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Platelet endothelial cell adhesion molecule 1 (PECAM-1) is capable of transducing signals in endothelial cells exposed to shear; however, the biological consequences of this signal transduction are unknown. Because shear stress elicits flow-mediated dilation (FMD), we examined whether steady-state FMD in mouse coronary arteries (MCAs) is affected in the PECAM-1 knockout (KO) mouse. MCAs were isolated from wild-type (WT) or KO mice and prepared for videomicroscopy, histofluorescence, Western blotting, and immunohistochemistry. FMD was examined in the absence and presence of Nω-nitro-l-arginine methyl ester (l-NAME) and l-NAME+indomethacin (INDO). FMD was reduced in KO relative to WT MCAs, but the l-NAME-inhibitable portion of FMD was similar between the two. The INDO-sensitive component of FMD was diminished in KO MCAs. In contrast, the residual component of dilation, presumably because of endothelium-derived hyperpolarizing factor (EDHF), was abolished in KO MCAs. Histofluorescence showed relatively more superoxide (O2−·; oxy-ethidium fluorescence) and peroxide production (dihydrochlorofluorescene fluoresecence) in KO MCAs at rest. Flow augmented O2−· and peroxide production in WT MCAs but had little effect on KO MCAs. Enhanced nitric oxide generation was observed in arteries from KO mice, accompanied with increased eNOS S1177 phosphorylation. In vessels from KO mice, treatment with ebselen decreased peroxynitrite (ONOO−) formation and improved the reduced FMD, largely due to restoration of the presumed EDHF component. These results suggest that PECAM-1 is necessary for normal FMD in the mouse coronary circulation. In the absence of this adhesion and signaling molecule, ONOO− production is increased concomitant with a reduction in both the EDHF and INDO-sensitive components of FMD.
- flow-induced dilation
- oxidative stress
shear stress acting on the endothelial cell apical surface serves as an important signaling mechanism for a variety of cell processes, including stimulated release of vasodilator factors (18, 31, 45), activation of ion channels in the cell membrane, changes in cellular pH, cell proliferation and vascular remodeling, and cytoskeletal rearrangement with cellular realignment (19, 41). Shear or flow-mediated vasodilation is arguably the most important physiological mechanism of vasodilation. It involves stimulated endothelial release of a vasodilating substance such as nitric oxide (NO), prostacyclin, or endothelium-derived hyperpolarizing factor (EDHF). Despite the prominence of shear-mediated vasodilation in numerous arterial beds, the initiating signal transduction mechanisms have not been clearly delineated. Shear responsiveness appears greatest in the most rigid nondeformable cellular regions, where the stress is highest. In endothelial cells, this occurs at the lateral cell-cell junctions (8). In many vascular tissues shear triggers endothelial release of nitric oxide through a complex pathway involving surface glycoprotein distortion, which is transmitted through the endothelial cytoskeleton to the basal membrane at focal adhesions at which tyrosine kinases are activated to increase intracellular calcium and activate nitric oxide synthase (5, 34). It is unclear which cell surface receptors are involved in propagating the shear signal to the underlying cytoskeleton.
Recent evidence suggests that in addition to its role in leukocyte migration, platelet endothelial cell adhesion molecule 1 (PECAM-1), CD31, is an important signaling molecule in endothelial cells. It is concentrated at cell junctions (1), in regions highly susceptible to the effects of shear and has been reported to be colocalized with endothelial nitric oxide synthase (eNOS) in the cell membrane (8, 14). PECAM-1 has also been reported to connect to remote cellular sites through the actin cytoskeleton (reviewed in Ref. 35) and is tyrosine-phosphorylated in response to shear stress (16). Thus the transmembrane protein PECAM-1 is a logical candidate component of the shear stress signaling pathway involved in flow-mediated vasodilation. In fact, recent evidence indicates that PECAM-1 contributes to NO-mediated dilation resulting from rapid changes in flow in skeletal muscle arterioles (2).
In this study, we examined the effect of PECAM-1 deficiency on the dilation of coronary arterioles in response to application of steady state shear stress. We observed an impairment in shear-induced vasodilation in PECAM-1-deficient relative to wild-type vessels, largely due to a reduction in the EDHF-mediated component of dilation. These findings confirm a modulatory role for PECAM-1 in the signaling pathway for flow-mediated dilation of the coronary circulation.
Preparation of mouse coronary arteries.
Eight-week-old male PECAM-1-knock-out (KO) mice that have been backcrossed for >12 generations onto a C57BL/6 background and age- and sex-matched wild-type (WT) mice were maintained in a pathogen-free facility of the Animal Resource Center of the Medical College of Wisconsin. All experiments were approved by the local institutional animal care and use committee at the Medical College of Wisconsin.
PECAM-1 KO and WT mice were anesthetized with tribromoethanol (0.4 mg/kg body wt) (Sigma) intraperitoneally and hearts were removed. Mouse coronary arteries (MCAs) were dissected from the left ventricle of the heart and prepared for videomicroscopy, histofluorescence, or immunohistochemistry.
MCAs were cannulated on glass micropipettes in an organ chamber filled with physiological saline solution (PSS) as described previously (33). Each pipette was attached to an individual pressure reservoir. The PSS was warmed to 37°C, continuously circulated, and bubbled with 21% O2-5% CO2-74% N2. Vessel diameter was recorded after development of spontaneous myogenic tone. When necessary U46619 (10−8 to 10−7 mol/l) was added to achieve 30–50% constriction. Flow was produced by changing the heights of the reservoirs in equal and opposite directions to generate a pressure gradient. Intraluminal diameter was measured in the presence of flow generated by pressure gradients of 20 and 100 cm H2O in the absence and the presence of antagonists. At the end of each experiment, vessels were treated with papaverine (100 μM) to determine the relaxation capacity of the arteriole. All measurements were made at steady state flow achieved 5 min after initiating the pressure gradient. Results are expressed as % maximal dilation, which was assessed as the change from constricted diameter (U46619) to the largest diameter observed at an intraluminal pressure of 60 mmHg (usually the diameter after treatment with 100 μM papaverine).
To identify the mediators responsible for dilation of MCAs in response to shear stress, pharmacological inhibitors were used. Nω-nitro-l-arginine methyl ester (l-NAME; 100 μmol/l), which inhibits nitric oxide synthase (NOS); indomethacin (INDO; 10 μmol/l), which inhibits cyclooxygenase (COX); or polyethylene glycolated catalase (PEG-CAT), which decomposes hydrogen peroxide, were administered to the vessel chamber after initial measurement of shear-induced vessel dilation, allowing 20–30 min incubation before measuring the effect of antagonist on the shear-induced dilation response. In some cases, sequential time control experiments were performed, which showed that the magnitudes of two consecutive flow-induced dilation responses were similar with no intervening treatment.
In separate experiments, MCAs from each type of mouse were incubated for 24 h at 37°C with ebselen (100 μmol/l, reapplied every 8 h) dissolved in DMEM with 10% fetal bovine serum, 100 U/ml penicillin G and 100 μg/ml streptomycin. After the 24-h incubation, flow-mediated dilation was assessed as described above.
Fluorescence detection of hydrogen peroxide and superoxide.
Dichlorodihydrofluorescein diacetate (DCFH-DA) and hydroethidine (HE) (27) were used to evaluate the production of hydrogen peroxide (H2O2) and superoxide (O2−·), respectively. Four MCAs from the same mouse were exposed to either no flow (pressurized, 0 gradient), or flow at a pressure gradient of 100 cm H2O. One vessel (not pressurized) served as a control. DCFH-DA (5 μmol/l) and HE (5 μmol/l) were added together in a light-protected chamber for 30 min at 37°C, either during flow or static conditions. Vessel segments were then washed with fresh PSS solution, and removed for fluorescence microscopy. DCF (the product of the reaction of DCFH with peroxide) and Oxy-ethidium (oxy-Etd, the fluorescent product of the reaction of HE with superoxide) were excited at 488 nm and 585 nm, and the emission was measured at 526 and 620 nm, respectively. Fresh untreated (control) and experimental tissues were examined in parallel and images were recorded using the same computer-specified gain and intensity settings. Results are expressed as relative fluorescence intensity of the user-defined vessel region, using a vessel treated with PEG-CAT (500 U/ml) and MnTBAP (300 μmol/l) as a baseline control [where reactive oxygen species (ROS) generation is maximally quenched].
Fluorescence detection of nitric oxide production.
MCAs were isolated from WT or KO mice and intraluminally exposed to 4,5-diaminofluorescein diacetate (DAF-2) (1 μmol/l, Molecular Probes), a NO indicator, for 15 min followed by a wash with PSS solution. Production of NO was examined under fluorescence microscopy at excitation 495 nm and emission 515 nm.
All fluorescence images were analyzed for intensity of fluorescence within a user-defined region of the arteriolar segment (maximal traceable area of the central portion of the vessel). Artifactual autofluorescent regions were manually eliminated from analysis. Relative average fluorescence intensity was normalized for surface area and compared between control and experimental vessels.
Western blot for detecting unphosphorylated and phosphorylated forms of eNOS.
Hearts were removed and homogenized. Protein samples (10 μg) were loaded onto an 8% acrylamide gel and transferred to a nitrocellulose membrane. The membrane was blocked with Tris-buffered saline-Tween 20 (TBST) buffer containing 10% nonfat milk at room temperature for 1 h. An antibody specific for eNOS phosphoserine 1177 (Cell Signaling), eNOS phosphothreonine 495 (Upstate Biotechnology), or native eNOS (Santa Cruz Biotechnology) was added to the membrane, which was incubated at 4°C overnight. After a 10-min wash with TBST 3 times, membranes were incubated with goat anti-rabbit IgG-HRP (1:10,000 Bio-Rad Laboratories) at room temperature for 1 h. The membranes were developed with ECL-Plus (Amersham) and analyzed with densitometry. Phospho-eNOS levels were expressed as the ratio of phospho-eNOS to total native eNOS band intensities.
