38 research outputs found
Esophageal impedance baselines in infants before and after placebo and proton pump inhibitor therapy
Author version made available in accordance with the publisher's policy.ABSTRACT
Background
Esophageal impedance monitoring records changes in conductivity. During esophageal rest impedance baseline values may represent mucosal integrity. The aim of this study was to assess the influence of acid suppression on impedance baselines in a placebo controlled setting.
Material and Methods
Impedance recordings from 40 infants (0-6months) enrolled in randomized placebo controlled trials of proton pump inhibitor (PPI) were retrospectively analyzed. Infants underwent 24hr pH-impedance monitoring prior to and after two weeks of double blind therapy with placebo or a PPI. Typical clinical signs of gastroesophageal reflux (GER) were recorded and I-GERQ-R questionnaire was completed.
Key results
Median (IQR) impedance baseline increased on PPI treatment (from 1217 (826-1514) to 1903 (1560-2194) Ohm, p<0.001) but not with placebo (from 1445 (1033-1791) to 1650 (1292-1983) Ohm, p=0.13). Baselines before treatment inversely correlate with the number of GER, acid GER, weakly acid GER, acid exposure and symptoms. The change in baseline on treatment inversely correlates with acid exposure and acid GER. Patients with initial low baselines have no improved symptomatic response to treatment.
Conclusions and Inferences
Impedance baselines are influenced by GER and increase significantly more with PPI therapy than with placebo. Clinical impact of this observation remains undefined as targeting therapy at infants with low baselines does not improve symptomatic response to treatment
Chemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis
Chemical tools to monitor drug-target engagement of endogenously expressed protein kinases are highly desirable for preclinical target validation in drug discovery. Here, we describe a chemical genetics strategy to selectively study target engagement of endogenous kinases. By substituting a serine residue into cysteine at the DFG-1 position in the ATP-binding pocket, we sensitize the non-receptor tyrosine kinase FES towards covalent labeling by a complementary fluorescent chemical probe. This mutation is introduced in the endogenous FES gene of HL-60 cells using CRISPR/Cas9 gene editing. Leveraging the temporal and acute control offered by our strategy, we show that FES activity is dispensable for differentiation of HL-60 cells towards macrophages. Instead, FES plays a key role in neutrophil phagocytosis via SYK kinase activation. This chemical genetics strategy holds promise as a target validation method for kinases.Medicinal Chemistr
A STUDY OF A WEAKLY IONIZED, ROTATING PLASMA
No abstract availabl