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For a number of antidepressants in current clinical use, concentrations in serum or plasma are a more reliable index of target drug concentrations than is dosage. For such drugs, therapeutic drug monitoring (TDM) may be a useful clinical guide for the purpose of maximizing the likelihood of favorable therapeutic outcome while minimizing the probability of clinical ineffectiveness or adverse side effects. TDM is of greatest benefit when a therapeutic range of serum concentrations has been well established. Even if such a range is not definitively determined, TDM can be of help in situations in which patients are refractory to therapy despite adequate or high dosages, when adverse events supervene even with low doses, or when noncompliance with the intended dosage plan is suspected. Serum antidepressant concentrations from TDM should be interpreted in the full context of the patient's demographic characteristics and clinical status, along with an understanding of the pharmacokinetics of the medication being taken, the timing of the sample in relation to the dosage regimen, and the specific laboratory assay procedure. TDM measurements may be costly, and the potential benefits of the information need to be weighed against the cost to the patient or to the health care system.

Lung immaturity is the major cause of morbidity and mortality in premature infants, especially those born <28 weeks of gestation. These infants are at high risk of developing respiratory distress syndrome (RDS), a lung disease caused by insufficient surfactant production and immaturity of saccular/alveolar type II epithelial cells in the lung. RDS treatment includes oxygen and respiratory support that improve survival but also increase the risk for bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by arrested alveolarization, airway hyperreactivity, and pulmonary hypertension. The mechanisms regulating normal alveolar development and how injury disrupts normal development to cause BPD are not well understood. We examined the role of the matricellular protein CCN5 (Cysteine-rich protein 61/Connective tissue growth factor/Nephroblastoma-overexpressed protein) in the development of BPD. Cultured non-proliferating alveolar type II cells expressed low levels of CCN5 protein, and displayed higher levels during proliferation. siRNA targeting of CCN5 reduced alveolar type II cell proliferation and migration in cell culture. In a mouse model of hyperoxia-induced BPD, CCN5 protein was increased only in proliferating alveolar type I cells. Alveolar epithelial cells co-expressing markers of type II cells and type I cells also appeared. The results suggest that hyperoxic injury in immature lungs induces proliferation of type I cells and trans-differentiation of type II cells into type I cells. We propose that the mechanism of the injury response in BPD includes CCN5 expression. Study of CCN5 in neonatal alveolar injury will further our understanding of BPD pathophysiology while providing a mechanistic foundation for therapeutic approaches.

Lung immaturity is the major cause of morbidity and mortality in premature infants, especially those born <28 weeks gestation. Proper lung development from 23-28 weeks requires coordinated cell proliferation and differentiation. Infants born at this age are at high risk for respiratory distress syndrome (RDS), a lung disease characterized by insufficient surfactant production due to immaturity of the alveoli and its constituent cells in the lung. The ErbB4 receptor and its stimulation by neuregulin (NRG) plays a critical role in surfactant synthesis by alveolar type II epithelial cells. In this review, we first provide an introduction to normal human alveolar development, followed by a discussion of the neuregulin and ErbB4-mediated mechanisms regulating alveolar development and surfactant production.

Neuregulin (NRG) stimulation of ErbB4 signaling is important for type II cell surfactant synthesis. ErbB4 may mediate gene expression via a non-canonical pathway involving enzymatic cleavage releasing its intracellular domain (4ICD) for nuclear trafficking and gene regulation. The accepted model for release of 4ICD is consecutive cleavage by Tumor necrosis factor alpha Converting Enzyme (TACE) and γ-secretase enzymes. Here, we show that 4ICD mediates surfactant synthesis and its release by γ-secretase is not dependent on previous TACE cleavage. We used siRNA to silence Presenilin-1 (PSEN-1) expression in a mouse lung type II epithelial cell line (MLE12 cells), and both siRNA knockdown and chemical inhibition of TACE. Knockdown of PSEN-1 significantly decreased baseline and NRG-stimulated surfactant phospholipid synthesis, expression of the surfactant proteins SP-B and SP-C, as well as 4ICD levels, with no change in ErbB4 ectodomain shedding. Neither siRNA knockdown nor chemical inhibition of TACE inhibited 4ICD release or surfactant synthesis. PSEN-1 cleavage of ErbB4 for non-canonical signaling through 4ICD release does not require prior cleavage by TACE., (Copyright © 2014 Elsevier B.V. All rights reserved.)