Immunohistochemical detection of nitrotyrosine.
Nitrotyrosine formation was detected in MCAs for evaluating the production of peroxynitrite (ONOO−). Frozen sections of MCAs (5 μm thick) were cut and mounted onto glass slides. After 5 min of washing with PBS, slides were treated with protein block serum-free solution (DAKO) for 30 min at room temperature. Slides were then incubated for 2 h with monoclonal mouse anti-nitrotyrosine antibodies (Upstate Biotechnology), followed by two 10-min washes with 0.3% Triton X-100 in PBS. Slides were then incubated for 1 h in biotin-conjugated secondary antibody and 30 min with streptavidin-horseradish peroxidase conjugated solution. The bound antibody was visualized by the addition of 0.5 mg/ml diaminobenzidine and 0.01% hydrogen peroxide in PBS, which formed the insoluble brown precipitate (positive staining). Negative controls (no primary antibody in incubation solution) were prepared to test the specificity of staining.
All data are expressed as means ± SE. Percent dilation was calculated as the percent change from preconstricted diameter to the diameter after flow (maximal diameter was measured after papaverine, 10−4 mol/l). In some cases the l-NAME-sensitive component of dilation was determined by the following calculation: % maximal dilation observed in the absence of inhibitors − % maximal dilation observed in the presence of l-NAME. The indomethacin-sensitive component of dilation was calculated as % maximal dilation observed in the presence of l-NAME+INDO − % maximal dilation observed in the presence of l-NAME alone. The residual component, presumably EDHF-mediated, was calculated according to the formula: % maximal dilation observed in the absence of inhibitors − % maximal dilation observed in the presence of l-NAME+INDO. Data from vessels exposed to flow before and after antagonists were compared using a one-way ANOVA with repeated measures for pressure gradient and condition (antagonist exposure). The relative fluorescence intensities observed in arterioles from WT or KO mice exposed to static conditions, flow, or ACh were compared using a two-way ANOVA. All differences were judged to be significant at the level of P < 0.05.
Mediators of flow-mediated dilation (FMD) in WT and PECAM-1 KO MCAs: roles of NO, PGs, and EDHF.
We first examined the role of traditional endothelium-mediated dilator substances, NO, prostacyclin, and EDHF, in the coronary arteriolar dilation to shear stress. The baseline diameter of MCAs from WT and KO mice was 105 ± 8 μm and 109 ± 8 μm, respectively. The contractile response to the preconstrictor U46619 was similar in MCAs from WT and KO mice and the dose of U46619 used to constrict WT (60 ± 15 nmol/l) and KO (65 ± 13 nmol/l) animals was similar as well. The magnitude of FMD was reduced in KO relative to WT MCAs (Fig. 1, A and B) (% maximum dilation, WT vs. KO, 26 ± 3% vs. 11 ± 4% and 68 ± 7% vs. 38 ± 3% at 20 and 100 cm H2O pressure gradient, respectively; n = 5, P < 0.05). The contribution of NO, vasodilator PGs, and EDHF to FMD was determined by the effect of l-NAME (an NO synthase inhibitor), INDO (a cyclooxygenase inhibitor), and a combination of l-NAME and INDO, respectively. The l-NAME-inhibitable portion of dilation to shear stress was similar in WT and KO animals. A slightly greater portion of the dilation, however, was sensitive to indomethacin in WT vs. KO animals. Surprisingly, the remaining, and presumed EDHF, component was abolished in KO MCAs, suggesting that the reduced FMD in KO mice is largely due to the loss of EDHF-mediated dilation (Fig. 1C).
H2O2 acts as an EDHF regulating flow-mediated dilation in MCAs of WT but not PECAM-1 KO mice.
We have previously demonstrated that H2O2 acts as an EDHF in regulating FMD in diseased human coronary arterioles(31); however, the chemical nature of EDHF is dependent upon the vascular bed, species, and experimental conditions (10) and has not been clearly defined in MCAs. Therefore, we examined the extent to which H2O2 contributes to FMD in MCAs. Figure 2A shows that FMD of WT MCAs was significantly reduced by intraluminal application of PEG-CAT (500 U/ml), a cell-permeable H2O2 scavenger, indicating a critical role for H2O2 in FMD in MCAs. PEG-CAT had no effect on FMD in KO MCAs (Fig. 2B). These data demonstrate that the H2O2 component of the dilation to shear stress in MCA, which is detectable in wild-type mice, is absent in mice lacking PECAM-1.
Flow increases both O2−· and H2O2 generation in WT but not KO MCAs.
The finding that PEG-CAT inhibited FMD of WT but not KO MCAs suggested that KO vessels are unable to either produce H2O2 or respond to H2O2 that is produced normally during shear stress. We therefore evaluated production of H2O2 and its precursor, superoxide anion (O2−·), in resting vessels and those exposed to increased flow. As shown in Fig. 3, in the absence of flow (resting condition) oxy-Etd and DCFH fluorescence intensities, which reflect production rates of superoxide and H2O2, respectively, were increased in MCAs from KO mice (fold-increase of 4.5 ± 1.6 and 3.5 ± 1.1, respectively) compared with WT (n = 4, P < 0.05). Flow augmented both O2−· and H2O2 formation in WT MCAs with average increases in oxy-Etd and DCF fluorescence intensities of 3.0 ± 1.3- and 3.7 ± 1.3-fold, respectively, in flow relative to no flow conditions. In contrast to WT, flow appeared to reduce both O2−· and H2O2 formation in KO MCAs (2.3 ± 1.2 and 3 ± 1.3, respectively); however, this reduction was not statistically significant.
NO production and eNOS serine phosphorylation are enhanced in PECAM-1 KO mice.
The production of NO in MCAs from WT or KO mice was determined using DAF-2 fluorescence. Enhanced DAF-2 fluorescence intensity was observed in KO MCAs compared with WT (Fig. 4A) indicating that NO generation was augmented in KO MCAs. The observed increase in NO formation could be due to increased expression or increased activity of the eNOS enzyme. Total heart eNOS expression levels did not differ between WT and KO mice (Fig. 4C, bottom). Therefore, enhanced expression of the enzyme does not account for the increase in NO formation. eNOS can be phosphorylated on a serine residue at position 1177 (pS1177) and on a threonine residue at position 495 (pT495), with the former correlating with increased and the latter with reduced enzyme activity (4). Heart homogenates showed increased levels of pS1177 in KO compared with WT mice (Fig. 4B, n = 6, P < 0.05). In contrast, pT495 levels were similar in KO and WT mice (Fig. 4C). These data suggest that an increase in eNOS activity, but not an increase in eNOS protein levels, contributes to the observed increase in NO formation in PECAM-1 KO relative to WT mice.
Tyrosine nitration is enhanced in PECAM-1 KO coronary arteries.
Because both NO and O2−· generation were increased in MCA from KO mice, ONOO−, which is formed by reaction of NO with O2−·, was assessed by immunohistochemistry, using antibodies specific for 3-nitrotyrosine (3-NT) to detect the product of ONOO−-mediated nitration of tyrosine residues on cellular proteins. No staining of untreated KO vessels was observed in the absence of primary antibody (negative control), indicating specificity. 3-NT-specific antibodies reacted much more strongly with MCAs dervied from KO, relative to WT, mice (Fig. 5). This reactivity was 3-NT-specific, as no staining of KO MCAs was observed in the absence of the primary 3-NT-specific antibody (negative control). Ebselen, a scavenger of ONOO−, reduced immunohistochemical evidence for 3-NT in MCAs derived from KO mice but had no effect on 3-NT antibody reactivity with MCAs obtained from WT animals. These data indicate that ONOO− formation is augmented in coronary vessels from PECAM-1 KO mice compared with WT animals.
Impaired flow-mediated dilation in KO MCAs can be restored by treatment with a scavenger of ONOO−.
To determine whether ONOO− has an inhibitory effect on FMD, FMD in MCAs was examined after 24 h of incubation with ebselen. Treatment with ebselen enhanced FMD of MCAs derived from KO mice (Fig. 6A compared with Fig. 1B) to a level similar to that observed with WT vessels (Fig. 1A). The proportion of the FMD of ebselen-treated KO vessels that was sensitive to l-NAME and INDO (Fig. 6A) remained the same as was observed in untreated vessels from KO animals (Fig. 1B). Therefore, the improved FMD that was observed upon ebselen treatment of vessels derived from PECAM-1 KO mice was largely due to restoration of the l-NAME- and INDO-insensitive component of the dilation, which is presumably mediated by EDHF (Fig. 6C). In addition to scavenging peroxynitrite, ebselen can also act as a peroxidase to destroy hydrogen peroxide. We do not believe ebselen is acting in this fashion in the present study as the catalase-sensitive component of dilation was in fact enhanced after treatment of KO vessels with ebselen (Fig. 6). Overall, these data suggest that enhanced ONOO− generation in PECAM-1 KO mice impairs FMD in MCAs by abolishing the bioactivity of H2O2, the presumed EDHF in mouse coronary arteries.
The novel findings of this study are three-fold. First, steady-state FMD was reduced in MCAs of PECAM-1 KO mice. Second, among the vasodilators responsible for FMD in MCA, which include products of NOS and COX, as well as EDHF, NOS-mediated dilator mechanisms were not impaired, whereas COX-dependent dilation was slightly reduced and dilation attributable to EDHF was absent in PECAM-1-deficient vessels. Third, levels of NO and O2−· were elevated in PECAM-1-deficient MCAs, accounting for formation of ONOO−, which contributed to the impaired EDHF and COX components of FMD in PECAM-1-deficient vessels. To our knowledge, this study provides the first evidence that PECAM-1 plays a critical role in shear-mediated dilation in the coronary circulation.
