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Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and suppressed apoptosis. This phenotype is sustained by the activation of the Src/signal transducer and activator of transcription 3 (STAT3) axis, maintained by a positive feedback loop involving miR-204 and followed by an aberrant expression/activation of its downstream targets such as Pim1 and nuclear factor of activated T-cells (NFATc2). Dehydroepiandrosterone (DHEA) is a steroid hormone shown to reverse vascular remodeling in systemic vessels. Since STAT3 has been described as modulated by DHEA, we hypothesized that DHEA reverses human pulmonary hypertension by inhibiting Src/STAT3 constitutive activation. Using PASMCs isolated from patients with PAH (n = 3), we demonstrated that DHEA decreases both Src and STAT3 activation (Western blot and nuclear translocation assay), resulting in a significant reduction of Pim1, NFATc2 expression/activation (quantitative RT-PCR and Western blot), as well as Survivin and upregulation of bone morphogenetic protein receptor 2 (BMPR2) and miR-204. Src/STAT3 axis inhibition by DHEA is associated with 1) mitochondrial membrane potential (tetramethylrhodamine methyl-ester perchlorate; n = 150; P < 0.05) depolarization increasing apoptosis by 25% (terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling; n = 150; P < 0.05); and 2) decreased intracellular Ca2+ concentration (fluo-3 AM; n = 150; P < 0.05) and proliferation by 30% (PCNA). Finally, in vivo similarly to STAT3 inhibition DHEA improves experimental PAH (monocrotaline rats) by decreasing mean PA pressure and right ventricle hypertrophy. These effects were associated with the inhibition of Src, STAT3, Pim1, NFATc2, and Survivin and the upregulation of BMPR2 and miR-204. We demonstrated that DHEA reverses pulmonary hypertension in part by inhibiting the Src/STAT3.
- proliferation
- apoptosis
- remodeling
- therapies
- signal transducer and activator of transcription 3
pulmonary arterial hypertension (PAH; WHO Group 1) is a devastating disease of the pulmonary vascular network defined by an increase in pulmonary arterial pressure due to a marked and sustained elevation of pulmonary vascular resistance. Progressively, patients develop a compensatory right ventricular hypertrophy, which becomes insufficient and leads to dilatation and failure (4).
At the cellular level, PAH is characterized by enhanced inflammation (29), proliferation, and resistance to apoptosis (4) of pulmonary artery smooth muscle cells (PASMCs). The sustainability of this phenotype is due in part to the activation of neoplasic pathways involving the transcription factor signal transducer and activator of transcription 3 (STAT3; Ref. 46). The mechanism accounting for STAT3 activation in PAH-PASMCs exclusively relies on the Src pathway and is independent of the regular STAT3 activator Janus-activated kinase (JAK2; Ref. 12). This suggests that Src/STAT3 inhibition could be of a great therapeutic interest for PAH. Similarly to cancer, Src/STAT3 activation in PAH has been associated with the upregulation of the oncogene provirus integration site for Moloney murine leukemia virus (Pim-1) promoting the activation of the transcription factor nuclear factor of activated T-cells (NFATc2). NFATc2 activation has been shown to account for both proliferation and resistance to apoptosis in cancer and PAH. Indeed, by downregulating K+ channels like Kv1.5, NFATc2 leads to cell depolarization, increasing intracellular Ca2+ concentration ([Ca2+]i), and promoting cell proliferation (7, 9, 10); while by upregulating Bcl-2, NFATc2 activation leads to mitochondrial hyperpolarization and apoptosis resistance (7, 9, 10). Moreover, the Src/STAT3 axis is implicated in tumoral upregulation of Survivin, described as an important protein in the pathogenesis of PAH (39). Finally, Src/STAT3 has been also associated with bone morphogenetic protein receptor 2 (BMPR2) downregulation (11), further promoting the proproliferative, antiapoptotic PAH phenotype (54, 58).
The Src-dependant activation of STAT3 is mediated (i.e., phosphorylated P-STAT3 and translocated to the nucleus) by cytokines (such as IL-6; Ref. 14), growth factors (such as PDGF; Ref. 14), or agonists [such as endothelin-1 (ET-1) and ANG II; Ref. 6], factors that all appear to be implicated in PAH (13, 21, 50, 51). Additionally, we (12) provided evidence showing that STAT3 regulates a positive feedback loop sustaining its proper activation. By downregulating miR-204 in PAH, STAT3 activation leads to a constitutive c-Src activation maintaining STAT3 activated. For all these reasons, STAT3 can be considered as a major signaling hub of PAH and associated distal PA remodeling processes.
Dehydroepiandrosterone (DHEA) is a naturally and abundantly produced hormone, known to improve PAH through its vasodilator properties. Indeed, by opening K+ channel-like Kv and BKCa (8, 20, 47) and increasing cGMP generation and responsiveness to nitric oxide (45), DHEA enhances VSMC relaxation (25). Nonetheless, the effects of DHEA on vascular remodeling processes seen in PAH remain unknown. Several literature evidences have demonstrated the implication of the Src/STAT3 axis in both K+ channel modulation (44) (enhancing vasocontriction) along with NFATc2 activation (12, 46) and BMPR2 downregulation (11, 57) (promoting PASMCs proliferation and resistance to apoptosis). Since DHEA has been associated with decreased STAT3 activation in liver cells (34), we hypothesized that DHEA could reverse PAH through the inhibition of the Src-dependent activation of STAT3. DHEA could potentiate its vasodilating effects by decreasing the NFAT-dependant proproliferative and antiapoptotic phenotype (10).
All the experiments were performed with the approval of the Laval University Ethic and Biosafety Committee. The investigation conforms the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996) and the principles outlined in the Declaration of Helsinki (1).
Cell culture.
PAH-PASMCs were isolated from <1,500-μm-diameter small PAs from two males with idiopathic PAH (31 and 48 yr old) and one female with PAH Group 1 (lupus; 54 yr old) from lung explants (38). All patients had right catheterization that confirmed pulmonary hypertension (mean pulmonary arterial pressure >25 mmHg at rest). Age- and sex-matched control-PASMCs (3 males 45, 21, and 64 yr old and 2 females 17 and 35 yr old) were used.
Control-PASMCs from five patients were purchased (Cell Application Group). PASMCs (less than passage 6) were grown in high-glucose DMEM media supplemented with 10% FBS (GIBCO, Invitrogen, Burlington, ON, Canada) and 1% antibiotic/antimytotic (GIBCO, Invitrogen; Ref. 7). All cells were used until the fifth passage.
Cell treatments.
DHEA was dissolved in methanol and used at a final concentration of 100 μmol/l (methanol final concentration ≤0.1%). IL-6 stimulations (100 μmol/l) were applied for 48 h (9). Small interfering (si)RNA (Ambion, Austin, TX) were transfected at a final concentration of 20 nmol/l with CaCl2 (46). After 24 h, medium was changed and experiments were performed 48 h after the beginning of the transfection.
Measurement of the mitochondrial membrane potential and [Ca2±]i.
Measurement of the mitochondrial membrane potential and [Ca2±]i in live PASMCs (37°C) was performed using a FV1000 confocal microscope equipped with a live cell apparatus (Olympus, Center Valley, PA).
Mitochondrial membrane potential was determined using 10 nM tetramethylrhodamine methyl-ester perchlorate (TMRM; Invitrogen, Branchburg, NJ). [Ca2+]i was determined using 5 μmol/l fluo-3 AM (Invitrogen; Refs. 9, 10). Nuclei were stained using 50 nM of Hoechst 33342 (Invitrogen). Between 100 and 150 cells were measured by experiment in 3 experiments by cell line in 5 control and 3 PAH-PASMCs cell lines.
Proliferation and apoptosis measurements.
PASMCs were exposed to 10% FBS (a condition known to promote proliferation; Refs. 7, 10) or 0.1% FBS (a "starvation" condition that promotes apoptosis; Refs. 7, 10). Apoptosis rates were measured using Apoptag apoptosis detection kit [terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL); Millipore, Temecula, CA]. Proliferation rates were measured by the PCNA antibody from (1/400; Dako, Carpinteria, CA) and Ki67 antibody (1/400; Millipore) according to the manufacturer's instructions (9, 10). The percentage of positive PASMCs for TUNEL or Ki67 was determined by the number of cell showing the presence of a nuclear staining over the total number of cell. The percentage of PCNA positive cell was determined using a threshold based on the intensity obtained in control PASMCs. This threshold was applied in all the other groups, and cells showing a nuclear fluorescent intensity superior to the threshold were considered as positive. Between 100 to 150 cells were measured by experiment in 3 experiments by cell line in 5 control and 3 PA-PASMCs cell lines.
Nuclear translocation assay.
In PASMCs, STAT3 and NFATc2 activation were measured in ≥100 to 150 cells were measured by experiment in 3 experiment by cell lines in 5 control and 3 PA-PASMCs cell lines.
Briefly, PY705-STAT3 (1/250; Cell Signaling) and NFATc2 (1/250; ABCam) staining were performed as previously described (10). Secondary antibodies used were Alexa Fluor 488 or 594 (1/1,000; Invitrogen). The percentage of positive cells was determined using a threshold based on the intensity obtained in control PASMCs. This threshold was applied in all the other groups, and cells showing a nuclear fluorescent intensity superior to the threshold were considered as positive.
The same analysis was performed in rats in 10 distal arteries (<100 μm)/rat in 5 rats per groups. Colocalization between the targeted protein stained in green and the nucleus stained in blue with DAPI was further assessed using Volocity software from Perkin Elmer.
Quantitative RT-PCR and immunoblots.
Quantitative RT-PCR and immunoblots were performed as previously described (9, 10). Quantitative RT-PCR 2ΔCt was calculated with 18S as housekeeping gene (Taqman Gene Expression Assay; Applied Biosystems, Foster, CA). For immunoblots, protein expression of PY705-STAT3, STAT3, PY419-Src (1/1,000; Cell Signaling), and c-Src (1/1,000; Santa Cruz) was quantified. PY705-STAT3/STAT3 and PS419-Src/c-Src ratio evaluations were obtained from the same membrane after a 30-min stripping at 50°. The phosphorylated forms were rapported on the total form of the protein, and normalized by the amido black as previously described (10).
In vivo experiments.
