A mouse platelet-derived growth factor A chain (PDGF-A) null allele is shown to be homozygous lethal, with two distinct restriction points, one prenatally before E10 and one postnatally. Postnatally surviving PDGF-A-deficient mice develop lung emphysema secondary to the failure of alveolar septation. This is apparently caused by the loss of alveolar myofibroblasts and associated elastin fiber deposits. PDGF alpha receptor-positive cells in the lung having the location of putative alveolar myofibroblast progenitors were specifically absent in PDGF-A null mutants. We conclude that PDGF-A is crucial for alveolar myofibroblast ontogeny. We have previously shown that PDGF-B is required in the ontogeny of kidney mesangial cells. The PDGFs therefore appear to regulate the generation of specific populations of myofibroblasts during mammalian development. The two PDGF null phenotypes also reveal analogous morphogenetic functions for myofibroblast-type cells in lung and kidney organogenesis.

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Caspofungin has a liver-dependent metabolism. Reduction of the dose is recommended based on Child-Pugh (C-P) score. In critically ill patients, drug pharmacokinetics (PK) may be altered. The aim of this study was to investigate the prevalence of abnormal liver function tests, increased C-P scores, their effects on caspofungin PK, and whether pharmacokinetic-pharmacodynamic (PK/PD) targets were attained in patients with suspected candidiasis. Intensive care unit patients receiving caspofungin were prospectively included. PK parameters were determined on days 2, 5, and 10, and their correlations to the individual liver function tests and the C-P score were analyzed. Forty-six patients were included with C-P class A (n ϭ 5), B (n ϭ 40), and C (n ϭ 1). On day 5 (steady state), the median and interquartile range for area under the curve from 0 to 24 h (AUC 0 -24 ), clearance (CL), and central volume of distribution (V 1 ) were 57.8 (51.6 to 69.8) mg·h/liter, 0.88 (0.78 to 1.04) liters/h, and 11.9 (9.6 to 13.1) liters, respectively. The C-P score did not correlate with AUC 0 -24 (r ϭ 0.03; P ϭ 0.84), CL (r ϭ Ϫ0.07; P ϭ 0.68), or V 1 (r ϭ 0.19; P ϭ 0.26), but there was a bilirubin-driven negative correlation with the elimination rate constant (r ϭ Ϫ0.46; P ϭ 0.004). Hypoalbuminemia correlated with low AUC 0 -24 (r ϭ 0.45; P ϭ 0.005) and was associated with higher clearance (r ϭ Ϫ0.31; P ϭ 0.062) and somewhat higher V 1 (r ϭ Ϫ0.15; P ϭ 0.37), resulting in a negative correlation with the elimination rate constant (r ϭ Ϫ0.34; P ϭ 0.042). For Candida strains with minimal inhibitory concentrations of Ն0.064 g/ml, PK/PD targets were not attained in all patients. The caspofungin dose should not be reduced in critically ill patients in the absence of cirrhosis, and we advise against the use of the C-P score in patients with trauma-or sepsis-induced liver injury.

Background The implantation rates of cardiac implantable electronic devices have steadily increased, accompanied by a steeper rise of device related infections (DRI). Hypothesis The prevalence of DRI for cardiac resynchronization therapy (CRT) is higher in clinical practice than reported previously, even at a university hospital, and likely higher than reported to the national device registry. Methods Electronic medical records of consecutive patients undergoing a CRT procedure between January 2016 and December 2017 were analyzed. Clinical history, procedure related variables and complications were reviewed by specialists in cardiology and infectious diseases. Results A total of 171 patients, mean aged 74 years, 138 males (80.7%) were included. Twelve DRI occurred in 10 patients during mean 2.5 years follow‐up, giving a prevalence of 7% (incidence of 29/1000 person‐years). Reoperation, pocket haematoma, ≥3 procedures, previous device infection and indwelling central venous line were the strongest predictive factors according to univariate analysis. Out of 63/171 (36.8%) major complications, 31(49.2%) were lead‐related. There were 49/171 (28.7%) reoperations and 15/171 (8.8%) minor complications. The number major complications and DRI reported to the national device registry were 7/171 (4.1%) and 2/171 (0.6%), respectively, reflecting a 5‐fold underreporting. Conclusions The high rate of CRT device infections is in sharp contrast to those reported by others and to the national device registry. Although a center specific explanation cannot be excluded, the high rates highlight a major issue with registries, reinforcing the need for better surveillance and automatic reporting of device related complications.

A total of 154 episodes of infective endocarditis (IE) in 149 patients were studied retrospectively with special regard to the major aetiological groups and the surgical evaluation. There were 136 episodes of native valve endocarditis (NVE) (88%) and 18 episodes of prosthetic valve endocarditis (PVE) (12%). Three major groups of NVE crystallized: Streptococcus viridans in 37 (27%), Staphylococcus aureus in 39 (29%) and culture negative IE in 28 (21%) episodes. In these groups surgery during the active phase was required in 41, 28 and 18%, respectively. At the operation myocardial abscess was found in as many as 7/15 cases with S. viridans, but in only in 3/11 cases with S. aureus and 1/5 cases with culture negative IE. The mean duration of preoperative antibiotic treatment was 34 d. This long period of unsuccessful pharmacotherapy, preceded by a mean of 47 d from start of symptoms to admission to hospital, has probably resulted in the high frequency of myocardial abscess in S. viridans NVE. Surgical evaluation should be considered when fever persists beyond 10 d of adequate treatment, even in the absence of clinically apparent complications. Among the PVE episodes, 11/18 were managed with pharmacological treatment alone. Uncomplicated PVE may thus often be successfully treated with antibiotics alone.