The techniques used to obtain the data limit, to some extent, the strength of the conclusions reached in this study. We used fluorescent dyes to assess levels of NO, O2−· and H2O2 and immunohistochemistry to detect nitrotyrosine, a product of ONOO− activity, in WT and PECAM-1-deficient MCAs. This is because quantitative assays for O2−· and H2O2 production, such as cytochrome c reduction or ESR, respectively, and Western blots for detection of nitrotyrosine residues are not possible because of the very small size of isolated mouse coronary arteries. However, fluorescent methods for ROS detection are highly sensitive (3, 39), and when simultaneous measurements are made in experimental and control vessels, they can accurately detect relative differences in amounts of ROS. We assessed total ethidium fluorescence changes in vessels. Recent experimental data indicate that both ethidium bromide and oxy-ethidium (the product of the reaction of superoxide with hydroethidine) contribute to the fluorescence intensity (11, 46). Therefore, some of the increased fluorescence observed may reflect oxidative products other than superoxide. Similarly, immunohistochemical data, although qualitative, clearly provide evidence for increased ONOO− production in PECAM-1 KO, relative to WT, mouse coronary arteries. Coupled with specific pharmacological approaches to reduce particular ROS, such as our use of ebselen to scavenge ONOO−, these approaches collectively support the conclusion that ONOO−, produced as a consequence of generation of NO and O2−·, plays a role in inhibiting the vascular response of PECAM-1-deficient MCAs to shear.
We observed in the present studies that EDHF- and COX-dependent components of FMD could be restored upon treatment of PECAM-1-deficient vessels with the ONOO− scavenger ebselen. With respect to EDHF, we found in these studies that EDHF-dependent (i.e., NOS- and COX-independent) dilation of MCAs in response to shear was due to the production of H2O2. Although we did not provide direct evidence for H2O2-mediated vascular smooth muscle cell (VSMC) hyperpolarization in MCAs, we demonstrated that both flow-mediated dilation and production of H2O2 in WT MCAs was blocked with PEG-CAT. Therefore, H2O2, which mediates FMD in human coronary arterioles and elicits hyperpolarization in that vascular bed (32) and also mediates endothelium-dependent dilation in mouse and human mesenteric arterioles (29, 30), most likely serves as an EDHF in murine coronary arteries. We propose that ONOO− generated in PECAM-1-deficient MCAs interfered with the ability of VSMC to respond to H2O2. In addition, ONOO− generation could also have reduced the ability of vascular endothelial cells to produce H2O2. In this study, we found that flow-induced superoxide generation and vasodilation are reduced in PECAM-1-deficient mice, and these impairments are most likely due to the formation of ONOO−, which consumes superoxide. These data suggest that in the absence of PECAM-1, superoxide reacts with NO to form ONOO−, which inhibits the ability of the vessel to respond to H2O2, which functions as an EDHF. These findings indicate an important role of PECAM-1 in protecting the EDHF component of flow-mediated vasodilation. Restoration of the EDHF component by ebselen further supports the idea that peroxynitrite associated with PECAM-1 deficiency is responsible for the impaired EDHF dilation induced by flow.
The mechanism underlying nonresponsiveness of PECAM-1-deficient MCAs to H2O2 may involve inhibition of the opening of KCa channels in VSMC, which have previously shown to be inactivated by ONOO− (26). Future studies using electrophysiological techniques to examine membrane potential changes to H2O2 in WT and PECAM-1-deficient mouse coronary arteries should be able to confirm this hypothesis. In the case of COX-dependent vasodilation, on the other hand, it is possible that ONOO−generated in PECAM-1-deficient MCAs interferes with the ability of vascular endothelial cells to produce the COX-dependent vasodilator, prostacyclin, rather than with the ability of VSMC to respond to it. This is because previous studies have demonstrated that prostacyclin synthase is exquisitely sensitive to and irreversibly inhibited by ONOO− (47). Future studies, in which prostacyclin production in WT and PECAM-1-deficient MCAs is measured, are required to validate this hypothesis.
The finding that ONOO− generated in PECAM-1-deficient MCAs did not interfere with the ability of these vessels to produce and respond to NO was interesting. This observation is consistent with those of Wigg et al.(42), who showed that in mesenteric and femoral arteries from diabetic rats, endothelium-dependent dilation to ACh was reduced, largely because of a reduction in the EDHF-mediated component, whereas the NO component of the dilation was preserved. It is also consistent with a recent study by Bagi et al. (2), who demonstrated a maintained NO-mediated dilation in skeletal muscle arterioles to shear in PECAM-1 KO mice. However, they found that the early NO-mediated dilation to ramped flow is modulated by PECAM-1. Our observation of an overall reduction in steady-state flow-induced dilation in KO animals may reflect the different vascular bed, in which other mediators, including cyclooxygenase products and EDHF contribute to the dilation. Indeed, the NO component of dilation in the coronary arteries was not different between WT and KO mice, consistent with the findings by Bagi et al. (2).
Multiple substances have been postulated to function as an EDHF in the vasculature, including cytochrome P450 metabolites (6), gap junction (13), and K+ (9), depending upon the vascular beds studied and experimental conditions used. In the present study, we cannot exclude the possibility that ebselen incubation may have stimulated production of one of these or another substance that acts as an EDHF. Whether other mechanisms in addition to H2O2 are involved in flow-mediated dilation after ebselen treatment will be defined in future studies.
Our finding that ONOO−, NO, O2−·, and H2O2 were all present at higher levels in PECAM-1-deficient relative to WT MCAs suggests that PECAM-1 normally functions to regulate levels of NO and O2−·, the precursors for production of ONOO− and H2O2, in the coronary vasculature. The mechanisms by which PECAM-1 regulates NO and O2−· levels in MCA are, however, currently unknown. To regulate NO synthesis, PECAM-1 must regulate the activity of any or all of the three isoforms of NOS, including nNOS, iNOS, and eNOS. The latter two of these are expressed in endothelial cells under normal (43) or pathological conditions (24, 25) and are therefore candidates for the regulatory effects of PECAM-1 described in this study. Our findings that NO was present at higher levels and that eNOS was hyperphosphorylated on a regulatory serine residue in PECAM-1 KO relative to WT MCAs and heart lysates, are consistent with the recent report that PECAM-1 associates with and inhibits the activity of eNOS in human umbilical vein endothelial cells (8). However, the extent to which PECAM-1 associates with and regulates eNOS activity in MCAs is not yet known. We postulate that the increased phosphorylation at pS1177 is responsible for the increased basal NO production in PECAM KO mice.
An alternative explanation for the paradoxical findings of increased NO levels and concomitant reduced FMD in PECAM-1 KO MCAs is that attenuated smooth muscle cGMP production lessens dilation in response to NO. To evaluate this possibility, we measured the basal level of cGMP in aortas from WT and KO, since the small size of MCAs precluded their use for this purpose. Preliminary results from studies of four paired KO and WT vessels revealed that aortas behaved similarly to MCAs in that enhanced NO production and upregulation of eNOS pS1177 was observed in KO relative to WT aortas; however, the baseline level of cGMP production was not significantly different in aortas from KO vs. WT mice (data not shown). Future studies are required to expand upon these initial observations and will include measurement of guanylyl cyclase expression, stimulated phosphorylation of eNOS and consequent functional effects.
With respect to PECAM-1 as a regulator of O2−· production, O2−· can be derived from several sources, including the mitochondria, NAD(P)H oxidase and uncoupled NOS (44). ONOO−, by oxidizing tetrahydrobiopterin, can uncouple NOS and increase formation of O2−· (23). However, our studies provide evidence against uncoupled NOS as the source of O2−· in PECAM-1-deficient vessels, as the NOS component of FMD was maintained and NO-dependent DAF-2 fluorescence was actually enhanced relative to WT in MCAs derived from PECAM-1-deficient mice. Further studies are needed to determine the sources of the increased levels NO and O2−· that we observed in PECAM-1-deficient MCAs and to explore indirect, as well as direct mechanisms for PECAM-1-mediated regulation of the enzymes or pathways responsible for production of these ROS in endothelial cells.
Our findings suggest that PECAM-1 regulates endothelial cell production of vasodilators in response to exposure to shear stress. Shear stress acting on the endothelial cell surface activates a signaling cascade that results in the formation of NO and other endothelium-derived substances that migrate to the underlying vascular smooth muscle to stimulate vasodilation (7, 17, 22). As shear is greatest in areas of endothelial cells with least deformability, molecules located at sites of cell-cell junctions are positioned to most efficiently transduce signals in response to shear stress (8). PECAM-1, which is highly concentrated at junctions between endothelial cells (1, 12, 35), is well positioned to function as a biosensor of shear stresses in the endothelial lining of blood vessels. PECAM-1 is a type I transmembrane protein that contains two tyrosine phosphorylation sites within its cytoplasmic domain that, when phosphorylated, support recruitment of the Scr homology 2 domain-containing protein tyrosine phosphatase (SHP-2) (reviewed in Ref. 35). Tyrosine phosphorylation of endothelial cell PECAM-1 in response to application of fluid shear stress or mechanical stretch has been previously reported (16, 21, 28, 37, 40). PECAM-1 tyrosine phosphorylation in response to shear has also been shown to correlate with rapid translocation of SHP-2 from its cytoplasmic distribution to the inner face of the endothelial cell plasma membrane (38). In addition, increases in intracellular calcium, potassium and stretch-activated cation channel opening, and prostacyclin release occur downstream of PECAM-1 engagement on PECAM-1-expressing endothelial cell-like cells (15, 36) in a manner that depends on tyrosine phosphorylation sites within the PECAM-1 cytoplasmic domain (20). It will be important to determine whether PECAM-1 must become tyrosine phosphorylated and bind SHP-2 to control endothelial cell production of ROS and thereby influence the ability of vessels to dilate in response to shear stress.