Sprague-Dawley rats (250–350 g) were injected subcutaneously with 60 mg/kg of monocrotaline (MCT; n = 20). Intratracheal nebulization (50 μl) of siSCR (Ambion; 1 nmol in n = 5 rats) and siSTAT3 (Ambion; 1 nmol in n = 5 rats) was performed under anesthesia on day 18, once pulmonary hypertension was established. Freshly prepared DHEA (Sigma-Aldrich, St. Louis, MO) was administered by gavage (n = 5 rats) once a day at the concentration of 10 mg·kg−1·day−1 (30) during 2 wk. Experiments were performed with the approval of the Laval University Animal Ethics Committee.
Hemodynamic measurements.
Rats were initially anesthetized with 3–4% isoflurane and maintained with 2% during procedures. All rats underwent hemodynamic and echocardiography studies as previously described (10, 53). Right catheterizations (closed chest) were performed using SciScence catheters to directly measure PA pressures. Longitudinal and noninvasive evaluations of PAH were performed by echocardiography (using Vevo 2100 VisualSonics equipment) as previously described (10, 53). Euthanasia was performed by exsanguinations.
Histology measurements.
Percent media wall thickness was assessed as previously described (10). Briefly, lungs slides were colored with hematoxylin-eosin, and distal PA <100 μm wall thickness was measured using image Proplus software (Media Cybernetics). Two measurements per artery in 5 to 10 distal arteries per rat in 5 rats per groups were performed.
We tested if the data sets we are using for statistical assessment are coming from a normal distribution using the Shapiro-Wilk test. As all our data sets passed the test significantly (all P > 0.05), we were able to apply parametric analysis to our study and to present our results as means ± SE. For comparison between two means, we used a Student's t-test. For comparison between more than two means, we used a one-way ANOVA followed by a Tukey-Kramer tests. Probability values <0.001, 0.01, and 0.05 were considered as statistically significant.
DHEA decreases Src/STAT3 activation in PAH-PASMCs.
Using Western blot, we showed an increase in the amount of phosphorylated STAT3 on tyrosine 705 (i.e., active form of STAT3) over total STAT3. STAT3 activation is increased by 3.4-fold in PAH-PASMCs compared with control (Fig. 1A). By immunofluorescence, we evaluated the level of P-STAT3 translocated to the nucleus, which is associated with its transcriptional activity. The percentage of P-STAT3-positive cells (presenting an increased nuclear P-STAT3 intensity compared with control cells) is increased by seven times in PAH-PASMCs compared with control-PASMCs (Fig. 1A).
PAH-PASMCs treated with DHEA (100 μmol/l) for 48 h showed a significant decrease in both P-STAT3/STAT3 ratio and nuclear translocation of P-STAT3 (Fig. 1A), suggesting that DHEA inhibits the transcriptional activity of this protein.
DHEA and STAT3 inhibition reverses miR-204 downregulation in human PAH-PASMCs.
In addition to the circulating cytokines and growth factors accounting for STAT3 activation in PAH-PASMCs, we (12) recently demonstrated that the sustained STAT3 activation in these cells also depends on a STAT3-dependent downregulation of the microRNA miR-204. This positive feedback loop mechanism relies on the binding of STAT3 on the host gene of miR-204 leading to its downregulation. This downregulation accounts for a sustained c-Src activation, which is responsible of the constitutive STAT3 activation (12). Since DHEA has the ability to decrease STAT3 activation (34), we speculated that this positive feedback loop should be disrupted by DHEA. To this end, we first studied the effect of STAT3 inhibition on Src activation. PAH-PASMCs were transfected by either scramble RNA or RNA directed against STAT3. As expected, STAT3 inhibition is associated with decreased Src activation in PAH-PASMCs compared with scramble sample (Fig. 1B). As miR-204 is one of the major players of this loop, miR-204 expression was measured in control-PASMCs, PAH-PASMCs, and in PAH-PASMCs treated with STAT3 siRNA, scramble siRNA, or DHEA. STAT3-dependent regulation of miR-204 was confirmed since STAT3 inhibition by siSTAT3 in PAH-PASMCs increases miR-204 expression to a level similar as the one seen in control PASMCs (Fig. 1B). Similarly, DHEA significantly increase miR-204 expression in PAH-PASMCs. Finally, to confirm our previous findings we studied whether c-Src activation (induced by miR-204 downregulation) is decreased by DHEA. Using Western Blot, we showed that DHEA decreases c-Src activation (i.e., phosphorylated Src on tyrosine 418/total c-Src ratio) in PAH-PASMCs (Fig. 1C), disrupting the STAT3-dependant positive feedback loop sustaining its proper activation.
DHEA-dependant inhibition of the Src/STAT3 decreases the oncogenic pim-1/NFATc2/survivin axis and promotes BMPR2 expression.
To determine whether DHEA-dependent STAT3 inhibition is transduced, we studied the effects of DHEA on the STAT3 downstream targets implicated in PAH including Pim-1, NFATc2, BMPR2, and Survivin (12, 46, 54, 58). Pim1 and NFATc2 mRNA levels were measured in PAH-PASMCs in presence or not of DHEA. As STAT3 molecular inhibition (siRNA), DHEA decreases Pim1 and NFATc2 mRNA expression in PAH-PASMCs (Fig. 2A). Since Pim1 accounts for NFATc2 activation in PAH (46), we measured the effects of DHEA on NFATc2 activation by a nuclear translocation assay/immunostaining. We previously described that >60% of PAH-PASMCs show NFATc2 activation, whereas only 20% are positive for activated NFATc3 and <5% for NFATc4. For these reasons, we consider that NFATc2 is the predominant NFAT isoform in PAH-PASMCs (10). DHEA, as well as STAT3 siRNA, decreases NFATc2 activation by sevenfold compared with untreated or scrambled treated PAH-PASMCs (Fig. 2A). These results show that through inhibition of STAT3 phosphorylation, DHEA has an inhibitory effect on the Pim1/NFATc2 axis.
BMPR2 downregulation is recognized as an important marker of the proproliferative, antiapoptotic PAH phenotype (54, 58). It has been recently suggested that STAT3 activation in PASMCs could be associated with repression of BMPR2 (11). We thus speculated that DHEA, by inhibiting STAT3, could rescue BMPR2 levels. Indeed, both STAT3 inhibition by siRNA and DHEA enhance BMPR2 mRNA levels in PAH-PASMCs (Fig. 2A).
STAT3 activation was also associated in cancer (22, 35) and systemic vascular remodeling (40) with an upregulation of Survivin mRNA levels. Survivin, a member of the inhibitor of apoptosis family of proteins, was described as a major player in PAH pathogenesis (39). For these reasons, we studied whether STAT3 inhibition by siRNA or DHEA can decrease Survivin expression in PAH. We observed a fivefold increase of Survivin expression in PAH-PASMCs compared with control PASMCs. Both siSTAT3 and DHEA normalized Survivin mRNA level in PAH compared with siSCR and untreated PAH-PASMCs respectively (Fig. 2A), showing for the first time that Survivin expression in PAH is dependent at least in part on STAT3 activation. All these results offer for the first time a putative mechanism explaining at the same time the activation of Pim-1/NFATc2/Survivin and the downregulation of BMPR2. The fact that STAT3 inhibition by DHEA reverses all these abnormalities and the fact that DHEA can also restore miR-204 expression place DHEA as an ideal candidate therapy for PAH (18).
DHEA and STAT3 inhibition decreases proliferation and resistance to mitochondria-dependent apoptosis in PAH-PASMCs.
In PAH, NFATc2 activation downregulates important K+ channels, like Kv1.5, leading to PASMCs depolarization, increasing [Ca2+]i and promoting PASMCs proliferation (7, 9, 10). Using fluo-3 AM, we measured the effects of STAT3 inhibition in PASMCs. PAH-PASMCs had greater [Ca2+]i compared with control-PASMCs. STAT3 inhibition by siRNA or DHEA in PAH-PASMCs decreases [Ca2+]i to a similar level as in control-PASMCs (n = 200; P < 0.05; Fig. 2B). PAH-PASMCs had increased proliferation rates (increased %PCNA-positive cells), and STAT3 inhibition by siRNA and DHEA in PAH-PASMCs (10% FBS) decreases proliferation by 2.3-fold (Fig. 2B).
The mitochondria transition pore is voltage-dependent (59), and the mitochondrial membrane potential (ΔΨm) depolarization is an index of the threshold for mitochondrial-dependent apoptosis. In this way, apoptosis is associated with decreased ΔΨm. Since STAT3 (23) and its downstream targets Pim1 (43, 52), NFATc2 (7, 9, 10), and Survivin (39) are implicated in (ΔΨm) regulation, we measured ΔΨm in PAH-PASMCs transfected with STAT3 siRNA, siSCR, or treated with DHEA, using TMRM. STAT3 inhibition by siRNA or DHEA treatment caused a significant ΔΨm depolarization, compared with scrambled-treated PAH-PASMCs and PAH-PASMCs, respectively (Fig. 2B). These data confirmed the role of STAT3 in ΔΨm regulation and in mitochondrial-dependant apoptosis. Apoptosis rates were studied using TUNEL assay. PAH-PASMCs appeared to be resistant to starvation (0.1% FBS)-induced apoptosis (decreased %TUNEL-positive cells compared with control-PASMCs; Fig. 2B). Similarly to STAT3 inhibition, DHEA in "starved" PAH-PASMCs increased apoptosis by fivefold.
DHEA decreases IL6-dependant Src/STAT3 activation and downstream target expression, reduces proliferation, and increases apoptosis in control-PASMCs stimulated by IL-6.
Since IL-6 is one of the major STAT3 activator (60) and plays a critical role in PAH (11, 49, 51), we studied the DHEA effect on control-PASMCs stimulated by IL-6 (100 μmol/l, 48 h). DHEA decreases IL-6-dependant Src/STAT3 activation measured by Western blot, as it can be seen in PAH-PASMCs (Fig. 3A). This result is confirmed by nuclear translocation assay, showing that DHEA reduces the percentage of cell presenting nuclear P-STAT3 (Fig. 3A). Moreover, DHEA decreases expression of STAT3 downstream targets Pim1, NFATc2, BMPR2, and Survivin in control-PASMCs stimulated by Il-6 (Fig. 3B). Finally, in this model, DHEA treatments were associated with decreased [Ca2+]i and proliferation rates, ΔΨm depolarization, and increased apoptosis rates (Fig. 3B).
DHEA and STAT3 inhibition reverse MCT-PAH.
To validate our in vitro findings, we performed in vivo studies using the MCT rat model of PAH to determine whether DHEA reverses PAH through the inhibition of STAT3. Therapeutical interventions were assessed with DHEA as well as STAT3 silencer RNA.
Rats subcutaneously injected with MCT-PAH (60 mg/kg) and control rats were followed using noninvasive measurements (Doppler and echocardiography) and exercise capacity on treadmill to evaluate disease development. After established PAH (decreased PA acceleration time at day 18), treatments were started. Freshly prepared DHEA (10 mg·kg−1·day−1) was administered by gavage once a day, and STAT3 siRNA (1 nmol) was selectively delivered into the lung by intratracheal nebulization (10). MCT-PAH nontreated rats and nebulized scrambled siRNA rats were used as PAH control. We showed that DHEA and STAT3 inhibition decreases PA pressure, right ventricular (RV) hypertrophy (RV/LVS; Fig. 4A), general cardiac functions (exercise capacity on treadmill; Fig. 4B), and PA wall remodeling (Fig. 4C).
