory to test the hypothesis of TeV scale strings and
D-brane models. An overview of these possibilities is presented in the spirit
that it will serve as a companion to the Technical Design Reports (TDRs) by the
particle detector groups ATLAS and CMS to facilitate the test of the new
theoretical ideas at the LHC. Which of these ideas stands the test of the LHC
data will govern the course of particle physics in the subsequent decades
pIL6-TRAIL-engineered umbilical cord mesenchymal/stromal stem cells are highly cytotoxic for myeloma cells both in vitro and in vivo
A core outcome set for preâeclampsia research: an international consensus development study
Objective
To develop a core outcome set for preâeclampsia.
Design
Consensus development study.
Setting
International.
Population
Two hundred and eightâone healthcare professionals, 41 researchers and 110 patients, representing 56 countries, participated.
Methods
Modified Delphi method and Modified Nominal Group Technique.
Results
A longâlist of 116 potential core outcomes was developed by combining the outcomes reported in 79 preâeclampsia trials with those derived from thematic analysis of 30 inâdepth interviews of women with lived experience of preâeclampsia. Fortyâseven consensus outcomes were identified from the Delphi process following which 14 maternal and eight offspring core outcomes were agreed at the consensus development meeting. Maternal core outcomes: death, eclampsia, stroke, cortical blindness, retinal detachment, pulmonary oedema, acute kidney injury, liver haematoma or rupture, abruption, postpartum haemorrhage, raised liver enzymes, low platelets, admission to intensive care required, and intubation and ventilation. Offspring core outcomes: stillbirth, gestational age at delivery, birthweight, smallâforâgestationalâage, neonatal mortality, seizures, admission to neonatal unit required and respiratory support.
Conclusions
The core outcome set for preâeclampsia should underpin future randomised trials and systematic reviews. Such implementation should ensure that future research holds the necessary reach and relevance to inform clinical practice, enhance women's care and improve the outcomes of pregnant women and their babies
Plasma cell labeling index and beta 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma [see comments]
Plasma cell labeling index and beta 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma [see comments]
Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance?
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