FMD in MCA requires production of NO, dilator COX products, and the EHDF, H2O2. Absence of PECAM-1 had no effect on the NOS component of FMD, but reduced the COX and abolished the H2O2 component with an associated increase in ONOO− production. Overall, the peak FMD response was reduced by 50% in PECAM-1-deficient relative to WT MCAs. We conclude that PECAM-1 is necessary for normal FMD in the mouse coronary circulation. In the absence of this adhesion molecule, ONOO− production is increased concomitant with a reduction in both the EDHF and COX-mediated components of FMD.
This work was supported by National Institutes of Health RO1 HL067948 (Y. Liu.), P50 HL65203 (P. Newman, D. Newman, D. Gutterman), P01 HL68769 (D. Gutterman), and VA Merit grant (D. Gutterman).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2006 the American Physiological Society


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subset: commoncrawl


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If you're like me, you spend too many hours online reading about anything and everything you can get your hands on. Personally, I tend to gravitate towards sports and technology websites, but whichever news site or blog your individual interests lead you to, you'll no doubt come across a host of social media share buttons within every article you read.
Despite the fact that social media has taken the Internet by storm over the last couple years, not all social platforms are created equal. For example, anyone who has spent time online could tell you about the overwhelming presence of Facebook. Because Facebook has a user base approaching one billion, if you're not making it easy for users to share your articles on Facebook, you're missing out on a huge opportunity for driving traffic to your site.
Other social media sites like Twitter and LinkedIn have also established a strong presence on the web, especially in niche communities. Even newcomer Pinterest, which grew at unprecedented rates in late 2011 and early 2012, has established itself as a force to be reckoned with in the social media world.
But where does that leave Google+, which was heralded as the latest and greatest social networking tool before its launch a little over nine months ago? Despite the initial hype, Google+ has thus far failed to match growth rates seen by Pinterest and Twitter and has thus fallen victim to the widespread perception that no one really uses Google+. Evidentially, even the creators Google+ addressed this perception in a blog post a few months ago.
But despite the negative perception and the "crowded" (I'll get to this in a moment) social media webspace, Google+ is, in fact, posting steady growth numbers. Most recently, it posted a healthy 27% increase in visitors from February to March.
As for the idea that the social media world is just too crowded for another Facebook or Twitter-esque giant, look no further than social media's latest flavor of the week: Pinterest. Even though plenty of other platforms existed for sharing images (Facebook, Tumblr, Instagram, and Imgur, for example), Pinterest broke onto the scene late in 2011 and is now the third most popular social network in the United States.
The lesson here is that even though there are plenty of social media sites out there, it's as good a time as ever to grow a new network. With its encouraging March numbers and early signs that Pinterest's explosive growth is stagnating, Google+ isn't out of the race just yet.


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Musselmans From Michigan
MY Name is Joshua John Musselman of Lake City Michigan. My Great great Grandfather came to Missaukee county in the Middle/Late 1800's and we have been here ever since. we are a large family here with lots of local history. although i am curious of our history before we settled here. my great great grandpa was Adam Musselman. I am told he came from pennsylvania. does anyone know any more about this branch of the enormous Musselman Family tree????


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New Delhi, July 23 (IANS) A 38-year-old man was arrested from Noida for duping a businessman on the pretext of selling him government land and another property in Delhi for Rs.20 crore using forged documents, police said Tuesday.
Pawan Solanki was arrested July 12 from his house in Uttar Pradesh's Noida for duping Ajay Chaudhary on the pretext of selling him two prime properties in south Delhi's Jorbagh and Mayfair Garden on the basis of forged agreement papers.
Chaudhary, a businessman based in south Delhi's Vasant Kunj, had reported the incident in December 2012 claiming that Solanki along with other co-accused had duped him of Rs. 20 crore in property deals.
"The victim was shown the documents having signatures and stamps of Delhi Development Authority officials and he paid the money believing these documents to be genuine," said Harendra Singh, additional deputy commissioner of police.
"The investigation revealed that the property in Jor Bagh area was a government land owned by the civil aviation ministry. In the case of the second property at Mayfair Garden, the DDA had cancelled the allotment to the orginal owner and allotted to another person," said the officer.
The accused are currently in judicial custody, said Harendra Singh.


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Martinez on song as Independiente claim victory
A Jackson Martinez hattrick helped Colombian side Independiente to a 4-0 victory over Uruguayan giants Penarol in the first stage of the Copa Libertadores.
Forward Martinez put Independiente ahead with a superb header in the 15th minute before he doubled his side's advantage four minutes later with a shot on the turn inside the box.
Ivan Corredor fired home from a free kick midway through the first half to ensure there was no way back for Penarol before Martinez completed his hattrick when he pounced on a rebound from off the bar early in the second half.
Elsewhere, Universidad de Chile saw off Mexican side Pachuca 1-0.
Sergio Markarian's side clinched the victory in the early stages when Emilio Hernandez set up Marcelo Diaz, who had the simple task of putting the ball into the net.
"I believe that the team played well during the first half, they controlled the ball and put pressure on their defence although we lacked pace," said Markarian.
Pachuca meet Universidad next Wednesday needing to win by two goals to go on into the group stage.
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Teenager Atticus Shaffer is an old soul. The 15-year-old actor plays whispering oddball Brick Heck on TV2 comedy The Middle, but he speaks like an adult, and his interests might baffle the typical teenager.
He's also experienced a lot more of life than your average adolescent. A sufferer of brittle bone disease (type IV osteogenesis imperfecta), Atticus walks with a limp, due to multiple breaks in his legs, resulting from his condition.
At 1.3m (4ft 3in), he's the perfect height to play a 12-year-old, and the show's directors work around his disability – he's hardly ever seen walking. But this May, the actor had another setback. A serious fall at his home in Burbank, California, caused a shoulder injury and fractures to both of his legs, one requiring extensive surgery. But the happy-go-lucky star was grateful to return to work, accepting the injuries as a reality of his life. He's also startlingly pragmatic about his future in the business.
"This is temporary and I know it's temporary," says Atticus, reflecting on the fickle nature of fame.
"I love being a storyteller, and my hope is that I might go to college and learn to be a director and writer when I'm older. I'd like to be the narrator of the story, rather than just a character.
"I was never the kind of kid that woke up one morning, went down the stairs and said, 'I want to be an actor.' And it's not like my parents were trying to shape me into a child actor," he says.
A copy of The California Child Actor's Bill hangs by the set door at Warner Bros. studios, a gentle reminder to the cast and crew of The Middle that, no matter how mature he may seem, Atticus is still a minor.
He has a social worker on set, and is legally required to have three hours of tutoring a day. Mum Debbie home-schools him the rest of the time.
A huge sci-fi and fantasy fan, Atticus is keen to visit New Zealand to check out Hobbiton – he's even put a picture of himself up on Twitter, greeting his fans "Kia ora".
The history buff is also keen to learn more about the Maori trenches used in the New Zealand Wars. It's esoteric interests like these that make him the perfect person to play Brick.
"He's quirky, and I am too. I'm a big movie nerd. I love to read and I love nature as well. It's not a big method [acting] thing for me, it's how I naturally am," says Atticus.
"When I first got into this business, my mum said, 'Just be yourself, don't let anyone change you, march to the beat of your own drum.' So that's how I've always been."


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What goes around comes around, at least when talking about the revolutions of a Ferris wheel.
A group in Phoenixville in Chester County is hoping that the story of one such attraction comes full circle: It's working to restore and display a 70-foot-tall historic ride, one of the first ever built, in the very city where it was constructed 114 years ago.
The push is the latest chapter of a decade-long effort to revitalize the downtown enclave that had fallen on hard times when the steel industry left and to help Phoenixville rise from the ashes, so to speak.
This particular artifact has witnessed a thing or two over its long lifetime. In fact, the entertainment apparatus happened to play a bit part in Israel's War for Independence, or at least in the effort on the part of many Americans Jews to illegally ship arms to the nascent Jewish army.
The wheel's one-time owner, a New Jersey man who counted David Ben-Gurion among his friends, often used the ride as a means to guarantee private conversation and help keep his clandestine activities under wraps.
Such a connection isn't lost on Barbara Cohen, a 68-year-old member of the Schuylkill Township Board of Supervisors who is spearheading the reclamation effort. Cohen previously helped raise $5 million to transform a crumbling foundry building near downtown Phoenixville into the home of the Schuylkill River Heritage Center, a nonprofit group that teaches about the city's industrial past; it also serves as a venue for corporate events and weddings.
For Cohen, a longtime member of Congregation B'nai Jacob in Phoenixville, the goal is to "reinvent urban areas, as opposed to building more strip malls. We want to try and rejuvenate the town, to create a memory of an industrial legacy, but at the same time reinvent it in a way that Manayunk has been reinvented."
Dan Baer, an octogenarian born in Phoenixville who still lives in the area, noted that less than a decade ago, "there was no reason for people to come downtown. There weren't enough stores to make it worthwhile."
Her Adopted City
But now, Bridge Street — the city's main thoroughfare — is lined with restaurants, pubs and coffeehouses, a far cry from five years ago, according to Barry Cassidy, executive director of the city's Community Development Corp. Things have changed so dramatically that the city is now in need of a parking garage, he said.