These findings were associated with significant decrease in Src/STAT3 activation in the lung (Western blot; Fig. 5A) and distal PA (decreased yellow staining; Fig. 5B) in rats treated with DHEA as those treated with siSTAT3. Since STAT3 transcriptional activity is decreased, STAT3 downstream target expressions were studied. We showed that miR-204 expression is increased in lung of rats treated with DHEA and siSTAT3 (Fig. 6A). Pim1 and NFATc2 mRNA levels are decreased in lungs, and NFATc2 activation is inhibited within distal PAs (Fig. 6, B and C). Survivin and BMPR2 mRNA levels are restored as well in lungs (Fig. 6, D and E).
To validate our therapeutical intervention, we studied proliferation and apoptosis rates within distal PAs. PASMCs proliferation (%PCNA- and Ki67-positive cells) is inhibited by 50% within PAs in rats treated with DHEA and siSTAT3. Resistance to apoptosis is decreased as well, with treatments increasing apoptosis in the vascular wall by 20% (%TUNEL-positive cells; Fig. 7A).
Here we provide, for the first time, evidence showing that DHEA decreases the Src/STAT3 constitutive activation seen in PAH. We showed that DHEA acts as a pharmacological STAT3 inhibitor since its effects are similar to those obtained by molecular inhibition of STAT3 with siRNA. DHEA-dependant Src/STAT3 inhibition reverses PAH phenotype both in vitro and in vivo. Indeed, DHEA restores most of the molecular and cellular abnormalities seen in PAH-PASMCs, including decreased expression of the onco-proteins Pim1 and Survivin, decreased activation of NFATc2, and upregulation of BMPR2 and miR-204 (Fig. 2A). All these findings contribute to the decrease in PAH-PASMC proliferation and resistance to apoptosis seen in our human PASMC and to the decrease in distal PA remodeling seen in our in vivo model. These findings are supportive of our comprehensive mechanism proposed in Fig. 7.
These findings provide a better understanding of the mechanism by which DHEA reverses PAH. In the past, several groups including us have demonstrated the beneficial effects of DHEA in experimental model of PAH. Indeed, by opening BKCa DHEA can decrease [Ca2+]i (8, 20, 47) and vasodilating PASMCs. Since Src and STAT3 are known as K+ channel inhibitors/Ca2+ channel openers (3, 17, 28, 44, 55), their inhibition could explain how DHEA upregulates Kv and BKCa channels (8). Our present findings provide a comprehensive mechanism linking all the previous findings to the Src/STAT3 axis. Indeed, several studies (5, 36) have demonstrated the implication of the Src/STAT3 axis in the upregulation of the RhoA/ROCK pathway; thus the Src/STAT3 axis inhibition by DHEA could be an explanation of how RhoA/ROCK are modulated by DHEA (26). Although STAT3/Pim1 are recognized as the regulators for both NFATc2 expression and activation in PAH (46), several new findings (15, 16) have proposed that RhoA/ROCK could also be implicated in NFAT activation in the vasculature. Thus whether the inhibition of RhoA (26) by DHEA is independent of the Src/STAT3 axis, we propose it will similarly affect the NFAT pathway. Further studies are thus necessary for a better understanding of how DHEA affect RhoA.
Our findings are not restricted to the PASMCs but could be extend to the PA endothelial cells (PAECs) as well. Indeed, STAT3-induced proliferation and resistance to apoptosis in PAH is also present in proliferative PAH-PAECs (Refs. 37, 41) that constitute plexiform lesions. Thus STAT3 inhibitory drugs like DHEA represent a putative ideal treatment for PAH (Fig. 7B).
To this end, we performed preclinical studies showing that indeed STAT3 inhibition reverses PAH in MCT-induced PAH in rats. As in our human PAH-PASMCs, STAT3 inhibition was associated with decreased PAH-PASMCs proliferation and resistance to apoptosis. Although the MCT model has limitations, this model has largely contributed to the development of new therapeutics for PAH over the last decade. A variety of therapeutic strategies have been tested in MCT-based models and were later shown to be effective in PAH patients; conversely, all clinically proven treatments also work in the MCT model. Nonetheless, STAT3 is activated in PAH-PAECs, it will be of a great clinical interest to determine whether or not STAT3 inhibition can reverse plexiform lesions. Thus, in a further study, we will measure the effects STAT3 inhibition in the hypoxia/Sugen model of PAH, which has been recently described (2).
Although we believe our findings are very promising, the translation to the clinic of STAT3 inhibition using nebulized STAT3 siRNA will be very challenging. Thus utilization of an already clinically approved drug like DHEA is of a great interest. DHEA supplementation is an efficient way in reducing carotid stenosis in response to angioplasty (9). In fact, we previously published that by inhibiting Akt DHEA increases glycogen synthase kinase 3 activation pushing NFAT out of the nucleus and thus limiting its transcriptional activity (9). We (46) recently showed that Akt is not activated in PAH-PASMCs excluding the possibility that the present DHEA effects seen in PAH are Akt mediated. Several studies have demonstrated the critical role of STAT3 in regulating Pim-1/NFAT axis in both cancer (27) and cardiovascular diseases (42, 43); thus inhibition of STAT3 could account for the DHEA effects seen in both our in vitro and in vivo models.
We provide evidence for the first time in vascular tissue that DHEA is an efficient STAT3 inhibitor confirming previous findings in the liver (34). The fact that DHEA can disrupt the positive feedback loop involving miR-204 (which sustained Src/STAT3 activated independently of the activation of the tyrosine kinase receptor; Ref. 12) and that DHEA inhibitory effects on STAT3 are sustained over long period of time (18) is clinically appealing.
Although we believe that our study provides for the first time evidence that DHEA is a good and efficient STAT3 inhibitor in human and rodent PASMCs, we have not elucidated the exact molecular mechanism by which DHEA decreases Src/STAT3 activation. This remain to be established and will constitute a further study. Nonetheless, we have evidence that the DHEA effects in vascular tissue are likely mediated through a plasma membrane receptor coupled to G protein (9). Indeed, we previously showed in carotid smooth muscle cells that through a plasma membrane receptor DHEA could decrease NFAT activation and expression. As STAT3 regulates both expression and activation (through Pim-1) of NFAT, we believe that the DHEA inhibitory effect on Src/STAT3 is also mediated by the plasma membrane DHEA receptor. Nonetheless, other mechanisms cannot be ruled out. For example, it has been demonstrated that activation of the peroxisome proliferator-activated receptor-γ (PPAR-γ), a member of the nuclear receptor family that is downregulated in PAH (24), has an inhibitory effect on STAT3 (31, 33, 56). A direct physical protein-protein interaction has been shown between PPAR-γ and activated STAT3, resulting in decreased transcriptional activity of STAT3. Moreover, treatment with PPAR-γ agonist ciglitazone in glioblastoma cell lines showed a decreased expression of phosphorylated form of STAT3 associated with an increased expression of STAT3 inhibitors like the Suppressor of cytokine signaling (SOCS) 3 and the protein inhibitor of activated STAT3 (PIAS3; Ref. 19). As DHEA has been shown to increase PPAR-γ mRNA levels (48), PPAR-γ could be implicated in the DHEA-dependant STAT3 inhibition. Considering that PPAR-γ agonists used in the treatment of PAH patients (rosiglitazone and pioglitazone) could be associated with adverse cardiovascular events (32), DHEA could offers an alternative therapeutic approach. Although the inhibitory effects of DHEA on the Src/STAT3 axis might link together all the previously published findings on DHEA in pulmonary hypertension, other uncovered pathways might also be affected including FAK, Rac1, and other pathways implicated in cell migration that are also implicated in vascular lesion formation seen in pulmonary and are currently understudied. Finally, enlarging our findings to other pulmonary hypertension isoforms including PA secondary to chronic obstructive pulmonary disease or left heart diseases could be beneficial to greater population.
In conclusion, our findings demonstrated for the first time that DHEA is an efficient inhibitor of the Src/STAT3 axis in human PASMCs. As described in our comprehensive schematic in Fig. 7, we showed that in both humans and rodents this newly characterized effect of DHEA links together all the previously published findings on the therapeutic effects of DHEA seen in rodent pulmonary hypertension including K+ channels and RhoA/ROCK abnormalities. Moreover, we provide evidence for the first time in PAH that DHEA a nontoxic, safe, and already available over the counter drug can reverse vascular remodeling processes seen in PAH. Thus, with a single drug we could affect many features associated with pulmonary hypertension including vasoconstriction and vascular remodeling. Moreover, as Src/STAT3 are activated by many different signals including inflammation, growth factor; extracellular matrix, hypoxia (all of which can trigger pulmonary hypertension), we believe that DHEA might be efficient in many different PH isoforms, which is not the case of the presently used medicine.
This finding is of a great clinical interest as it offers us the perspective to enlarge the ongoing clinical trial NCT01273259 actually restricted to hypoxic pulmonary hypertension patients to PAH patients. Finally, our findings also offer new therapeutic perspective to clinician to treat diseases in which STAT3 is implicated including cancer.
This work was supported by the Heart and Stroke Foundation of Canada, Canadian Institute for Health Research, and Canadian Research Chair (to S. Bonnet).
No conflicts of interest, financial or otherwise, are declared by the author(s).
R. P. and S. B. conception and design of research; R. P., J. M., M. H. J., M. B., and A. C. performed experiments; R. P., J. M., M. H. J., M. B., and A. C. analyzed data; R. P. prepared figures; R. P. and S. B. drafted manuscript; R. P., J. M., M. H. J., M. B., A. C., and S. B. approved final version of manuscript; J. M. interpreted results of experiments; S. B. edited and revised manuscript.
We thank the "Societé Québecoise d'Hypertension Artérielle" (scholarships to J. Meloche and R. Paulin). M. H. Jacob was supported by CAPES (Brazilian Research Agency).
- Copyright © 2011 the American Physiological Society


