Age Limit of Pediatrics.

Pediatrics is a multifaceted specialty that encompasses children's physical, psychosocial, developmental, and mental health. Pediatric care may begin periconceptionally and continues through gestation, infancy, childhood, adolescence, and young adulthood. Although adolescence and young adulthood are recognizable phases of life, an upper age limit is not easily demarcated and varies depending on the individual patient. The establishment of arbitrary age limits on pediatric care by health care providers should be discouraged. The decision to continue care with a pediatrician or pediatric medical or surgical subspecialist should be made solely by the patient (and family, when appropriate) and the physician and must take into account the physical and psychosocial needs of the patient and the abilities of the pediatric provider to meet these needs.

AAP principles concerning retail-based clinics.

The American Academy of Pediatrics views retail-based clinics (RBCs) as an inappropriate source of primary care for pediatric patients, as they fragment medical care and are detrimental to the medical home concept of longitudinal and coordinated care. This statement updates the original 2006 American Academy of Pediatrics statement on RBCs, which flatly opposed these sites as appropriate for pediatric care, discussing the shift in RBC focus and comparing attributes of RBCs with those of the pediatric medical home.

SHP-1 inhibits LPS-mediated TNF and iNOS production in murine macrophages.

Several lines of evidence have suggested that protein tyrosine phosphatases, including CD45 and SHP-1, regulate macrophage activation. Macrophages from mice lacking SHP-1 (motheaten mice) are hyper-responsive to many stimuli, suggesting that SHP-1 may negatively regulate macrophage activation. Herein we report that the repressible/inducible over-expression of wild-type SHP-1 in a subclone of RAW 264.7 macrophages (RAW-TT10 cells) inhibited both TNF secretion and iNOS protein accumulation in response to stimulation with lipopolysaccharide (LPS) and recombinant murine interferon-gamma and led to diminished LPS-mediated tyrosine phosphorylation of vav1. In contrast, expression of a truncated SHP-1 construct previously shown to interfere with endogenous SHP-1 function modestly augmented LPS-mediated TNF and iNOS production and did not inhibit vav1 tyrosine phosphorylation. Taken together, these data provide the first direct evidence that SHP-1 inhibits macrophage activation by LPS and suggest that this effect may be mediated in part by dephosphorylation of vav1.

Plasma monitoring of the myocardial specific tissue inhibitor of metalloproteinase-4 after alcohol septal ablation in hypertrophic obstructive cardiomyopathy.

BACKGROUND: The overall goal of this study was to develop an assay procedure for measuring the relative abundance of tissue inhibitor of metalloproteinase (TIMP)-4 in plasma, and then use this approach to determine dynamic changes of TIMP-4 levels in hypertrophic obstructive cardiomyopathic (HOCM) patients after an acute myocardial infarction (MI). Matrix metalloproteinases (MMPs) contribute to tissue remodeling and are regulated by the endogenous TIMPs. TIMP-4 is observed to be expressed in higher abundance in the myocardium when compared with other types of tissues. Recent clinical studies have measured changes in TIMP-4 levels; however, these studies have been limited to measuring this protein from myocardial tissue samples. To date, no studies have monitored TIMP-4 levels in plasma samples. METHODS AND RESULTS: Plasma TIMP-4 levels were examined (by semiquantitative immunoblotting) in normal (n=18) and HOCM (n=16) patients after alcohol-induced MI. Serial measurements of plasma TIMP-4 levels were examined up to 60 hours after alcohol-induced MI in patients with HOCM. Unglycosylated plasma TIMP-4 levels increased 250% in the HOCM patients when compared with normal controls. Total plasma TIMP-4 levels decreased by 20% at 30 hours after alcohol-induced MI. CONCLUSIONS: The unique results demonstrated that an induction of a controlled MI, specifically through alcohol ablation, caused a reduction in plasma TIMP-4 levels in HOCM patients after alcohol-induced MI that would facilitate myocardial remodeling in the early post-MI setting.

Caspase inhibition attenuates contractile dysfunction following cardioplegic arrest and rewarming in the setting of left ventricular failure.

Hyperkalemic cardioplegic arrest (HCA) and rewarming evokes postoperative myocyte contractile dysfunction, a phenomenon of particular importance in settings of preexisting left ventricular (LV) failure. Caspases are intracellular proteolytic enzymes recently demonstrated to degrade myocardial contractile proteins. This study tested the hypothesis that myocyte contractile dysfunction induced by HCA could be ameliorated with caspase inhibition in the setting of compromised myocardial function. LV myocytes were isolated from control pigs (n = 9, 30 kg) or pigs with LV failure induced by rapid pacing (n = 6, 240 bpm for 21 days) and were randomized to the following: (1) normothermia (2003 myocytes), incubation in cell culture medium for 2 hours at 37 degrees C; (2) HCA only (506 myocytes), incubation for 2 hours in hypothermic HCA solution (4 degrees C, 24 mEq K); or (3) HCA + z-VAD, incubation in hypothermic HCA solution supplemented with 10 microM of the caspase inhibitor z-VAD (z-Val-Ala-Asp-fluoromethyl-ketone, 415 myocytes). Inotropic responsiveness was examined using beta-adrenergic stimulation (25 nM isoproterenol). Ambient normothermic myocyte shortening velocity (microm/s) was reduced with LV failure compared with control values (54 +/- 2 versus 75 +/- 2, respectively, P < 0.05). Following HCA, shortening velocity decreased in the LV failure and control groups (27 +/- 5 and 45 +/- 3, P < 0.05). Institution of z-VAD increased myocyte shortening velocity following HCA in both the LV failure and control groups (49 +/- 5 and 65 +/- 5, P < 0.05). Moreover, HCA supplementation with z-VAD increased beta-adrenergic responsiveness in both groups compared with HCA-only values. This study provides proof of concept that caspase activity contributes to myocyte contractile dysfunction following simulated HCA. Pharmacologic caspase inhibition may hold particular relevance in the execution of cardiac surgical procedures requiring HCA in the context of preexisting LV failure.