"I have adopted Phoenixville because of my appreciation of the amazing legacy of this community, both social and industrial," said Cohen, who has also served as the director of the Chamber of Commerce and the Phoenixville Area Economic Development Corporation.
Cohen's idea is to have an item that speaks to the city's history as a steel producer like no other — thus, the Ferris wheel — erected in the vicinity, possibly near the proposed garage. It would no longer function as a working ride, but would instead serve as a kind of "industrial sculpture."
Cohen, a lover of history who once gave Jewish bicentennial tours in downtown Philadelphia and holds a master's degree in design, has delved into the history of this particular amusement-park ride.
In 1895, just two years after George Ferris unveiled his invention at the World's Fair in Chicago, Ernest Schnitzler, owner of an amusement park in Asbury Park, N.J., approached the Phoenix Bridge Company in Phoenixville with a similar design, according to Cohen and other sources. The company ultimately built four such wheels.
Despite the fact that the design of the Ferris wheel underwent some changes — such as going from 20 to 16 carriages because of a tendency for them to lock in midair — the "Phoenixville" ride remained at Asbury Park's Palace Amusement, a seashore arcade and theme park, for the better part of 100 years.
In the 1930s, a New Jersey man named Zimel Resnick — who was born in Russia in 1897 and immigrated to the United States in 1911 — became co-owner of the park. A committed Zionist, Resnick had served with the Jewish Legion during World War I, where he had befriended Israel's future prime minister, Ben-Gurion.
According to The Pledge, a book by Leonard Slater about the underground movement to ship arms to Israel after World War II, Resnick collected guns and arms for the Jewish cause.
When Resnick wanted to discuss activities that were at the time illegal, Slater noted that he would lead his contacts "to the Ferris wheel at the amusement park into one of its gaudy carriages, where swinging round and round above the seaside resort, they could talk without fear of being overheard" — something like a scene taken from the Orson Welles movie "The Third Man."
Jules Resnick, 83, worked for a time at his uncle's amusement park and recalled Ben-Gurion calling the office. The younger Resnick, of Ocean Township, N.J., recalled that as a teenager, his uncle asked him to drive an Israeli who wore an eye patch from Asbury Park to New York City. Only later did the younger Resnick realize that the gentleman was none other than Moshe Dayan.
"When it came to Israel, [my uncle] had complete, 110 percent dedication. He had no children — really, Israel was his child," said his nephew, adding that his uncle spoke with a Yiddish-inflected accent, but commanded the respect of statesmen. "He's a legend."
Zimel Resnick died in 1971 at age 74; he was buried in Israel.
So, what might the amusement-park owner have thought of having his beloved Ferris wheel standing in downtown Phoenixville?
His nephew isn't sure, but said that his uncle would have "turned in his grave" if he knew about the precipitous economic decline in Asbury Park, as well as the closing of much of the seashore attractions.
Coming Back Home
Indeed, the amusement park closed in the late 1980s, and the Ferris wheel was sold to a park in Mississippi. It stayed there, operating for almost 10 years until New Jersey developer Bill Sitar purchased it, hoping to return the wheel to its home in Asbury Park.
But that plan languished, and Cohen's group, the Schuylkill River Heritage Center, was able to purchase it instead. (Asbury Park, however, thanks in large part to the efforts of rock superstar Bruce Springsteen, has been seeing a resurgence of its own.) In 2008, the wheel was moved, in pieces, back to Phoenixville, where much of it sits in a welding and fabrication shop.
Actually, Cohen said that they paid Sitar $25,000, but still owe him $50,000. She said that she has raised $78,000 of the $146,000 needed to pay for the entire project.
A number of area businesses, including the Phoenixville Federal Bank and even the Borough of Phoenixville itself, have purchased naming rights for 12 of the 16 individual passenger carriages.
Refurbished Ferris wheel seats have been placed on the front lawns of several supporting businesses — at least, until the go-ahead is given to rebuild the whole thing.
"This happens to be a relic from Phoenixville's past," said Carol Buckwalter of Phoenixville Federal Band & Trust.
The hope, said Cohen, is to have it stand on privately owned land adjacent to the refurbished foundry building and next to a new parking garage. Where exactly it will be placed, she said, is a "work in progress."
Yet once situated, it will remain an homage to the past.


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By Kevin Kelley
Fairview Park
Mayor Eileen Patton wants to emphasize the "park" in Fairview Park.
Last week, the Patton administration proposed a three-year, $536,000 plan to improve the city's parks. Under the plan, $152,000 will be spent this year, $194,000 in 2015 and $190,000 in 2016.
Much of the focus will be on Nelson Russ Park, located off MacBeth Avenue. Named after the city's first recreation director, the park is largely empty after the recreation department headquarters was relocated to the Gemini Center when that facility opened in 2008. The city's safety town for children was also relocated to the Gemini Center.
A long-term plan for Nelson Russ Park will be determined this year. Possible features for the site include a tree nursery, a playground and soccer fields, Patton told West Life.
Under the plan, $30,000 has been earmarked this year for resurfacing the Nelson Russ parking lot. Fifty-thousand dollars will be used to implement whatever plan is decided on for the park in 2015 and 2016.
The city's four other parks will also see improvements under the plan.
"We tried to touch on all the parks," recreation Director Kenn Kaminski said.
All parks will have new signage installed. At Grannis Park, located off West 202nd Street, the rec department will install seven new trees, which Kaminski said will improve drainage problems. Playground equipment now at Morton Park will be relocated to Grannis, and benches and picnic tables will be installed later this year. Next year, basketball courts there will be resurfaced and new hoops installed. In 2016, a pavilion area will be added at an estimated cost of $19,000.
At Morton Park, located at West 223rd Street and Morton Avenue, 12 trees and a shade area will be installed this year, and the tennis courts will be resurfaced. New playground equipment paid for largely through a state grant will also be installed this summer. The park's restrooms will be renovated in 2016 under the proposal.
At Bain Park, steps will be installed along North Park Drive later this year. In 2016, the roof on a pavilion will be replaced and the restroom facilities renovated.
The focus will be on athletic and sports fields at Bohlken Park, the 25-acre park located south of Westgate shopping center. A new fence will be added to Field No. 4 this year, with lights coming in 2016. In 2015, basketball courts will be resurfaced and the hoops replaced.
Tri-City Park, located off Westwood Avenue and co-owned with Westlake and Rocky River, is not part of the city's park improvement plan.
Despite the difficult financial climate of the past several years, Patton said she is confident the plan can be implemented. The $152,000 to be spent this year will come from both the city's general fund and its parks maintenance fund.
The Patton administration's budget for 2015 estimates expenditures to exceed revenues by approximately $2 million. The budget will be balanced using surplus funds from other years, though the conservative budgeting approach used by the city means the final shortfall may not be as bad as the budget estimate.
Despite the budgeting challenges, Patton said providing quality parks is a priority for her administration. Younger families that are moving into the city need parks for their children to play in, she noted.
Patton and Kaminski said the parks improvement plan will not jeopardize ongoing maintenance at the Gemini Center, as money has been budgeted for anticipated capital projects at that facility.
Members of City Council, who must approve the park plan appropriations, are scheduled to tour the city's parks Saturday morning with Kaminski and Patton.


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Ask the Experts
Skin cracks from eczema and HIV in the public restroomDear Doctor, I'd like to ask the direct&short questions. Please help me. I've many skin crack and open cuts on hands and fingers (they were not heal yet at that time). I use the the hotel lobby restroom on August29,2010 and accidentally drop my...
Response from Robert J. Frascino, M.D.
The Robert James Frascino AIDS Foundation...needed to be on your cell phone while peeing and pooping in the hotel lobby restroom???Even with eczema-indued skin cracks, the HIV risk of diving into the unflushed tidy bowel to rescue your iPhone is nonexistent. Dr. Bob Read more »
HIV transmission from water splash in the eye/s in public restroomI went to a movie theater yesterday. I was splashed in the eye with water by someone who had just... Read more »
Hiv transmission or paranoiaHello.I have been so paranoid with hiv in the last three years that it has really changed my life... Read more »
The Role of Public Private Partnerships in the National HIV/AIDS Strategy... This article was cross-posted from the AIDS.gov blog. James Albino is the Senior Program Manager in the Office of National AIDS Policy. Today, the White Office of National Read more »
American Journal of Public Health Publishes Supplement on HIV/AIDS... The April 2009 supplement of the American Journal of Public Health focuses on issues surrounding HIV/AIDS, diversity and other topics. It includes editorials, commentaries, essays and research articles ( American Journal of PublicRead more »
Arkansas HIV/AIDS Task Force Examines Ways to Encourage HIV-Positive People to Attend Public Forums, Provide Testimony... The Arkansas HIV/AIDS Minority Task Force on Monday examined ways to encourage HIV-positive people to attend three upcoming public forums and provide Read more »
Greater Awareness of HIV/AIDS, Other Global Health Issues Attributed to the Growth in Public Health Students, Washington Post Reports...undergraduate college students who are taking classes in epidemiology, global health and public health, driven in part by the HIV/AIDS pandemic and a motivation to contribute to the field. According to a recent survey by the Association of... Read more »
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How to fight HIV - Public Health Reform
Posted by Anonymous, 3 Replies...response to HIV is lilke pitting Kermit the Frog against a Pit Bull Terrier - all you do is reduce the devastating effect of AIDS while more people get infected with HIV LetUsReason Read more »
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Posted by GamboJim, 2 Replies...Industry) - for her thougts on the ELISA test. I think the Government needs to fight this HIV thing to the fullest for the sake of Public Health. You can't put a spark and gasoline together and not get an explosion. Young folks and adults are... Read more »
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Posted by Anonymous...Looking for an individual who can help us with our public relations initiatives. This person should have experience in public relations, have contacts at web journals, and trade magazines Read more »


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Mahasi Sayadaw wrote:Some people say that an intelligent act of dana must involve the contemplation of the anicca, dukkha and anatta of the donor, the recipient and the offering. This view is based on Atthasalini (a commentary on Abhidhammapitaka) which mentions the contemplation on the impermanence of everything after giving alms. But the reference is to contemplation after the act of dana, not before or while doing it. Moreover, the object is not to make the act intelligent but to create wholesome kamma in vipassana practice. If by intelligent dana is meant only the dana that pre-supposes such contemplation, all the other dana of non-Buddhists would have to be dubbed unintelligent acts and it is of course absurd to do so.
