Plastic bronchitis (PB) is a rare disease that often occurs in patients with congenital heart disease (CHD) who have undergone staged single ventricle palliation. It is characterized by the formation of rubbery “casts” in the airways. PB treatment frequently includes inhaled tPA. However, the efficacy of tPA to reduce cast burden is unknown. This is further complicated by our lack of knowledge of cast composition. We obtained spontaneously expectorated PB casts from children (n=4) with CHD and one adult patient with idiopathic PB. Pathological assessment was made from paraffin-preserved samples. Casts were treated with phosphate-buffered saline (PBS) or tPA. Cast response to tPA was assessed by changes in cast weight and the production of fibrin D-dimer. Independent of dose, tPA reduced cast weight compared with PBS-treatment (p=0.001) and increased D-dimer levels. Histological staining showed that PB casts from all patients were comprised of fibrin and contained notable numbers of lymphocytes. Cast composition did not change over time. Collectively, these data support that in our PB patients, casts are comprised of fibrin and are responsive to tPA treatment. This makes inhaled tPA a potentially viable option for symptomatic relief of PB while we work to unravel the complexity of PB pathogenesis.

Regulator of G protein signaling 2 (RGS2), a G q -specific GTPase-activating protein, is strongly implicated in cardiovascular function. RGS2(Ϫ/Ϫ) mice are hypertensive and prone to heart failure, and several rare human mutations that accelerate RGS2 degradation have been identified among patients with hypertension. Therefore, pharmacological up-regulation of RGS2 protein levels might be beneficial. We used a ␤-galactosidase complementation method to screen several thousand compounds with known pharmacological functions for those that increased RGS2 protein levels. Several cardiotonic steroids (CTSs), including ouabain and digoxin, increased RGS2 but not RGS4 protein levels. CTSs increased RGS2 protein levels through a post-transcriptional mechanism, by slowing protein degradation. RGS2 mRNA levels in primary vascular smooth muscle cells were unaffected by CTS treatment, whereas protein levels were increased 2-to 3-fold. Na ϩ /K ϩ -ATPase was required for the increase in RGS2 protein levels, because the effect was lost in Na ϩ /K ϩ -ATPase-knockdown cells. Furthermore, we demonstrated that CTS-induced increases in RGS2 levels were functional and reduced receptor-stimulated, G qdependent, extracellular signal-regulated kinase phosphorylation. Finally, we showed that in vivo treatment with digoxin led to increased RGS2 protein levels in heart and kidney. CTSinduced increases in RGS2 protein levels and function might modify several deleterious mechanisms in hypertension and heart failure. This novel CTS mechanism might contribute to the beneficial actions of low-dose digoxin treatment in heart failure. Our results support the concept of small-molecule modulation of RGS2 protein levels as a new strategy for cardiovascular therapy.

Guidelines recommend patient follow-up within 2 weeks of antidepressant initiation or uptitration to minimize treatment discontinuation and suicidal ideation risks; however, time constraints and lack of systematic processes remain barriers in primary care. A pharmacist-led multidisciplinary telemonitoring service aimed to address these barriers. This was a retrospective, observational study of adults with depression initiated or uptitrated on an antidepressant between May and October 2016. Outcomes included the proportion of eligible patients successfully contacted, adherence, adverse effects, suicidal ideations, and pharmacist interventions. Clinical pharmacists successfully reached 258 of 380 (68%) patients and provided follow-up in 298 calls. Patients endorsed antidepressant nonadherence during 56 (19%) calls, adverse effects in 81 (27%) calls, and suicidal ideations in 13 (4%) calls. Pharmacists provided 109 total interventions for 102 patients. The clinical pharmacist-led multidisciplinary antidepressant telemonitoring service is an alternative resource to monitor patients after antidepressant initiation or titration in primary care settings.