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A beautiful Roma woman, murderous jealousy, a Basque hidalgo, fortune telling, knife fights, sexual persuasion, the occult.
Carmen is full of tension and surprise while traveling a well-worn road that reaches from Spain through France and into Italy. Commissioned for a new edition of Prosper Merimée's book Carmen, Andreu Balius tells us that this Didone typeface draws inspiration from 1830s Spanish type specimens that were clearly rooted in the famous work of the Frenchman Firmin Didot. While there seem to be new Didone faces every day, the refined Carmen brings something new to the table, balancing somewhere between the illustrious work of Frutiger for Linotype and the smart, witty approach of a face like Porchez's Ambroise. And if jealousy and murder seems too heavy for the occasion, you can always visit the circus in Paris with Carmen Fiesta.
Christian Palino is a designer and educator living in San Francisco. He is currently a Product Design Manager at Facebook and teaches Interaction Design at CCA. He previously worked at OpenTable, IDEO and Adaptive Path.


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Here is the Pingouin pattern legend translated. I chose to describe step by step what needed to be done in each cable cross instead of writing a literal translation (for example: "right cross two stitches over 2 knit stitches"), as I think it will be more helpful and clear.
I hope I didn't make any mistakes!!


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- Albania
- Bosnia and Herzegovina
- Bulgaria
- Croatia
- Kosovo
- Macedonia
- Montenegro
- Romania
- Serbia
- All Balkan Countries
Privatisation is a hot topic in Belgrade once more, as the Serbian government is forced to examine the sale of more than 20 companies following EU concerns the deals were marred by corruption.
'Privatisation is riddled with incomplete regulations, weaknesses, gaps and holes,' says Vladimir Goati (Photo: Media Center Belgrade)
All of sudden, the issue of privatisation has become a hot topic in Serbia. Ten days ago, representatives of the Serbian government disclosed that the European Union has asked it to investigate 20 privatisation deals because of suspicions of corruption.
For years, the government insisted that the economic reforms involved in transition to a free market economy were entirely successful in Serbia. How things change.
With the former Bosnian-Serb general Ratko Mladic extradited to The Hague, where he will be tried on charges of committing war crimes in Bosnia during the 1992-1995 war, one of the last barriers to Serbia joining the EU has been removed.
Now the Serbian state has acknowledged it must tackle other serious EU concerns that prevent Belgrade from joining the union, primarily related to crime and corruption.
This will not make the government particularly popular with some among the Serbian business community, something Boris Tadic, the Serbian president, acknowledged during an appearance on the national RTS TV channel the day before the official announcement.
"I think most of them do not come to their capital in the economic conditions of the regular game, but they used the privileged conditions at the time of Milosevic and also after October 5, 2000 [the day Milosevic was removed from power]. I cannot prevent all abuses, I do not have super powers, but I am trying," he said.
This speech was highly unusual and sparked much excitement among the general public and expert observers alike. Tadic's comments were interpreted in many ways, but mainly as the government preparing for a major confrontation with the domestic 'business elite'.
Then, the day after the president's interview, Ivica Dacic, the interior minister, explained what was going on; Brussels had sent a letter to the Serbian authorities requesting they investigate the privatisation of more than 20 companies.
It should be noted that this statement came hot on the heels of last month's announcement that the Serbian government has received a €2.2 million grant from the EU to more effectively combat money laundering.
Dacic, who is chairman of the Socialist Party of Serbia and part of the coalition government led by Tadic, said in an interview with Tanjug news agency that his party supports the testing of privatisation.
"We have nothing against privatisation… but we should see what should be in public and what in private hands, in a way that privatisation should not be reduced only to robbery and abuse of rights," he said.
This has provoked more excitement among the public, as the media began to speculate which privatised companies will be subject to investigation, as the government has so far refused to identify them.
I called Tomo Zoric, spokesman at the State Prosecutor's Office, to find out what was going on, but he declined to identify the companies concerned saying only: "The prosecution office is checking all questionable privatisation in Serbia, because the priority is the fight against corruption and abuses that occurred during the process of privatisation and the public will be duly notified of the results".
Vladimir Goati, a politics and economics expert and director of Transparency Serbia, told me that privatisation in Serbia was not done in the best possible way.
"It is riddled with incomplete regulations, weaknesses, gaps and holes," he said.
According to Goati, those managing privatisation in Serbia have failed to learn by the experiences of other countries in eastern Europe while crime and corruption have also had a negative impact.
"Individuals who acquired money in completely illegal ways involved themselves in privatisation in order to legalise the money. Also, dozens of companies were sold… without prominent conditions that the owner is obliged to act responsibly toward the company and its employees," Goati stressed.
"It is difficult to tell [if these problems were a result of] ignorance on behalf of the state, a lack of a sense of danger, or if it was the desire to make it happen."
Goati added that people who paid the highest price for poorly regulated privatisation were those employed by the firms.
Commenting on the EU's close monitoring of Serbia's financial affairs, Goati said: "It is not normal that economic transactions of a country should come under the scrutiny of international organisations, but the fact is that we want to become a member of the community and we should have an understanding of their interest… [in which country] becomes a member and that they should respect important rules and norms.''
I was unable to interview the EU ambassador to Serbia as he is on holiday, but his spokesman has promised he will consider an interview when he returns to Serbia.
In the meantime, I intend to interview the people who are responsible for monitoring the privatisation process in Serbia and preventing money laundering, but also those who are responsible for this abroad.
I will also investigate the case of a company that was privatised and ended up in the hands of a criminal who had spent seven years in prison for attempting to kill police officers in a bomb attack.
I hope my story will help raise awareness that privatisation in Serbia has been very poorly regulated and I hope to find a more positive foreign experience for comparison.
Stevan Dojčinović is a Belgrade-based journalist who is participating in the 2011 Balkan Fellowship for Journalistic Excellence.
He will be writing regular updates on his investigation into the privatisation of industry since the collapse of communism in Serbia, Montenegro and Poland.
The Hague Tribunal delivers its verdict on six Bosnian Croat ex-officials next week - but the trial has already revealed how Croatia funded the self-proclaimed Herzeg-Bosnia statelet's forces while they fought the Bosnian Army.
Despite laws against the denial or diminishment of genocide crimes, the EU's newest member state has done little to crack down on voices downplaying World War II atrocities.


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|GOVERNOR'S DISGRACE "I try not to revisit that place too often, but when I think about his speech, I think of her face, her eyes, the hurt," Ashley Alexandra Dupre said of Eliot Spitzer and his wife.
Prostitute apologizes to wife of Spitzer
- |
NEW YORK - The prostitute at the center of the scandal that brought down former New York governor Eliot Spitzer has apologized to his wife.
Ashley Alexandra Dupre told People magazine that the FBI informed her in early March that it was investigating one of her clients. A few days later, she found out which client when she recognized Spitzer on TV - resigning. That was March 12, after revelations Spitzer had used Emperors Club VIP, where Dupre worked.
She says she was stricken by the pained expression on Silda Wall Spitzer's face.
"I try not to revisit that place too often, but when I think about his speech, I think of her face, her eyes, the hurt," Dupre said.
Her message to Silda Wall Spitzer: "I'm sorry for your pain."
Dupre, 23, said Spitzer was polite and businesslike when they met.
"Some guys, they want to have conversations and really get to know each other," she said. "With him, it clearly was not like that. It was more of a transaction. Strictly business."
Dupre said she practiced safe sex with her clients, including Spitzer. On her lawyer's advice, she would not elaborate on their liaison, or say whether Spitzer visited her more than once. She did say that he dressed casually, and she did not see his security detail.
Dupre also spoke with Diane Sawyer for a "20/20" segment to be aired tomorrow. In the interview, ABC said, she describes how an "upper middle-class girl next door got into the profession and the psychological journey she continues to experience."
Four people have pleaded guilty to running the prostitution operation. Last week prosecutors said they wouldn't bring criminal charges against Spitzer.
Dupre envisions her future in music, fashion, and writing books, but not prostitution.
"Never again," she said.


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A veteran Los Angeles police detective has pleaded not guilty to embezzling more than $30,000 in witness protection funds.
Leonard Avalos entered pleas Monday to an embezzlement charge and six counts of grand theft. Avalos, who's 44, could face nearly 6 1/2 years in prison if convicted.
The 17-year LAPD veteran was arrested Thursday and he remained jailed Tuesday on $120,000 bail.
Prosecutors say that in 2008 he stole money intended to relocate three witnesses to crimes in South Los Angeles. Only one person was relocated.