The accounts of alms-giving by bodhisattas make no mention of contemplation nor did the Buddha insist on it as a pre-requisite to an act of dana. The scriptures say only that the kammic potential of dana depends on the spiritual level of the recipient and this is the only teaching that we should consider in alms-giving. If the donor and the recipient were to be regarded as mere nama-rupa subject to anicca, etc., they would be on equal footing. The act of dana would then lack inspiration and much kammic potential.
From: A Discourse on Paticcasamuppada: The Doctrine of Dependent Origination by Ven Mahasi Sayadaw
Thanissaro Bhikkhu wrote:AN7.49 Dana Sutta discusses the motivations one might have for being generous, and rates in ascending order the results that different motivations can lead to. The Commentary notes that the highest motivation, untainted by lower motivations and leading to nonreturning (anagami – third stage of enlightenment), requires a certain level of mastery in concentration and insight in order to be one's genuine motivation for giving.
http://www.accesstoinsight.org/canon/su ... 7-049.html
starter wrote:...been wondering if it's right or not.
Thanissaro Bhikkhu wrote:...the type that produces a pleasure conducive to the goal, or the type that doesn't. Those that do, the Buddha labeled the "path." These activities include acts of generosity, acts of virtue, and the practice of mental absorption, or concentration. Even though they fall under the Three Characteristics, these activities produce a sense of pleasure relatively stable and secure, more deeply gratifying and nourishing than the act of producing and consuming ordinary sensual pleasures. So if you're aiming at happiness within the cycles of change, you should look to generosity, virtue, and mental absorption to produce that happiness.
From: All About Change by Thanissaro Bhikkhu
Punna means that which purifies the mind, which in fact means good deeds. Kiriya means that which ought to be done. Vatthu means that which produces prosperity and welfare. These ten moral deeds give you the highest blessing called Mangala (the Auspicious).
The Ten Punna Kiriya Vatthu are:
1. Dana (charity)
2. Sila (morality)
3. Bhavana (meditation)
4. Apacayana (giving due respect to others)
5. Veyyavaca (rendering service and assistance)
6. Patti-dana (sharing merits)
7. Pattanumodhana (rejoicing at and appreciation of merits of others)
8. Dhammassavana (listening to the Dhamma)
9. Dhammadesana (teaching the Dhamma to others)
10. Ditthijukamma (right belief*)
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Press Kits | Press Releases | PR | Prof. Development | Programming |
Project Management | Publishing/Licensing | Resumes/Letters | Self-Employment |
Taxes | Teaching Artists | Teaching Statements | Ticketing | Touring |
Visas | Voice | Websites
Acoustical Studies
Arts Administration
- Administrative Roles in Presenting Organizations. An introduction, by MECC
- Americans for the Arts
- ArtsJournal.com
- ArtsManagement.net
- Association of Arts Administration Educators
- League of American Orchestras
- Local Arts Agency Salaries from Americans for the Arts, 2013
- Top 10 Free Web Resources for Arts & Culture Leaders, via Arts Consulting Group (2016)
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Arts Advocacy
Arts Councils
Arts Medicine
Audio Engineering – See Recording
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- International Horn Society
- International Trombone Association
- International Trumpet Guild
- International Tuba Euphonium Association
- International Women's Brass Conference
- Resources for Brass Musicians compiled at MusiciansWay.com
Business Cards & Printing
- Moo.com. VistaPrint.com. PrintPlace.com (cards, posters and more)
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Business Plans (also see Entrepreneurship)
- Business Model Canvas
- Business Model Fiddle
- DiscoverBusiness.com guide to writing a business plan
- Get a Business Plan or Get a Real Job, by Cory Huff
- Sample Business Plans, from bplans.com
- Sample Music Business Plan | Sample Financial Statements, by Kevin English
- Writing a Business Plan, from the US Small Business Administration.
CD Manufacture
Chamber Music
- Chamber Music America
- Examples of Innovative Ensembles. Compiled by MECC
- Sample Chamber Ensemble Websites. Compiled by MECC
- Sample Piano Trio Concert Programs. Compiled by MECC
- Sample String Quartet Concert Programs. Compiled by MECC
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- American Choral Directors Association
- ChoralNet resouces and links
- Choral Resources compiled at MusiciansWay.com
- Chorus America
- Choruses in the Baltimore-Washington Region
- GALA Choruses
Church & Sacred Music
- American Guild of Organists | Alternative Resources for Salary Guidelines (the AGO guidlines were taken down in early 2017)
- Church Job Listing Sites compiled by MECC
- Church Music Association of America
- National Association of Pastoral Musicians
- Association of Lutheran Church Musicians. Salary/Employment Guidlines
- The Cantors Assembly
- Church Music Jobs in Baltimore/DC, compiled by MECC
- Presbyterian Assoc. of Musicians | Employment Guidelines
- Selected MD/DC Churches that Hire Musicians, compiled by MECC
- Tips for Singers Seeking Work in Religious Organizations, by MECC
Community Music
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Commissioning Music
- Commissioning Music: A Basic Guide. Valuable tips & pricing chart via NewMusicUSA
- Commissioning New Works. Broadly applicable guidelines via GALA Choruses
- Funding Resources for Composers (useful for funding commissions; curated by MECC)
- American Composers Alliance
- American Composers Forum
- American Composers Orchestra. Readings, advice, more
- Asian Composers League
- Baltimore Composers Forum
- BMI | ASCAP | SESAC (performing rights organizations; join as composer & publisher)
- ASCAP Foundation Morton Gould Young Composer Awards
- BMI Student Composer Awards
- Careers in Composition. Concise summary from Catholic Univ. of America
- College Music Society
- Commissioning Music: A Basic Guide | Commissioning Fees Calulator. Via NewMusicUSA
- Also see: Composing music for dance
- Components of a Commission Contract, via ComposerInklings.com
- Sample Commission Contracts, via GALA Choruses
- The Composer's Site
- Music and Copyright in the Digital Age, via Indiana University (pdf)
- Music Theory/Composition Jobs Wiki (info about higher ed jobs)
- Musical Arrangements and Copyright Law, by Serona Elton, esq
- National Association of Composers/USA
- New Music USA | New Music USA Online Library
- New Music Box
- Society of Composers
- Society for Electro-Acoustic Music in the United States
- Resources for Composers Curated by MECC (pdf) – also see our Opportunities Page
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Conducting (also see Orchestra, Voice, Winds)
- College Orchestra Directors Association
- Conductors Guild
- Conducting Masterclasses. A listing of diverse opportunities
- Part-Time Orchestras in the Baltimore-DC Region. Compiled by MECC
- Choruses in the Baltimore-Washington Region. Compiled by MECC
Contractors – see Unions
Crowdfunding (also see Grants)
- Kickstarter (largest)
- IndieGoGo.com
- IndieGoGo Field Guide. 22-page guidebook to running a crowdfunding campaign
- RocketHub.com
- "The Musician's Guide to Fan Funding" by Jonathan Ostrow
- Budgeting and planning documents, by Kevin Clark
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Direct-to-Fan Platforms (also see Newsletters)
Directories (also see Touring Resources on our Job Search Page)
- Resources for African-American & Latino Musicians, compiled by MECC
- Asian Composers League (also see Composition Resources)
- Asian Cultural Council. Grants, events, resources
- AsiaSociety.org
- Japan Foundation Arts & Cultural Exchange
- JHU Cultural Groups
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Early Music
- American Recorder Society
- Boston Early Music Festival
- Early Music America
- EarlyMusicNews.org
- Early Music Online
- Gotham Early Music Scene
- Lute Society of America
- Online Resources for Music Scholars. Compiled by the Harvard Library
- Society for Seventeenth Century Music
- Viola da Gamba Society of America
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Elevator Pitch
- Articles about Music Entrepreneurship by Gerald Klickstein
- ArtsStart.org | Booklet
- Entrepreneur the Arts
- Freelancers Union
- JHU Idea Lab
- JHU Ventures. Resources, funding & mentorship for Peabody/JHU students
- JHU Entrepreneurship Bootcamp
- JHU Social Innovation Lab
- O'Connor Fund, for JHU Undergraduate Entrepreneurs
- Kauffman Foundation
- National Arts Strategies
- Score.org. Free business advice from volunteer mentors
- Self-Employment Basics, from the US Bureau of Labor Statistics
- Society for Arts Entrepreneurship Education
- Artivate. Online journal of entrepreneurship in the arts
- US Association for Small Business and Entrepreneurship
- US Small Business Administration
- Venture for America
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Event Calendars
- Baltimore Online Event Calendars (free). Compiled by MECC
- Washington DC Online Event Calendars (free). Compiled by MECC
Financial Literacy
- YouNeedaBudget.com. Free for college students
- Budget templates: MS Office; Google Docs
- Financial Literacy Basics. Online tool from UMBC
- Personal Finance Tips for Musicians (via NEC)
Grants (also see Crowdfunding & Scholarships)
- Grant Resources listed on the MECC job/opportunity search page
- Grants Available to Peabody Students
- Grantsmanship Center Index of US Funding Sources by State
- Resources for Grantseekers. An annotated list of links by Gerald Klickstein
- Partnering with Non-Profits, by Gerald Klickstein
- Pay As You Earn, student loan repayment assistance from the US Dept. of Education
- Public Service Loan Forgiveness. Student debt relief from the US Dept. of Education
- Teacher Loan Forgiveness, from the US Dept. of Education
- Tips for Writing Grant Proposals. Concise guidelines by MECC
- Budget templates: MS Office; Google Docs
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- European Guitar Teachers Association
- Guitar Foundation of America
- Guitar Resources compiled at MusiciansWay.com
- American Harp Society
- Harp Resources compiled at MusiciansWay.com
- World Harp Congress
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Health Insurance
- Artists Health Insurance Resource Center (AHIRC)
- Understanding Health Care Reform. Free report and guidelines from the AHIRC
Higher Education (also see Music Education)
- Chronicle of Higher Education
- College Music Society
- How to Win a Music Faculty Position, slides from a talk given by Gerald Klickstein
- Inside Higher Ed
- Association Européenne des Conservatories
- Higher Education Job Search Sites, compiled by MECC
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International Students/Visas
- JHU Office of International Services (OIS)