Myocyte contractility with caspase inhibition and simulated hyperkalemic cardioplegic arrest.

BACKGROUND: Exposure of left ventricular (LV) myocytes to simulated hyperkalemic cardioplegic arrest (HCA) has been demonstrated to perturb ionic homeostasis and adversely affect myocyte contractility on rewarming. Altered ionic homeostasis can cause cytosolic activation of the caspases. While caspases participate in apoptosis, these proteases can degrade myocyte contractile proteins, and thereby alter myocyte contractility. Accordingly, this study tested the hypothesis that caspase inhibition during HCA would attenuate the degree of myocyte contractile dysfunction upon rewarming, independent of a loss in myocyte viability. METHODS: Porcine (n = 8) LV myocytes were isolated and assigned to the following treatment groups: normothermic control: incubation in cell culture media for 2 hours at 37 degrees C; HCA only: incubation for 2 hours in hypothermic HCA solution (4 degrees C, 24 mEq K(+)); or incubation in hypothermic HCA solution supplemented with 10 microM of the caspase inhibitor, z-VAD (z-Val-Ala-Asp-fluoromethyl-ketone, HCA+zVAD). Myocyte viability, assayed as a function of mitochondrial function, was determined to be similar in the normothermic and both HCA groups. RESULTS: The HCA caused a significant reduction in myocyte shortening velocity compared with normothermic control values (41 +/- 6 versus 86 +/- 8 microm/s, p < 0.05). The HCA+zVAD group had significantly improved myocyte shortening velocity compared with the HCA only group (63 +/- 7 microm/s, p < 0.05). CONCLUSIONS: Independent of changes in viability, caspase inhibition attenuated myocyte contractile dysfunction after HCA and rewarming. Thus, caspase activation during HCA contributes, at least in part, to impaired myocyte contractility with rewarming. Supplementation of HCA with caspase inhibitors may provide a means to preserve myocyte contractile function after cardioplegic arrest.

Pharmacologic inhibition of intracellular caspases after myocardial infarction attenuates left ventricular remodeling: a potentially novel pathway.

OBJECTIVE: Myocyte death occurs by necrosis and caspase-mediated apoptosis in the setting of myocardial infarction. In vitro studies suggest that caspase activation within myocytes causes contractile protein degradation without inducing cell death. Thus, caspase activation may evoke left ventricular remodeling through 2 independent processes post-myocardial infarction. However, the effects of caspase activation on left ventricular geometry post-myocardial infarction remain unclear. This project applied broad-spectrum caspase inhibition to a chronic porcine model of myocardial infarction. METHODS: Coronary snares and sonomicrometry crystals in remote and area-at-risk regions were placed in pigs (n = 22, 34 kg). Geometric measurements at end diastole and end systole, including left ventricular area by echocardiography and interregional distance by sonomicrometry, were obtained at baseline. Coronary occlusion was instituted for 60 minutes, followed by reperfusion and repeated geometric measurements at 7 days, including left ventriculography. At reperfusion, pigs were randomized to saline (n = 12) or caspase inhibition (n = 10, IDN6734, 2 mg/kg intravenously, then 2 mg x kg x h for 24 hours) at a dose that achieved desired plasma concentrations (790 +/- 142 ng/mL) as predicted by prior pharmacokinetic studies. RESULTS: Infarct size and 24-hour troponin-I values were not significantly different between the saline and caspase inhibition groups (51% +/- 8% vs 42% +/- 6% and 189 +/- 20 ng/mL vs 152 +/- 26 ng/mL, respectively, P >.10). At 7 days, end-diastole volume was increased in both groups compared with reference control values (47 +/- 1 mL, P <.05), but it was decreased with caspase inhibition (72 +/- 4 mL) compared with saline (84 +/- 4 mL, P <.05). Similarly, end-diastole and end-systole areas increased by 32% +/- 3% and 81% +/- 16% in the saline group but were attenuated with caspase inhibition (19% +/- 3% and 31% +/- 10%, respectively, P <.05). End-diastole interregional distance increased by 30% +/- 7% in the saline group but was attenuated with caspase inhibition (12% +/- 5%, P <.05). CONCLUSION: Despite equivalent degrees of myocardial injury, caspase inhibition reduced post-myocardial infarction left ventricular remodeling as evidenced by multiple, independent assessments of left ventricular dilation. Thus, caspase activation alters left ventricular geometry in the absence of significant effects on myocardial injury.