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Luxury Villa in Moraira Costa, presented by your luxury real estate agency on the Costa Blanca: ENGEL & VÖLKERS. This stunning and modern high quality property offers breathtaking views up to the Mediterranean Sea, the landscape and the Peñón de Ifach. The concrete and the natural stone walls, inside and outside, offer an unparalleled charm. Its practical and optimal room distribution allows enjoying the wonderful sea views from every room. The first floor of this spectacular luxury property offers 4 spacious double bedrooms with en suite bathrooms and fitted ward robes. The master bedroom suite offers 45 m² including a private living room and a dressing room. The ground floor offers one impressive and luminous living-dining room with direct access to the beautiful terrace with infinity swimming pool, a modern fully equipped open kitchen, a guest suite, a guest toilet and the 150 m² garage. The basement level offers another spacious living room, a guest toilet, a multi-purpose room, a wine cellar and a complete guest suite with private living room. The 3 levels are connected by elevator and interior/ outdoor stairs.
For more information contact Engel Voelkers Moraira at +34 965 50 81 81 or email email@example.com
Availability to be agreed. Data shown are offered by third parties, are just informative and assumed correct. Our company does not guarantee its accuracy. The offer is subject to errors, price changes, omissions and/or withdrawal without notice. Transmission expenses taxes, VAT, notary and registry fees are paid by the buyer. Following Spanish law, the commission charges are paid by the seller.


text:
Spoilers ahead!
A few not-so-shocking giveaways about this week's new movie releases, including Justice League and Frank Serpico
Matthew Lickona 6 p.m., Nov. 17
The Dubai request to delay interest payments on billions in debt servicing may be cause for investors to look for ties to current holdings.
Among the major financial firms with a hand in Dubai World's debt is Royal Bank of Scotland (see http://www.stamfordadvocate.com/ci_13880454).
RBS is a partner with Sempra Energy in the development of natural gas infrastructure projects while also managing a global logistical reach over a diverse basket of commodities (see http://www.rbssempra.com/). Sempra Energy is the corporate owner of San Diego utility franchise holder SDG&E.
Also see "US Business Group Delays Trip to UAE" or "Sempra Profit Engine Threatened..."


text:
I really really love this line. I have a baby boy who is now 8 mos. old and I think I first seen this line when I was pregnant and I knew I was having a boy, so I got it. I still haven't got the entire collection yet, but i am working on it. I love every single item of it. Completely adorable!!
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text:
Quintana rewarded with second opportunity
Quintana rewarded with second opportunity
Quintana started Friday against Cleveland and allowed two runs on four hits and three walks over six innings for his first Major League win.
"He's still here, so that's a good sign," Ventura said of Quintana. "He threw great the last game."
General manager Ken Williams didn't think Danks, who has been playing catch, would need to go on a rehab assignment before returning. Williams explained that Danks' situation is different than that of reliever Jesse Crain, who had a rehab stint with Triple-A Charlotte during his return from a left-oblique strain, because Crain's high-leverage role doesn't allow him time to "find himself" on the mound.
"In John's case, he's got a lot of innings and a lot of starts behind him, working on some things on the side a couple times and everything. I think it's easier for him to fall back into rhythm," Williams said. "He can have that inning or two where he's trying to find his location and his rhythm and command and all that stuff.
"I don't know if it's that necessary, and I'm not afraid of a re-tweak because he's had so much time in between to get himself together and it wasn't that serious to begin with."


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Oil Futures Little Changed as Market Awaits U.S. Fed
NEW YORK—Oil futures finished little changed Monday, as traders held off on big bets ahead of a meeting this week of Federal Reserve officials on U.S. monetary policy.
Light, sweet crude for September delivery settled 15 cents, or 0.1%, lower at $104.55 a barrel on the New York Mercantile Exchange. Brent crude on the ICE futures exchange settled 28 cents, or 0.3%, higher at $107.45 a barrel.
Futures stuck to a tight range in...


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Looking for a vacation rental in Cochabamba? Tripping.com has 92 rental homes available in Cochabamba. Potential renters will find 0 studios, 73 1-bedroom, 11 2-bedroom and 8 rentals with 3 or more bedrooms ranging from $25 a night to $139 a night. Many of these properties are instantly bookable.
The average price of a nightly rental in Cochabamba is $55 while the average price of a weekly rental is $131. For those looking for more than a short term rental such as corporate rentals, extended stays or long term rentals, the average monthly price of a Cochabamba home is $522.
Wondering if you can bring your favorite dog or cat with you? We have 0 pet friendly vacation rentals available for you. In addition to accommodating pets, Cochabamba rentals offer a variety of amenities. In particular, 62 rentals have internet and wifi, 32 have TV and/or cable and 16 have a pool or hot tub.Search properties from 5 rental sites in Cochabamba where the top providers in that area are Booking.com, HomeAway, and HomeStay. There are 79 Booking.com rentals, 8 HomeAway short term rentals and 3 HomeStay vacation rentals.


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D-tek is a manufacturer of in-vitro diagnostics kits specialized in auto-immunity. The companydevelopes and produces different type of kits : ELISA (BlueWell ) IMMUNODOT(BlueDot ) IMMUNODOT automatized (BlueDiver Dot ) MICROARRAY automatized (BlueDiver Quantrix ) IMMUNODOT automatized and customized (BlueDiver Combi ) The BlueDiver Dot, BlueDiver Quantrix and BlueDiver Combi kits are automatized on theBlueDiver Instrument .
Morever and thanks to its long experience in diagnostic kit development, D-tek proposes different products that may interest diagnostic companies, Reserach centers or University laboratories : Liquid Substrates : NBT, pNPP, TMB ELISA, TMB Membrane Liquid Stabilizers : AP-Stabilizer, HRP-Stabilizer and Antibody-Stabilizer Coating and blocking solutions for membrane and ELISA plates application Nitrocellulose Membrane devices D-tek is ISO 9001, ISO 13485and all its diagnostic kits are CE IVD certified.


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Adele has broken the 24-Hour Vevo Record as "Hello" received over 24 million views in a single day.
The video had over 24 million views on Youtube shattering Taylor Swift and Kendrick Lamar's previous record of 20.1 million views in a day for their "Bad Blood" collaboration.
As at 8am on Sunday, barely 48hours after the release, Hello had gotten 47million views and might just be on its way to becoming the video with the highest page views of all time.
The album, '25' drops on Friday, November 20, 2015.


text: 52. I know his name, however, i don't remember how to write it. :snicker If you follow it on youtube, you can see it in the description. He murdered a chick. He deceived her by telling her he needed a translator for a German school thing. He then shot her, raped her, then ate her. He got off with insanity charges. He wrote like 20 books and even did porn. It's a odd story for sure. You should look into it.


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Patty Vision Center of Burlington
Dr. Reid Patty opened an office in his hometown of Burlington in the fall of 1984 and operated it under the name of Burlington Eye Care for a number of years.
In the summer of 1996, the office moved into a 3,300 square-foot facility which provided a larger optical, more contact lens care solutions, and increased professional opportunities. The office's name was changed to Patty Vision Center of Burlington when it was incorporated with the Patty Vision Center of Yanceyville.
Map and Directions
2326-A South Church Street
Burlington, NC 27215