- EducationUSA.info. Sponsored by the US Department of State
- Journal of International Students
- Study in the States. A US Government site with extensive information
- Glossary of US Immigration Law Terminology
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- Interviewing Tips. Links and articles compiled by MECC
- All About Jazz. Online magazine and artist listing service
- BaltimoreJazz.com. Teacher listing, calendar, resources
- CapitalBop.com. News, calendar, clubs list
- DCJazz.com. Artist listing, club index, and more
- Jazz Corner. Portal to jazz websites
- Jazz Education Resources, via NAfME
- Jazz Near You. Listing service. Instructions to upload events here
- Jazz Resources compiled at MusiciansWay.com
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K-12 Education (also see Music Education)
- Occupational Outlook: Kindergarten/Elementary | Middle School | High School
- National Association for Music Education
- American String Teachers Association
- Peabody Music Ed Certification/Programs
- Certification & Employment Info for Maryland:
- Praxis exam info for MD (Passing required for MD public school teaching certification)
- MD Dept. of Education Certification Info | MD Dept. of Education Homepage
- Baltimore Teaching Fellows
- Maryland Education Recruitment Consortium
- JHU Master of Arts in Teaching (Other universities offer similar degrees)
- Reciprocity Certification (How certified teachers gain certification in other states)
- Private School Info & Organizations:
- Private School Teacher Salaries & Information (certification not required; salaries often lower than in public schools)
- Council for American Private Education
- National Association of Independent Schools
- Association of Independent Schools in Maryland/DC
- Private Schools in Maryland
- Teach for America (2-year commitment)
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Legal Advice
- Maryland Volunteer Lawyers for the Arts
- IP Legal Freebies Blog
- Musical Arrangements and Copyright Law, by Serona Elton, esq
- Business Tools for Teaching Artists. Sample contracts, invoices and more via TASC
- Resources from ggartslaw.com
- Volunteer Lawyers for the Arts National Directory
- Washington Area Lawyers for the Arts (DC)
- Music Library Association
- Major Orchestra Librarians' Association
- Orchestra Library Information Group (small to medium-size orchestras)
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Military Bands (premier level)
- Air Force Band
- Army Band
- Army Field Band
- Army Fife and Drum Corps
- Coast Guard Band
- Marine Band
- Marine Drum & Bugle Corps
- Military Academy Band (West Point)
- Naval Academy Band
- Navy Band
- US military bands, general info via Wikipedia
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Music Career Advice (general). Also see Touring
- Future of Music Coalition. "Education, research and advocacy for musicians."
- Guide to Careers in Music. Info about 150+ types of music careers
- Music Career Articles & Music Career Resources by Gerald Klickstein
- Music Career Juice. By Peter Spellman of the Berklee College of Music
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Music Education (also see Higher Education & K-12 Education)
- American String Teachers Association
- Association of Teaching Artists
- BandDirector.com
- College Band Directors National Association
- Jazz Education Network
- MusicTeachersHelper.com. Create a studio website.
- Music Teachers National Association
- National Association for Music Education
- National Guild for Community Arts Education
- Suzuki Association of the Americas Teacher Training
- Technology Institute for Music Educators
- Young Audiences – Maryland
Music Industry (also see Publishing)
- American Federation of Musicians
- Future of Music Coalition | Musician Revenue Streams | Music Industry Quizzes
- Grammy U
- International Federation of the Phonographic Industry (IFPI)
- Music Business Association
- National Association of Music Merchants (NAMM)
- Recording Industry Association of America (RIAA)
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Music Theory (also see Composition)
- Society for Music Theory
- Regional Music Theory Societies
- Music Theory/Composition Jobs Wiki (info about higher ed jobs)
Music Therapy
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Newsletters (also see Direct-to-Fan Platforms)
- MailChimp.com. Free for lists<2000
Opera – see Voice
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- American Orchestra Forum
- College Orchestra Directors Association
- International Conference of Symphony and Opera Musicians
- League of American Orchestras. Extensive info about the US orchestra industry
- List of Symphony Orchestras Worldwide. Via Wikipedia
- Musical America
- Orchestra Academies (paying & fellowship programs). A selected list compiled by MECC
- Orchestra Library Information Group
- Part-Time Orchestras in the Baltimore-DC Region. Compiled by MECC
- Polyphonic.org
- Regional Orchestra Players Association
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Organ (also see Church)
- Alternative Resources for Salary Guidelines (these guidelines were taken down in early 2017)
- American Guild of Organists
- Church Job Listing Sites compiled by MECC
- Selected US Churches that Present Organ Concerts (published by MECC)
- Selected MD/DC Churches that Hire Musicians (curated by MECC)
- Washington National Cathedral Organ Recitals. Apply to perform, Sun. afternoons, Sept-May
- Percussive Arts Society
- Resources for Percussionists compiled at MusiciansWay.com
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- Homewood Photo. Photography services for the JHU community
- Baltimore Area Vocal Accompanists Facebook Group
- Music Teachers National Association
- Piano Technicians Guild
- Places to Perform in the Baltimore area, compiled by MECC
- Places to Teach in the Baltimore-DC region, compiled by MECC
- Resources for Pianists compiled at MusiciansWay.com
- Sample Piano Trio Concert Programs, compiled by MECC
- Sample Solo Piano Recital Programs, compiled by MECC
- 3 Traits of Successful Concert Programs, by Gerald Klickstein
- Don't Be a White Egg, by Gerald Klickstein
- Tips for Aspiring Collaborative Pianists, compiled by MECC
- Touring Resources for Musicians
- Website Development Tips for Musicians
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Presenting (also see Programming)
- Association of Performing Arts Presenters
- International Performing Arts for Youth
- MusicalAmerica.com. Online tool to search for presenters, performers, and more
- National Association for Campus Activities
Press Kits
- How to Make a Killer Press Kit, via the DIY Musician Blog
- Press kit example and functionality, via Sonicbids
Press Releases
- Basic Press Release Format and Design, from Publicity Insider
- Sample Press Releases: MusicalAmerica.com | E. Jacobs PR
- Tips for Writing Press Releases, from Greg Sandow
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Professional Development
- JHU Entrepreneurship Bootcamp
- JHU Social Innovation Lab
- JHU Teaching Academy
- JHU Technology Ventures
- MECC Career & Creativity Seminars
Programming (also see Presenting)
- 3 Traits of Successful Concert Programs | Don't Be a White Egg, by Gerald Klickstein
- Sample Piano Trio Concert Programs. Compiled by MECC
- Sample Solo Piano Recital Programs. Compiled by MECC
- Sample String Quartet Concert Programs. Compiled by MECC
- Sample Voice Recital Programs | Also see SongFest programs (scroll down)
Project Management
Public Relations
- Press Contacts & Info: Annapolis and Baltimore
- Public Relations Sydney Blog. Diverse tips and ideas
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Publishing & Licensing
- Harry Fox Agency
- Music Distributors Association
- Music Publishers Association
- Music Publishing: Copyright Demystified. Via MusicalAmerica.com (2014)
- National Music Publishers Association
- SESAC | SoundExchange
Recording & Audio Engineering
- Audio Engineering Society
- Grammy U
- MIDI Manufacturers Association
- National Academy of Recording Arts and Sciences
- Recording Industry Association of America
- Society of Motion Picture & Television Engineers
- Society of Professional Audio Recording Services
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- Resume and cover letter guidelines compiled by MECC
Self-Employment (see Entrepreneurship)
- American String Teachers Association
- American Viola Society
- International Society of Bassists
- Sample Piano Trio Concert Programs. Compiled by MECC
- Sample String Quartet Concert Programs. Compiled by MECC
- Stringed Instrument Resources compiled at MusiciansWay.com
- Three Traits of Successful Concert Programs, by Gerald Klickstein
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Taxes & Accounting
- Bookkeeping for Artists
- Self Employment in the Arts
- Student Loan Repayment Plans. Comparison chart. Also see Grants
Teaching Artists
- Arts Every Day (Baltimore)
- Association of Teaching Artists (National)
- Business Tools for Teaching Artists. Sample contracts, invoices and more via TASC
- Young Audiences Maryland
- See the Touring Resources on our Job Search page
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- American Federation of Musicians (AFM)
- American Guild of Musical Artists
- Musicians' Union of Metropolitan Baltimore (AFM local 40-453)
- Washington DC Federation of Musicians (AFM local 161-710)
- Freelancers Union
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Visas – see International Students
Voice/Opera (also see Chorus)
- Wolf Trap Opera Blog
- Opera America | Opera America Career Guide for Opera
- National Opera Association | Operabase
- Classical Singer
- National Association of Teachers of Singing
- Voice Care Guidelines and Resources for Singers, via MusiciansWay.com
- Johns Hopkins Voice Center. Diagnosis and treatment of voice disorders
- Resources for Singers Curated by MECC (pdf):
- Acting Resources
- Audition Tips
- Career-related Articles
- Choruses in the Baltimore-Washington Region
- Churches that Hire Musicians (selected; MD/DC region)
- Diction and Translation Resources
- Interviews with Singers
- Musical Theater for Classical Singers
- Opera Companies in the Baltimore-Washington Region
- Repertoire & Role Study Guides
- Sample Voice Recital Programs | Also see SongFest programs (see links on the right)
- 3 Traits of Successful Concert Programs, by Gerald Klickstein
- Sample Websites of Classical Singers (also see Build a Website)
- Tips for Singers Seeking Work in Religious Organizations
- Vocal Pedagogy Resources – Online
- Vocal Pedagogy Resources – Print
- Voiceover Resources
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- See Build a Website
- National Flute Association | Flute Jobs Facebook Page
- American Recorder Society
- International Clarinet Association | Clarinet Jobs Facebook Page
- International Double Reed Society
- Band Instrument Repair Technicians
- Wind Instrument Resources at compiled at MusiciansWay.com.
