Doxycycline induces mitochondrial dysfunction in aortic smooth muscle cells.

The antibiotic doxycycline is known to inhibit inflammation and was therefore considered as a therapeutic to prevent abdominal aortic aneurysm (AAA) growth. Yet mitochondrial dysfunction is a key-characteristic of clinical AAA disease. We hypothesize that doxycycline impairs mitochondrial function in the aorta and aortic smooth muscle cells (SMCs). Doxycycline induced mitonuclear imbalance, reduced proliferation and diminished expression of typical contractile smooth muscle cell (SMC) proteins. To understand the underlying mechanism, we studied krüppel-like factor 4 (KLF4). The expression of this transcription factor was enhanced in SMCs after doxycycline treatment. Knockdown of KLF4, however, did not affect the doxycycline-induced SMC phenotypic changes. Then we used the bioenergetics drug elamipretide (SS-31). Doxycycline-induced loss of SMC contractility markers was not rescued, but mitochondrial genes and mitochondrial connectivity improved upon elamipretide. Thus while doxycycline is anti-inflammatory, it also induces mitochondrial dysfunction in aortic SMCs and causes SMC phenotypic switching, potentially contributing to aortic aneurysm pathology. The drug elamipretide helps mitigate the harmful effects of doxycycline on mitochondrial function in aortic SMC, and may be of interest for treatment of aneurysm diseases with pre-existing mitochondrial dysfunction.

Hemodynamic Response to Fluid Boluses for Hypotension in Children in a Cardiac ICU.

OBJECTIVES: To describe the hemodynamic response to fluid boluses for hypotension in children in a cardiac ICU. DESIGN: A prospective, observational study. SETTING: Single-centered cardiac ICU. PATIENTS: Children in a cardiac ICU with hypotension. INTERVENTIONS: Clinician prescribed fluid bolus. MEASUREMENTS AND MAIN RESULTS: Sixty-four fluid boluses were administered to 52 children. Fluid composition was 4% albumin in 36/64 (56%), 0.9% saline in 18/64 (28%), and cardiopulmonary bypass pump blood in 10/64 (16%). The median volume and duration were 5.0 mL/kg (interquartile range, 4.8-5.4) and 8 minutes (interquartile range, 4-19), respectively. Hypovolemia/low filling pressures was the most common additional indication (25/102 [25%]). Mean arterial pressure response, defined as a 10% increase from baseline, occurred in 42/64 (66%) of all fluid boluses at a median time of 6 minutes (interquartile range, 4-11). Mean arterial pressure responders had a median peak increase in the mean arterial pressure of 15 mm Hg (43 mm Hg [interquartile range, 29-50 mm Hg] to 58 mm Hg [interquartile range, 49-65 mm Hg]) at 17 minutes (interquartile range, 14-24 min) compared with 4 mm Hg (48 mm Hg [interquartile range, 40-51 mm Hg] to 52 mm Hg [interquartile range, 45-56 mm Hg]) at 10 minutes (interquartile range, 3-18 min) in nonresponders. Dissipation of mean arterial pressure response, when defined as a subsequent decrement in mean arterial pressure below 10%, 5%, and 2% increases from baseline, occurred in 28/42 (67%), 18/42 (43%), and 13/42 (31%) of mean arterial pressure responders, respectively. Cardiopulmonary bypass pump blood was strongly associated with peak change in mean arterial pressure from baseline (coefficient 11.0 [95% CI, 4.3-17.7]; p = 0.02). Fifty out of 64 (78%) were receiving a vasoactive agent. However, change in vasoactive inotrope score was not associated with change in mean arterial pressure (coefficient 2.3 [95% CI, -2.5 to -7.2]; p = 0.35). Timing from admission, nor fluid bolus duration, influenced mean arterial pressure response. CONCLUSIONS: In children with hypotension in a cardiac ICU, the median dose and duration of fluid boluses were 5 mL/kg and 8 minutes. Peak response occurred shortly following administration and commonly returned to baseline.

[Neonatal sepsis caused by group B streptococci: atypical and recurrent disease episodes]. / Neonatale sepsis door groep B-streptokokken: atypisch en recidiverend beloop.

Both neonates of male twins born at 30 weeks and 3 days gestation presented with late-onset sepsis caused by an infection with group B streptococci (GBS), shortly after one another. Although the younger twin recovered with a standard regimen of 10 days penicillin G i.v., the older twin had three recurrent episodes with GBS positive blood cultures. Oropharyngeal, faecal, urine, liquor and breast milk cultures were GBS negative. Using echocardiography and a PET/CT scan, a persistent endovascular focus was discovered. We treated him with penicillin G i.v. for 4 weeks, after which he recovered completely. Another male neonate born at 26 weeks gestation presented with GBS sepsis and developed an erythematous swelling of the right mandibula within 12 hours. Ultrasound revealed parotitis, which is rare in neonates (3.8 per 10,000). Risk factors for parotitis include prematurity, low birth weight and dehydration (i.e., diuretic usage). Parotitis can be complicated by abscess formation.

Gender, age, and educational level attribute to blood alcohol concentration in hospitalized intoxicated adolescents; a cohort study.

BACKGROUND: The prevalence of adolescents hospitalized with acute alcohol intoxication, mainly because of severe reduced consciousness, is increasing. However, the characteristics of these adolescents are mainly unidentified. In this clinical research, we aimed to identify factors that attribute to higher ethanol concentration, on which targeted alcohol health interventions can be designed. METHODS: Since 2007, alcohol intoxication among adolescents has been one of the leading topics of the Dutch Pediatric Surveillance System. In the current study, we have analyzed which demographic characteristics, general alcohol use behaviors, and clinical intoxication data were related to the blood alcohol concentration (BAC) levels at hospital admittance. We included all adolescents aged <18 years, admitted with BAC >0.0 g/l, and reduced consciousness during the years 2007, 2008, 2009, and 2010. RESULTS: A total of 2,023 adolescents with alcohol intoxication were reported, and 1,618 questionnaires were returned, of which 1,350 met our inclusion criteria. In univariate analysis, age, gender, educational level, place of alcohol purchase, place of alcohol consumption, age of first drink, and regular alcohol use during the weekend correlated with higher BAC. After multivariate analysis, older adolescents, boys, and higher educational level significantly attributed to higher BAC at admittance. CONCLUSIONS: In alcohol-intoxicated adolescents with reduced consciousness, gender, age, and also educational level correlate with BAC at admittance. Explanatory factors could be found in sensitivity to alcohol, but also in socioeconomic factors, which influence availability. Intervention strategies could be targeted more specific now for the subgroups found in this study to decrease the growing burden of adolescent alcohol intoxication, both on the societal level and on the clinical level.