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Corky Romano (2001)
Directed by
Rob Pritts
Starring (View all)
Chris Kattan
Corky Romano
Corky Romano
Vinessa Shaw
Agent Kate Russo
Agent Kate Russo
Peter Falk
Francis A. Romano
Francis A. Romano
Peter Berg
Paulie Romano
Paulie Romano
Chris Penn
Peter Romano
Peter Romano
Fred Ward
Leo Corrigan
Leo Corrigan
Richard Roundtree
Howard Shuster
Howard Shuster
Matthew Glave
Agent Brick Davis
Agent Brick Davis
Written by
David Garrett
(written by)
(written by)
Jason Ward
(written by)
(written by)
40 votesIs this film supposed to be funny? (208 items)
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Published 7 months ago 20 comments
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Published 8 years, 3 months ago 15 comments
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Corky Romano
8 years, 7 months ago at Apr 16 22:30
This comedy, directed by Rob Pritts, does not provide quite enough laughs to warrant a recommendation. It's not as bad as some people are saying, and if you are into fart, klutz, crotch, and gay jokes, and lowbrow physical humor, "Corky Romano" might be your ticket to fun. I prefer my humor a little more sophisticated, though.
Corky Romano is a bumbling, simpleton, veterinarian and the youngest, outcast son of an aging gangster, Pops Romano, who calls upon Corky to infiltrate the local FBI and retrieve and destroy evidence being used to incriminate Pops for racketeering charges.
Release date: 12 October 2001
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By >Daimaou - G.G-B
[Review] Canon 60D… A real step forward for every DSLR enthusiast
There have been rampant rumors about a possible replacement of the not-so-fantastic Canon 50D for YEARS – actually over a year and half! Where many gave up on a 50D replacement and moved away to Nikon with their fantastic D90, others wanted to believe that one day, Canon will fix the underwhelming 50D and release a better, faster and up-to-date DSLR with what we knew will be the 60D. And today, two years after the 50D was released, Canon officially reveals to the world its 60D, and it does not disappoint!
First Impression.
The 60D keeps pretty much the same "shape" and lines that we have seen since the 20D, but with a huge list of design tweaks and hardware improvements, make it a worthy successor to the 30D, 40D and 50D.
Many things have changed on this camera, and it is difficult to know where to start describing the changes. The first thing however that you will notice if you have ever owned either a 20D, 30D, 40D and 50D is huge weight decrease between the 50D (822g) compared to the 60D, of just 755g. Sure 67g does not look much on the paper, but believe me, after a while you will love the difference! Moving away from the usual, but heavier Magnesium Alloy found on previous models, the 60D comes with a new Polycarbonate resin with glass fiber on aluminum chassis, which, according to Canon, will offer the same level of robustness and quality. As far as I am concerned, although I welcome the lighter weight, I am however not so impressed by the "Plastic" look & and feel of the 60D, and while I would prefer the magnesium alloy body feel in my hands, I have to admit that the 60D body will better handle time than, for example, our 30D, where paint vanished in certain areas, uncovering the "silverish" color of the magnesium alloy body.
Despite its overall resemblance to previous models, the D60 comes with an entirely redesigned button layout similar to the 7D and with, a first, flat buttons on next to the upper LCD Control. One of the primary reasons for Canon to rethink and disrupt loyal customers' long-standing/groomed/developed habits is the appearance of the nice articulating 3" monitor, a first for Canon on its DLSR line-up.
It is true that at first it was quite puzzling, and I had to completely rethink the way I use the camera to get used to its new button layout – especially for the "Delete" button that is now no longer placed at the bottom left on the rear panel of the camera but on its Top Left just bellow the "On-Off" Switch. Closer to a 7D in its button layout, the 60D offers however a less cluttered design with just what you need concentrated in one area to be easily manipulated with your right thumb, making the transition from any previous Canon DSLR smooth and simple.
One of the major changes on the 60D is its articulating 3" Monitor, and while this may sound crazy for many hardcore DSLR users, I on the other hand welcome the move and hope to see more on Canon's future replacements of both the 7D and 5D MK II.
So why is such an LCD a good thing on a DSLR? Although it is true that I am not a huge fan of shooting photos with most cameras'LiveView modes, an articulating LCD makes it easier to shoot pictures in previously impossible situations, and believe me on this one, there are many! The second advantage of such an LCD is when you are shooting Video with your DSLR installed on a tripod, having the possibility to control your LCD position is a HUGE plus.
Finally, and this may not seem trivial for some, this new LCD will give you for the first time in Canon DSLR history the ability to safely hide your monitor from scratches or worse.
Add to this long list of improvements, the support of SD, SDHC and SDXC cards (bye bye CF) and a lock on the camera Mode Dial, that I personally can't stand, and you have here pretty much all that you should know on the 60D once you hold it for the first time.
Let's Shoot Baby.
On paper, both the 7D and 60D are not too different. Both come with an 18 Megapixel APS-C sensor, are capable of achieving a 100-6400 ISO Sensitivity, have a basic 1/8000 to 1/30 sec shutter speed and the same 1080/24/25/30p and 720/60p Video mode, but, that's pretty much all. Both the 60D and 7D are in fact very different in that the 7D comes with two DIGIC 4 Image processors offering a stunning 8fps continuous burst speed (126 Jpeg or 15 Raw shots Max), compared to the 5.3fps mode on the 60D (58 Jpeg / 16 RAW Max), a 100% viewfinder coverage on the 7D compare to only 96% on the 60D, 19 Point AF on the 7D compare to the 9 AF point on the 60D and no AF Microfocus Adjustment for the 60D.
Clearly both the 7D and 60D aims at a different target market, but luckily (for potential 60D customers) both offer quite similar results when shooting photo in perfect lighting conditions; with, however, a huge advantage for the 7D in low light, whereas the 60D does not "shine" here and where you will have to quickly jump into higher ISO and take the risk to get pictures with more noise.
Mounted with Canon's stock 18-55mm Lens Kit, the very same one without a focus ring, the 60D offered some pretty descent shots, but like usual on this kind of Camera we will strongly advise you to go for a better lens like Canon's latest EF-S17-85mm F4-5.6 IS USM, sold in the 7D Kit for example, or even better if you can afford Canon's higher-end models
To be fair, it is fairly difficult for me to tell the difference between the 7D and 60D under perfect lighting conditions; only when things get darker and the camera needs an ISO speed boost does the gap between both become more visible.
Video Mode.
The 60D comes with the same video mode available on the 7D with the difference being the offering of the same manual Audio control on the 60D found so far only on the 5D MK II.
The 60D, unlike both the 7D and 5D MK II for example, does not come with a 100% viewfinder, and only displays 96% of the image making a difference in specific composition. But it comes with an interesting AF mode while shooting video, similar from what can be found on a GH1 or GH2 for example.
Now in reality, I have to admit that I was impressed by the video capability of the 60D, which seems slightly better for me than the one on the 7D. Now, we tested the 7D at its launch and Canon had released several firmware updates since then, and testing a 7D with its latest firmware may produce a different result – although that would be quite difficult to accomplish without one in our hands – but, while the 60D does not match the 5D MK II in video sharpness and quality, the result was way better than what we used to have on entry level Kiss or Rebel models. Even in low light and at high ISO, the 60D was handling things well. You can even check the result here in one of our "Let's Visit Tokyo" series : Shinagawa Business Center by Night.
Add to this the fact that you can now tilt your LCD at will, the 60D offers a powerful video mode in a nonetheless powerful DSLR.
Last but Not least, the 60D is aimed for a more casual user than the 7D, for example, and unlike the 7D, the 60D does not come with an "All Weather" capable body; but, it does come with many little handy things as well, like an artificial horizon, In-Camera RAW image processing and a very interesting "Creative Effect" mode often found on Point & Shoots or Bridge (offering the possibility to have a "Tilt Shift" or "Toy" effect on your pictures), and support for both PictBridge and DPOF V1.1 if you ever feel like printing pictures without a computer.
There is so much more to say about this camera and its impressive number of features and functionalities, but I would rather advise you to go and check out other reviews made by professionals who are making a living with their photography… Like usual we are giving you here a "user-oriented" review or first impression review if you like. But bottom line, while the 60D aims for casual shooters, it offers near professional – or should I say near-7D – capabilities and quality, making the 60D a highly recommended DSLR for anyone who just want more than an entry level model but does not need a professional tool.
Last word will be to get the 60D only (Body) and get the 7D Kit lens EF-S17-85mm F4-5.6 IS USM to go along with your camera if you want the ultimate kit.
- - [Review] Canon EOS 7D the Review… Nice Camera but Could have been a bit better (November 22nd,2009 at 8:27 AM)
- - Canon EOS-1D Mark IV… Now Official (October 20th,2009 at 2:44 PM)
- - Canon Rebel T2i a powerful entry level all-in-One DSLR (February 9th,2010 at 12:19 AM)
- - RED Scarlet now official… (December 1st,2009 at 11:43 AM)
- - Canon 7D Firmware Update… Bye Bye Artifact! Update no.. Still there ! (October 19th,2009 at 12:27 PM)
- - Japan Probe – News from Japan (Subscribe)


text:
Mmmh, when I let it run on my PC, it does indeed work. But since it's designed to run on an Atmel Chip, I have to cross-compile and there seems to be something going wrong with scanf and sscanf.
Oh, well, nevermind, it will work with atof just as well. At least I'm happy that I seem to be able to write code that actually works


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Goneril is Lear's eldest daughter, and the wife of the Duke of Albany.
She knows how to play the court games and speak as her father requires when he asks for avowals of love, and is rewarded for this ability with a third of the kingdom, which becomes half when her youngest sister Cordelia fails the test. Though she advises Cordelia to obey her husband in all things, she despises her own husband as a weakling, and is not shy about reminding him that hers is the royal blood, not his, and that all of his authority was acquired by marrying her. She has always recognized that her little sister Cordelia was their father's favorite, and has little regard for Lear. Exasperated by Lear and his train's continued presence and wild behavior in her house, by his unwillingness to recognize that he has given up his powers, and by what she considers his senility, she insults him into leaving in a rage. When her husband asks what's going on, she tells him to mind his own business. She plans with her sister Regan to make their father more manageable, and callously leaves him to himself when he rushes out into the storm. She is a cruel woman, quick to think of blinding a traitor. Sent by Cornwall to raise her husband Albany and his army, she is accompanied by Edmund, with whom she falls quite in love, finding him a real man compared to Albany. Hearing that Cornwall is dead, she is worried that Regan, being now free, will be able to snare Edmund. She sends the bastard a letter, requesting that he kill Albany for her, Edmund now being her only aim in life. To be absolutely sure of catching him, she poisons her sister. Faced with the fact that Albany has her letter to Edmund, she tries to claim her royal status, but finds she has no way out but stabbing herself.


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Where 'Mad Men' left off
After extended contract negotiations, the critically acclaimed show 'Mad Men' went on an unexpected hiatus last year, ending its fourth season in October 2011 and not returning until last month. Fans who were agonizing over some of the cliffhangers in the fourth season finale have waited impatiently for the return of ad executive Don Draper, his staff, and his family. But it's been a long time since the last new episode aired. Here's a guide to where we left the 1960s men and women last season.
1. Don Draper
After the company lost Lucky Strike as a client, the new business was in trouble, and Don tried to fix things by writing a full-page ad in The New York Times saying the company would no longer represent tobacco companies, but the bold move alienates the other partners, and the company is still forced to lay off many employees. When Don was left by himself to take his children to Disneyland after the family's housekeeper was unable to go, he asked his secretary Megan Calvet (Jessica Paré) to come with him, and while there, unexpectedly proposed. Megan said yes, and Don announced the news at work, but when the season finale ended, he was staring out the window, looking like he was still unsure of himself and not feeling content.
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Angela Hartnett(1968-), Restaurateur
Sitter in 2 portraits
Angela Hartnett is an Anglo-Welsh-Italian chef. A protégé of Gordon Ramsay who was made famous by her appearances on British television, she was chef-patron at The Connaught Hotel in London. Hartnett was taught to cook by her Italian grandmother. After taking a history degree at Cambridge Polytechnic, she worked in a number of small family-run restaurants before joining Midsummer House in Cambridge, where she learnt her craft. She has worked for Gordon Ramsay in a number of restaurants since 1994.
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Well maybe, but I enjoyed Bob Goldthwait's dark comedy "God Bless America" last night. It isn't in theaters yet but it is available streaming from a number of services as a "theatrical per-release." I dare Thom to go watch it but it probably expresses what a lot of us would like to do the right wing. Since it isn't in theaters until next month and probably limited release then since it would be considered an "art house" film the right wing doesn't seem to know about it yet. Just wait for their howls. :D
The trailer:


