365 research outputs found
Peripartum Cardiomyopathy as a Part of Familial Dilated Cardiomyopathy
BACKGROUND-: Anecdotal cases of familial clustering of peripartum cardiomyopathy (PPCM) and familial occurrences of PPCM and idiopathic dilated cardiomyopathy (DCM) together have been observed, suggesting that genetic factors play a role in the pathogenesis of PPCM. We hypothesized that some cases of PPCM are part of the spectrum of familial DCM, presenting in the peripartum period. METHODS AND RESULTS-: We reviewed our database of 90 DCM families, focusing specifically on the presence of PPCM patients. Then, in a reverse approach, we reviewed 10 PPCM patients seen in our clinic since the early 1990s and performed cardiological screening of the first-degree relatives of 3 PPCM patients who did not show a full recovery. Finally, we analyzed the genes known to be most commonly involved in DCM in the PPCM patients. We identified a substantial number (5 of 90, 6%) of DCM families with PPCM patients. Second, cardiological screening of first-degree relatives of 3 PPCM patients who did not show full recovery revealed undiagnosed DCM in all 3 families. Finally, genetic analyses revealed a mutation (c.149A>G, p.Gln50Arg) in the gene encoding cardiac troponin C (TNNC1) segregating with disease in a DCM family with a member with PPCM, supporting the genetic nature of disease in this case. CONCLUSIONS-: Our findings strongly suggest that a subset of PPCM is an initial manifestation of familial DCM. This may have important implications for cardiological screening in such families
Receptor activation using multi-biomarker pharmacokinetic/pharmacodynamic modelling
receptor activation was evaluated using quinpirole as a paradigm compound.
), as well as plasma concentrations of 13 hormones and neuropeptides, were measured. Experiments were performed at day 1 and repeated after 7-day s.c. drug administration. PK/PD modelling was applied to identify the in vivo concentration-effect relations and neuroendocrine dynamics.
receptor expression levels on the pituitary hormone-releasing cells predicted the concentration-effect relationship differences. Baseline levels (ACTH, prolactin, TSH), hormone release (ACTH) and potency (TSH) changed with treatment duration.
agonists in clinical practice. Further development towards quantitative systems pharmacology models will eventually facilitate mechanistic drug development.
BACKGROUND AND PURPOSE
EXPERIMENTAL APPROACH
KEY RESULTS
CONCLUSIONS AND IMPLICATION
Peripartum Cardiomyopathy: Euro Observational Research Program
Peripartum cardiomyopathy is a rare but potentially life-threatening form of heart failure affecting women late in pregnancy or in the first months after delivery. Peripartum cardiomyopathy is difficult to diagnose and its onset and progression are variable between individuals. The pathophysiology remains poorly understood, hence treatment options are limited and possibly harmful to the foetus. Furthermore, geographical incidence varies greatly and little is known about the incidence in Western countries. To gain further understanding of the pathophysiology and incidence of peripartum cardiomyopathy, the European Society of Cardiology initiated a study group to implement a registry. This review provides an overview of current insights into peripartum cardiomyopathy, highlights the need for such a registry and provides information about this Euro Observational Research Program
A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy
CC Chemokine Receptor 2 (CCR2) and its endogenous ligand CCL2 are involved in a number of diseases, including atherosclerosis. Several CCR2 antagonists have been developed as potential therapeutic agents, however their in vivo clinical efficacy was limited. In this report, we aimed to determine whether 15a, an antagonist with a long residence time on the human CCR2, is effective in inhibiting the development of atherosclerosis in a mouse disease model. First, radioligand binding assays were performed to determine affinity and binding kinetics of 15a on murine CCR2. To assess the in vivo efficacy, western-type diet fed apoE-/- mice were treated daily with 15a or vehicle as control. Treatment with 15a reduced the amount of circulating CCR2+ monocytes and the size of the atherosclerotic plaques in both the carotid artery and the aortic root. We then showed that the long pharmacokinetic half-life of 15a combined with the high drug concentrations ensured prolonged CCR2 occupancy. These data render 15a a promising compound for drug development and confirms high receptor occupancy as a key parameter when targeting chemokine receptors