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Notice: MECC maintains this site as a service to Peabody students & alumni. Announcements and external sites can be accessed via this site, but our making these resources available does not constitute an endorsement by Peabody or JHU of the companies publishing those announcements and sites. Site users should check the credentials of any organization or publisher and contact MECC with questions. Peabody and JHU are also not responsible for any misinformation that might be found on external sites nor for the results obtained from the use of this information.
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text:
It's called Florida Choices, and it's sparking students' education and career awareness, getting them ready for high school and college.
The program's giving students a chance to make a career portfolio, even offering assessment tests to help teenagers choose what career path best suits them.
"It's great for them to discuss what they know and what they want to do. If they already know they can research that particular job, they can find what the earnings are, the outlook and how much education you need, so it's a great tool," said Kim Brumage, a Chiles guidance counselor.
The program has been used in the Sunshine State for a few years. Leon County schools are catching on even offering workshops for students.


text: Sign inNot A Member? Join now! Find A Grave - Odessa Cemetery Changes are coming to Find A Grave. See a preview now. Browse by Cemetery: Odessa Cemetery One record foundFilter by fame level: All Famous NamesSomewhat FamousVery FamousAttention:You are browsing our famous burial locations. If you arelooking for a non-famous grave, please start from our home page. Specker, SGT. Joe C. b. January 10, 1921 d. January 7, 1944World War II Congressional Medal of Honor Recipient. He served in the United States Army during World War II as a Sergeant int he 48th Engineer Combat Battalion. He was awarded the CMOH for his bravery at Mount Porchia, Italy, on January 7, 1944. His citation reads "For conspicuous gallantry and intrepidity at risk of life, above and beyond the call of duty, in action involving actual conflict. On the night of 7 January 1944, Sgt. Specker, with his company, was advancing up the slope of Mount...[Read More]Cause of death: Killed in line of dutyOdessa Cemetery, Odessa, Lafayette County, Missouri, USA One record found Privacy Statement and Terms of Service


text:
If you're anything like I was when my kids were starting primary school, it's never crossed your mind that a child in his single digits could be clinically anxious or depressed. There is deceptively little public discourse about pediatric mental illnesses. I believe this is partly due to a collective blindness, in Western cultures, to "adult" ailments in young children, whom we wish to believe immune to the darkest aspects of life--and partly the consequence of a long-standing and pervasive stigmatization of people of all ages with mental illness. The statistics on pediatric and adolescent mental illness are sobering.
According to the National Alliance on Mental Illness (NAMI):
Four million children and adolescents in this country suffer from a serious mental disorder that causes significant functional impairments at home, at school and with peers. Of children ages 9 to 17, 21 percent have a diagnosable mental or addictive disorder that causes at least minimal impairment.
Half of all lifetime cases of mental disorders begin by age 14. Despite effective treatments, there are long delays, sometimes decades, between the first onset of symptoms and when people seek and receive treatment. An untreated mental disorder can lead to a more severe, more difficult to treat illness and to the development of co-occurring mental illnesses.
In any given year, only 20 percent of children with mental disorders are identified and receive mental health services.
I don't mean to suggest that every kid with school anxiety, or every victim of bullying, is at risk for developing a clinically significant psychiatric disorder. But that doesn't mean you shouldn't be paying close attention. Sometimes a stomach ache is just a stomach ache--but sometimes it's a somatic response to a serious emotional dysregulation. If your child consistently displays any of these 5 behaviors once the school year has begun, it's worth scheduling a meeting with her teacher, guidance counselor, or even her pediatrician--just to be on the safe side.
1. An all-consuming dread of school that seeps into other areas of life, interfering with functionality at home and in the community.
Look for things like striking personality changes or obsessive focus (perseveration) on one or two school-related topics--for example: recess, a particular peer, the cafeteria experience, or using the bathrooms at school. If he's talking about something more frequently than makes sense, or with clear signals of emotional distress--hand-wringing, fidgeting, teariness--you should follow up. After all, you know your kid better than anyone. Start the ball rolling by touching base with people who can help you figure things out.
2. Chronic stomach pains or hypochondria. I doubt there is a child to be found, anywhere, who has not on one occasion or another presented with a stomach ache just before leaving for school. Malingerers? Possibly, some of them. But children's somatic complaints always deserve to be taken seriously, because there is usually something going on behind them. Chronic stomach aches, for instance, can mean a lot of different things. Constipation is not unusual in young children--especially the ones who subsist on frozen waffles, pasta, and french fries. (N.B. This does not constitute any kind of admission on my part. Really and truly. Because I would NEVER have given in to my kids' demands to dine solely on white foods. I always insisted on something pigmented gracing their plates. Even if that pigmented food ended up being chocolate.) But seriously, after ruling out medical causes of chronic somatic complaints, talk to the school counselor, or make a consultation with a therapist. Imagine being eight years old and facing every school day with that same internal maelstrom you feel at age 45, when your boss grimly invites you in for a one-on-one chat. While most school children overcome the anxiety that causes them to wake up each day with a stomach ache, some don't--because the issues at play are complex, and liable to grow only more so if unaddressed. That kind of inner turmoil cannot be sustained without causing serious emotional damage.
3. Disrupted sleep patterns. Was your kid a champion night-time sleeper until she started second grade? Did he never, ever nap during the day since the age of 18 months, but now can't stay awake after school in spite of a good ten hours of sleep at night? A lot of parents wrestle with their children's sleep issues (not to mention their own!). A host of things could be responsible for troubled sleep, some physical, some emotional. If it lasts for more than a week or two, and there is no obvious cause, have the issue checked out. My rule of thumb has always been: start with the pediatrician, and if she finds no medical reason for the problem, approach the appropriate member of the school's staff--or an outside mental health professional. Anxiety and depression often make their first appearance in response to school-related triggers--and an excess of either can impact sleep. Remember: a child who is chronically under- or over-slept is a child who's not accessing his curriculum to his full capacity, OR his necessary social and life-skills experiences.
4. Too much time in the nurse's office. Has the nurse's office become your child's second bedroom? It's no secret that children dealing with emotional turmoil tend to end up in the nurse's office. And if it's once or twice a term, no big deal. Like their parents, kids sometimes need to take a "personal day"--even if it takes the form of an hour's respite on a cool, Naugahyde bed under the sympathetic eye of the least stress-inducing person available. But if you're receiving calls from the nurse on a daily basis, over an extended period of time, assume there's a problem--and don't ever assume your child's school will act on it for you. The most important lesson my husband and I learned over many years of serious struggle was that, if an issue needed to be addressed, WE had to make it happen.
5. Talking about, writing about, or drawing dark topics and images. This may seem like a no-brainer, but we humans have evolved a wonderful capacity for self-deception. As my husband Lars likes to say, "Denial is not a river in Egypt." True enough. Even if it feels like you can't possibly deal with yet another problem, if your child is fixated on violent narratives, obsessively drawing or seeking out dark images, expressing fantasies or plans to harm himself or others, take it seriously. Get a referral for therapeutic services immediately. Yes, the availability, accessibility, and affordability of pediatric mental health care is outrageously inadequate (that is a post for another time--when you and I have a few hours to spare). Yes, it may take days and weeks of effort. You'll lose those days and weeks and never get them back. But you will gain something priceless, if you summon your inner-bulldog and push relentlessly until you get your child the help he needs. School counselors can often help with referrals, and even bump your child up to the top of the waiting list, if the need is severe.
I know that accepting the possibility your child may have some sort of psychiatric disorder is acutely painful. I know the waters of Denial are delightfully refreshing. But there are crocodiles in those waters. I've encountered them while treading water there.
To end with a personal anecdote, some years ago, when my son Benjy was in fourth or fifth grade, he found a little animation program to use with his handheld gaming device. And he made a moving picture. It was brief; you had to pay close attention or it was over before it started. And it was drawn in such a way that you had to look closely to see what the action really was. The first several times he showed it to me I did not look closely enough. I thought I saw a stick figure standing and then falling down.
"How cool," I said. (Oh, if only I could redo that moment!)
It was only after I stepped away from it for a whole day and he brought it back to me again that I saw what the vignette was actually about. Suicide. It was a male figure holding a gun to his head and blowing his brains out. When I saw it for what it was, I felt like I was drowning. When I could breathe again I got moving. And thank goodness I did.
Readers, feel free to tell your stories, or ask questions about how to navigate the crocodile-infested waters of parenting a child with mental illness.