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Jordan ready to defend itself at any moment - King Abdullah
King Abdullah II of Jordan. (Al Bawaba file photo)
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Jordan's King Abdullah said on Sunday the Kingdom was ready to defend itself from any threat to its security from the conflict in neighboring Syria.
"If the world does not help as it should, and if the matter becomes a danger to our country, we are able at any moment to take the necessary measures to protect the country and the interest of our people," he said.
In the past week, the United States has moved Patriot missiles and fighter jets into Jordan, officially as part of an annual exercise, but making clear that the military assets could stay on when the war games are over.
The Wall Street Journal reported this week that a U.S. military proposal to arm rebels fighting against Assad also calls for a limited no-fly zone inside Syria that could been forced by U.S. and allied planes on Jordanian territory.
Top Headlines
- King Abdullah II's Full Text of Address to the Opening Session of Arab League Conference
- Syrian Conflict: Jordan to "take measures" to protect itself
- Jordan seizes weapons by Syria border
- Jordan "ready" to face "any aggression" from Iraq, says military
- No Tahrir but Jordan's protestors not ready to go home yet


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As she went about the Indian Wells Tennis Garden on Tuesday, Victoria Azarenka was wearing a T-shirt bearing the message, "I Got This."
"I don't know what 'This' means, really," she said, "but I guess I got something."
Know this: the words on her T-shirt did not go far enough. Azarenka has everything. What she is doing as a tennis player is establishing herself as a possible successor to such figures in the women's game as Helen Wills, Alice Marble, Martina Navratilova, Monica Seles, Steffi Graf and Serena Williams.
Azarenka resists being likened to these players. "They are legends," she protested. But there is the stuff of legend in how the slender native of Belarus has started the season — with 20 consecutive victories, the last a 6-3, 6-1 conquest of Julia Goerges of Germany in the round of 16 at the BNP Paribas Open.
In Tuesday night's feature, Roger Federer took a set to adjust to the lightning thrusts of Milos Raonic's serve then brushed away the young Canadian 6-7 (4-7), 6-2, 6-4. The victory was the 73rd in a row for Federer against players outside the Top 20. Raonic is ranked No. 27.
To this point in the women's season, none of her peers is in the ballpark with Azarenka. She is the WTA Tour's only multiple winner, having triumphed at Sydney, the Australian Open and Doha. She has gained at least the final in her last five tournaments. Martina Hingis' record of beginning a season with 37 consecutive victories would seem within her reach.
Serena Williams ran off 21 straight victories at the outset of the 2003 season. With one more triumph, Azarenka will match that. Her chances are excellent; her next opponent here is Agnieszka Radwanska, a puzzle to most players, but not to Azarenka, who has bested the Polish player three times in 2012.
For Azarenka, the ultimate would be going through a season without defeat. It has not been done, although Navratilova came close in 1983 when she went 86-1. Her only loss was to Kathy Horvath, an American, in the fourth round of the French Open.
Her perfect record is not preventing Azarenka from striving to improve.
"I always try to work on different things because I think there is never a limit that you can achieve," she said. "It may not work right away, but at least you can start the process."
Changing her game comes as easily to Azarenka as changing her T-shirts. "I love these T-shirts," she said of the one she was wearing on Tuesday. "I think they're kinda funny. Everybody stops you and says, 'What have you got there?' "
One day, Azarenka said she may produce her own line of T-shirts.
"It's an idea that might come up," she said. "We'll see."


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Andy Kahan sits at his Compaq computer and summons forth the Internet auction house eBay, which boasts of helping "people trade practically anything on earth."
Among the items up for bid are more than 90 pieces of speciality collectibles -- locks of hair, photo prints, autographs, artwork, even authentic samples of nothing more than dirt.
But the souvenirs are not from your average Hollywood or rock-and-roll celebrity. Kahan, director of Houston's crime victims assistance office, is appalled to learn these items are the products of much darker stars, a smorgasbord of serial killer memorabilia.
An oil painting of a white horse is on the auction block for a beginning bid of $420. The artist: Texan Henry Lee Lucas. Along with accomplice Otis Toole, he confessed to killing more than 600 people.
A $9.99 envelope sounds expensive, until prospective bidders read that its writing comes from Elmer Wayne Henley's hand, the same hand that helped strangle some of the 26 victims of the murder ring headed by Houston's Dean Arnold Corll in the early 1970s.
"This envelope is completely handwritten and a nice addition to any crime collection!" says the Web page touting the Henley relic. It was going, going, gone by last Thursday.
Bids begin at $49.99 for crime scene photos of one of the victims of coed stalker Ted Bundy. And eBay is the Macy's for John Wayne Gacy's treasures. One item for sale is actual dirt collected from the crawl space of Gacy's Chicago home, where the remains of 27 of his 33 victims were found.
For a minimum $41, there's a sketch done by Gacy himself. While the former amateur clown's style is somewhat cartoonish, he can relate to his subject: fellow serial slayer Jeffrey Dahmer.
A recent addition to the eBay auction site is a wire story clipped from the Houston Chronicle about the sentencing of Michael Fortier, who was involved in the Oklahoma City federal building bombing. However, the clipping is signed not by Fortier but purportedly by Angel Maturino Resendiz, a.k.a. Rafael Resendez-Ramirez, the man accused of being the railway serial killer.
Those auction items and more are available in time for the early Christmas shopping season, for that really hard-to-buy-for person on every gift list.
Paul Wishnow, a Houston appraiser of collectibles, says it is difficult to determine the ultimate value of such grisly items. Market interest in them is tied to the fact that their creators are infamous criminals, rather than for the quality of the artwork, but that element can attract customers. "There are plenty of kooks out there willing to buy," Wishnow says.
Kahan is no critic of the free enterprise system. "But you have to draw the line somewhere. And I don't think a reputable site like eBay ought to be taking convicted killers and mass murderers and putting them on a pedestal," Kahan says. "There's something about that that's just not kosher. This is pretty sick stuff."
Kahan became interested in the eBay site about a month ago. That was just after he saw news reports about protests by relatives of the victims of Arthur Shawcross, a cannibal who butchered 11 young women in New York state during the 1980s.
Families of the murder victims complained that Shawcross was marketing his prison paintings and autographs electronically via eBay.
Kahan suspected that if there was one serial killer on-line, there were bound to be more. He was right. Along with the Shawcross items, Internet shoppers could bid on macabre souvenirs from at least 20 other mass murderers. Potential buyers only had to enter the names of the murderers or "serial killer" into the eBay search engine.
Each item is offered through an anonymous broker, making Kahan wonder where the money goes and if the killers are getting a cut of the profits. He also points out there are few restrictions preventing someone under 18 years of age from purchasing serial killer merchandise.
Last week Kahan sent e-mail to eBay's Community Watch urging the company to pull the items.
"Give victims' families some piece of mind," wrote Kahan, "with the notion that none of their family members will have the nauseating feeling of seeing the person who murdered their family member selling their personal wares for the world to gawk at."
In response to his letter, Kahan received a friendly, albeit anonymous, non-committal form-letter reply from eBay:
"We appreciate you taking the time to send us this information on either a prohibited, questionable or infringing item," wrote eBay's Community Watch. "We understand your concern and will be happy to look into this matter for you."
If Kahan is expecting eBay to remove serial killer memorabilia from its auction site, he may be disappointed. Company spokesman Kevin Purseglove says eBay plans to continue selling anything and everything, as long as it's legal.
"The bottom line is if the item is appropriate or legal to sell between two private individuals in the real world, that item can be listed [for sale] on eBay," says Purseglove. "These are items that can be sold on a street corner or a bookstore or a mail-order service. It's the exact same thing."
Purseglove also maintains there are safeguards to ensure that minors are not buying restricted items. Additionally, he says, eBay does not sell that material in states such as New York, with laws that prohibit inmates from profiting from their crimes.
Texas has a law that relates to the issue. The state Code of Criminal Procedure says, "the victim of a crime shall be the first one compensated from any revenue collected from the perpetrator of the crime for that purpose."
However, enforcing that regulation may be difficult with regard to eBay activity. A spokesperson for the state attorney general's office reviewed the Web site and pointed out that since sellers are anonymous, it is difficult, if not impossible, to determine who actually gets the money from the electronic auctions.
As for the families of the victims of serial killers, Purseglove maintains that if they are upset, they should focus their attention on pressing for new laws in their state to prevent killers from making money off their celebrity.
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But his words are of little comfort to 74-year-old Walter Scott. His 17-year-old son, Mark, was the last identified victim of the Henley-Corll murder ring.
Twice in the last couple of years, Scott was outraged when Henley's artwork went on sale in a one-convict show at a Houston gallery. He is equally disgusted by on-line sales involving serial killings.
"I just don't know how people can do this," says Scott. "There ought to be a law against it."
E-mail Steve McVicker at email@example.com.