Fingerprints of CNS drug effects: a plasma neuroendocrine reflection of D2 receptor activation using multi-biomarker pharmacokinetic/pharmacodynamic modelling
Background and PurposeBecause biological systems behave as networks, multiâbiomarker approaches increasingly replace single biomarker approaches in drug development. To improve the mechanistic insights into CNS drug effects, a plasma neuroendocrine fingerprint was identified using multiâbiomarker pharmacokinetic/pharmacodynamic (PK/PD) modelling. Shortâ and longâterm D2 receptor activation was evaluated using quinpirole as a paradigm compound.Experimental ApproachRats received 0, 0.17 or 0.86 mg·kgâ1 of the D2 agonist quinpirole i.v. Quinpirole concentrations in plasma and brain extracellular fluid (brainECF), as well as plasma concentrations of 13 hormones and neuropeptides, were measured. Experiments were performed at day 1 and repeated after 7âday s.c. drug administration. PK/PD modelling was applied to identify the in vivo concentrationâeffect relations and neuroendocrine dynamics.Key ResultsThe quinpirole pharmacokinetics were adequately described by a twoâcompartment model with an unbound brainECFâtoâplasma concentration ratio of 5. The release of adenocorticotropic hormone (ACTH), growth hormone, prolactin and thyroidâstimulating hormone (TSH) from the pituitary was influenced. Except for ACTH, D2 receptor expression levels on the pituitary hormoneâreleasing cells predicted the concentrationâeffect relationship differences. Baseline levels (ACTH, prolactin, TSH), hormone release (ACTH) and potency (TSH) changed with treatment duration.Conclusions and ImplicationsThe integrated multiâbiomarker PK/PD approach revealed a fingerprint reflecting D2 receptor activation. This forms the conceptual basis for in vivo evaluation of onâ and offâtarget CNS drug effects. The effect of treatment duration is highly relevant given the longâterm use of D2 agonists in clinical practice. Further development towards quantitative systems pharmacology models will eventually facilitate mechanistic drug development.Pharmacolog
Response to Letter Regarding Article, "Peripartum Cardiomyopathy as a Part of Familial Dilated Cardiomyopathy"
Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer
Introduction Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC). Materials and methods Treatment-naĂŻve patients with an activating EGFR mutation, ECOG performance score of 0â3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2â16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity. Results Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2â18.8) for CPE and 10.3 months (95% CI 7.1â15.5; hazard ratio (HR) 0.62, 95% CI 0.25â1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07â0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8â61.9 months) for CPE compared to 17.2 months (95% CI 11.5â45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22â1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity. Conclusion Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity
On-line Excited-State Laser Spectroscopy of Trapped Short-Lived Ra Ions
As an important step towards an atomic parity violation experiment in one single trapped Ra ion, laser spectroscopy experiments were performed with on-line produced short-lived Ra ions. The isotope shift of the 6\,^2D\,-\,7\,^2P and 6\,^2D\,-\,7\,^2P transitions and the hyperfine structure constant of the 7\,^2S and 6\,^2D states in Ra were measured. These values provide a benchmark for the required atomic theory. A lower limit of ms for the lifetime of the metastable 6\,^2D state was measured by optical shelving
The Alexander-Orbach conjecture holds in high dimensions
We examine the incipient infinite cluster (IIC) of critical percolation in
regimes where mean-field behavior has been established, namely when the
dimension d is large enough or when d>6 and the lattice is sufficiently spread
out. We find that random walk on the IIC exhibits anomalous diffusion with the
spectral dimension d_s=4/3, that is, p_t(x,x)= t^{-2/3+o(1)}. This establishes
a conjecture of Alexander and Orbach. En route we calculate the one-arm
exponent with respect to the intrinsic distance.Comment: 25 pages, 2 figures. To appear in Inventiones Mathematica
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