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RALEIGH � North Carolina coach Larry Fedora preaches before each game that at some point, his team will face adversity.
So when North Carolina State jumped on two early miscues by the Tar Heels for two scores in the first eight minutes, outspoken North Carolina tight end Eric Ebron wasn�t worried.
�Laugh at it, put it in our pocket and run with it. And that�s exactly what we did,� Ebron said.
The Tar Heels ran their way to a 27-19 victory against rival N.C. State in an Atlantic Coast Conference football game Saturday afternoon at Carter-Finley Stadium.
Ebron was guilty of that second miscue, fumbling after receiving a shovel pass. He was able to recover the loose ball for a 16-yard loss.
That led to a punt and N.C. State drove inside the Tar Heels� 10-yard line before settling for a field goal and a 10-0 lead.
�Coach Fedora always says we�re going to get adversity. Somewhere throughout the game, we�re going to get adversity,� Ebron said. �May have it on the first play, may not. Adversity happened to us, 10-0. We responded just like he said.�
The spark came in the form of quarterback Marquise Williams, who engineered an answer in the form of an eight-play, 74-yard drive that ended with his 2-yard touchdown pass to Quinshad Davis.
When the Tar Heels snuffed out a fake punt on the next possession � Fedora said it was the first time this season that North Carolina has made a �game-changing� special teams play � Ebron hauled in a 19-yard catch and quarterback Bryn Renner finished a three-play possession with a 1-yard touchdown run.
�Whether we went up or down, there were going to be a lot of ups and downs in the game,� Fedora said. �It�s typical of this game. We went up, we went down, it didn�t matter. �Play at it the same way, with the same emotion, same enthusiasm, the same energy.� Nobody was down, they just kept playing.�
That emotion might have eclipsed anything during the game when the Tar Heels ran to midfield � and a new midfield logo of the Wolfpack�s mascot within the silhouette of the state � to celebrate after the game�s final play.
�Believe me, this team and this university and all of our fans take a lot of pride in that. Tremendous amount of pride in that,� Fedora said. �As far as I know, it�s always been the Tar Heel state and always will be.�
Ebron, who backed up his fair share of pre-game talk on Twitter with plenty during the game, said he wanted to erase a taste of his first visit to Carter-Finley Stadium.
�My freshman year, we came here and we were shut out,� said Ebron, a junior. �And that feeling, that taste that was in your mouth for two years, just sat there. We came back and we were relentless.�
After a field goal pushed N.C. State in front 16-14, North Carolina used a trick play to retake the lead for good.
Three plays after catching a backward pass and running for 3 yards, Ryan Switzer took a backward pass and fired a strike to Davis for a 59-yard touchdown.
�Ryan did a great job throwing that ball, he put it on the money and I made a play for us,� Davis said, who threw a touchdown earlier this season against East Carolina. �In practice it wasn�t looking good. You know I�ve got the arm for the receivers.�
After Davis� touchdown catch from Switzer, it became a matter of which offense could do the least. Eight of the nine possessions after that score ended with punts, with the exception being a two-play drive for N.C. State that ended the first half.
N.C. State cut the lead to 21-19 on Niklas Sade�s fourth field goal of the game in the third quarter.
North Carolina�s response came a few possessions later, when freshman running back T.J. Logan burst through a gaping hole for a 14-yard touchdown with 11:14 left.
�I saw the line get up to the linebackers, my eyes got wide. So I just tried to finish up,� he said of his first career touchdown, which came on a zone-read play similar to the offense that featured him at Northern Guilford. �I�m just thinking get to the end zone.�
North Carolina survived injuries to both quarterbacks late in the third quarter. Renner suffered a separated shoulder and Williams was shaken up after a brutal hit by Robert Caldwell on a scramble. Both returned to the game.
N.C. State�s best chance to score came on a drive that started with 6:20 left from its 9-yard line. The Tar Heels came up with a stop when safety Tre Boston broke up passes on third and fourth down.
�I thought our defense did an outstanding job of making them kick field goals throughout the game and keeping us in the game,� Fedora said. �We haven�t given up the big play. Early in the season, we gave up too many of those and we were playing solid all the way through (Saturday), and I think we�ve gotten better at stopping those explosive plays.�
-- EXTRA POINTS �: With nine catches for 70 yards, Ebron set school records for receptions (44) and receiving yards (669) in a season by a tight end. � North Carolina center Russell Bodine was called for three holding penalties. � The game started with a chuckle when N.C. State deferred to the second half after winning the coin toss. Referee Brad Allen said to North Carolina�s captains, �I assume you want to receive?� Earlier this season, North Carolina jumbled the decision and kicked off twice against Middle Tennessee.


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From today's S'pore media:
"Robuchon, who has 25 Michelin stars, will make his debut in Singapore in May with three restaurants - Joel Robuchon Fine Dining, a high-end French restaurant, the more casual L'Atelier de Joel Robuchon, known for its swanky red and black decor and bar counter dining, and The Pastry Shop and Lounge."
Other chefs also opening their restaurants at Sentosa included Kunio Tokuoka (from 3-Michelin star Kyoto Kitcho Arashimaya) who's opening Kunio, a kaiseki restaurant, NY-based Toronto chef Susur Lee and Sydney chef-restaurateur, Scott Webster.
Sentosa's fine dining options will go head-to-head against the other upcoming Marina Bay Sands' eateries by Wolgang Puck, Daniel Boulud, Santi Santamaria and Mario Batali. Looks like foodies in S'pore will have more to savour & write about this year!


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New hockey rules appropriate, local coaches say
Just weeks after hockey injuries left two Minnesota prep athletes seriously injured on the ice, state officials announced a change in rules that stiffens penalties for certain hockey hits.
The Minnesota State High School League's board of directors on Friday approved immediate changes to hockey policies governing dangerous contact.
Local coaches expressed support for the change, saying it sends a positive message that safety is priority in prep sports.
"As long as it's enforced, then that's great," said Woodbury boys hockey coach Wes Bolin. "It should have a good impact on the game."
East Ridge boys hockey coach Doug Long said the league changes make sense.
"It'll be interesting to see what happens," he said. "I appreciate it just from the standpoint of it being for the safety of the game."
The Minnesota hockey for weeks has rallied around Benilde-St. Margaret hockey player Jack Jabonblonski, who was paralyzed after a Dec. 30 check from behind. One week later, St. Croix Lutheran girls hockey player Jenna Privette was seriously injured during contact in a game; like Jablonski, remains hospitalized.
Bolin said the time had come for a change.
"Yeah, there probably is a need for some sort of a change or an emphasis," he said.
The changes call for three collision-related penalties to be intensified.
Checking from behind - the hit Jablonski received - now becomes a five-minute major penalty, plus a 10-minute misconduct penalty. Players who are deemed to have issued flagrant hits from behind that send opponents into the boards or goalie's frame will continue to receive a game disqualification, which also calls for the offending player to sit out the next game.
Any hit that sends an opponent "violently into the boards" is now an automatic major penalty, beefing up the term from two minutes.
The third change applies to head contact and also generates a new five-minute major penalty for those hits. It replaced a rule that allowed for discretion on whether it could be a two-minute minor or a five-minute major.
Bolin said he would be discussing the changes with his players at this week's first practice.
"We emphasize safety and respect for our opponent," Bolin said, "but (the changes) will enhance what we do even now."
Long planned to talk with his players about the changes when they returned to practice early this week. He hoped to stress on the players that the changes could benefit them if they play smart.
"I'm going to see it to them as, 'Hey, look, this is an opportunity for us,'" Long said, adding that East Ridge has seen "some pretty flagrant hits against us" and has been fortunate to avoid serious injuries.
"I think it's the right direction to go," he said of the new rules.
Bolin doubted the changes will require major adjustments, saying most players already abide rules governing violent contact.
But not everyone, he said.
"Everyone will get the message after the first one is called," Bolin said.
South Washington County Editor Scott Wente contributed to this report


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Security cameras are becoming more prevalent in home security monitoring, especially with the added convenience of smartphones and wireless connectivity. A security camera gives homeowners greater ability to visually monitor their homes, whether they have a professionally monitored system or a DIY home alarm.
Home security cameras also provide peace of mind, because they act as an extra set of eyes watching over your property.
Many companies, like those profiled on HomeSecuritySystem.com, offer security camera systems with some of their monitoring packages. The provider can also help you choose the type of security camera and the location that will best suit your security needs.
Security camera systems: Protection and monitoring
Home security cameras offer an effective way to increase your home's overall safety. Adding a security camera can deliver extra protection, because the technology provides real-time visual information about what's happening around your home. Plus, surveillance camera footage is routinely used to apprehend and prosecute burglars and other criminals.
Security camera systems can monitor a large area and expand the capabilities of a standard home security alarm system. You can use security cameras to monitor multiple areas of your home, such as entrances, yards and garages.
Things to consider about home security cameras
While the pros of a security camera definitely outweigh the cons, there are a few things to consider before purchasing a home alarm system equipped with a surveillance camera or adding a camera to your existing system.
As home security cameras become more commonly used in the security industry, trends of supply and demand should eventually bring prices down. Consumers will probably see the same process with security systems that incorporate home automation.
Wireless security camera models generally cost more than hard-wired models since they are usually more technologically advanced.
Wireless vs. wired
Some of the main differences between hard-wired and wireless security camera systems include price, installation and connectivity. While wireless security cameras tend to cost more, the installation process is not as difficult or time-consuming.
In addition to the camera itself, the main components of a wireless surveillance system include:
- Monitor – Users can view either real-time or recorded video footage from the security camera.
- Wireless receiver – Transmits video and audio information from security cameras to the monitor.
- Digital recorder – Captures security camera footage for replay and storage.
With most security camera systems, features like remote access are available for added convenience and connectivity. With mobile online access, users can manage and interact with their home security systems and home security cameras when they're away from home and even watch video footage on their smartphones.
Digital video recorders are another security camera technology upgrade. These high-tech systems record and store high-definition video instead of black and white, low-resolution footage.


text: Share on Facebook Follow on Facebook Add to Google+ Connect on Linked in Subscribe by Email Print This Post See Image Gallery. Volunteer Jason Springston loads a discarded printer into a bin during Keep Fallbrook Clean and Green Volunteers load an old TV onto a pallet during the community-wide recycling day on Sept. 15. USMC Lance Cpl. Mike Magda is one of the many volunteers who helped clean up day during the annual clean up/recycling day sponsored by Keep Fallbrook Clean and Green. Volunteers clean up Fallbrook added by Newsroom on September 27, 2012 View all posts by Newsroom → Leave a Reply Cancel Reply Your email address will not be published.


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Edit Article
wikiHow to Make a Restore Potion in RuneScape
Basic restore potions restores your defence, ranged, magic, strength, and attack levels by 30% of your own levels.
1Achieve a level 22 in herblore.
2Collect the ingredients.
- Collect a harralander herb. Invest in clean harralander for faster times or if you are planning to make a huge batch. Grimy harralanders are a drop of certain NPCs and monsters, as well as farming.
- Purchase a vial. Acquire water-filled vial packs to save you time. Any unused vials can be stored in your bank for later usage.
- Collect 1 red spiders' egg. There's egg respawns located in the Chaos Tunnels, Varrock Sewers, and Edgeville Dungeon. If a player has a level of 10 summoning, they can get eggs using a spirit spider familiar.
3Mix a clean harralander with a vial of water. This will create a "Harralander Potion (cleaning solution)".
4Use the red spiders' egg on it. This will create a three dose restore potion.
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