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Factor XII can contribute to thrombus formation in human and nonhuman primate blood.
An antibody that blocks factor XII activation (15H8) produces an antithrombotic effect in a primate thrombosis model.
The plasma zymogens factor XII (fXII) and factor XI (fXI) contribute to thrombosis in a variety of mouse models. These proteins serve a limited role in hemostasis, suggesting that antithrombotic therapies targeting them may be associated with low bleeding risks. Although there is substantial epidemiologic evidence supporting a role for fXI in human thrombosis, the situation is not as clear for fXII. We generated monoclonal antibodies (9A2 and 15H8) against the human fXII heavy chain that interfere with fXII conversion to the protease factor XIIa (fXIIa). The anti-fXII antibodies were tested in models in which anti-fXI antibodies are known to have antithrombotic effects. Both anti-fXII antibodies reduced fibrin formation in human blood perfused through collagen-coated tubes. fXII-deficient mice are resistant to ferric chloride–induced arterial thrombosis, and this resistance can be reversed by infusion of human fXII. 9A2 partially blocks, and 15H8 completely blocks, the prothrombotic effect of fXII in this model. 15H8 prolonged the activated partial thromboplastin time of baboon and human plasmas. 15H8 reduced fibrin formation in collagen-coated vascular grafts inserted into arteriovenous shunts in baboons, and reduced fibrin and platelet accumulation downstream of the graft. These findings support a role for fXII in thrombus formation in primates.
There is considerable interest in the possibility that targeted inhibition of the plasma protease factor XIIa (fXIIa) and factor XIa (fXIa) may be useful for preventing or treating thrombosis.1,2,3,4-5 Mice lacking factor XII (fXII) or factor XI (fXI), the zymogens of fXIIa and fXIa, respectively, are resistant to injury-induced arterial and venous thrombosis,6,7,8-9 and to ischemia-reperfusion injury in the brain10 and heart.11 fXI inhibition also reduces experimental thrombus formation in primates.8,12,13 Humans lacking fXII do not bleed abnormally,5,14 and fXI-deficient patients have a relatively mild bleeding disorder,14,15 raising the prospect that drugs targeting these proteins will produce antithrombotic effects without significantly compromising hemostasis. In the cascade/waterfall models of plasma coagulation, sequential proteolytic reactions initiated by conversion of fXII to fXIIa lead to thrombin generation and fibrin formation.16,17 fXIIa catalyzes conversion of fXI to fXIa during this process. Autoactivation of fXII in plasma is readily induced by adding minerals such as silica or kaolin that provide a surface on which the reaction occurs, and amplified by reciprocal activation of fXII and prekallikrein (PK) in a process called contact activation.4,14 In vivo, polymers such as collagen,18 laminin,19 RNA,20 DNA,21 and polyphosphate,9 as well as misfolded protein aggregates (such as occur in systemic amyloidosis),22 may facilitate fXII activation by similar processes, contributing to thrombosis. fXII may also be activated on membranes of vascular endothelial cells by a distinct mechanism initiated by prolylcarboxypeptidase-mediated conversion of PK to α-kallikrein.23,24
Consistent with data from mouse studies, there is substantial evidence supporting a role for fXI in arterial and venous thrombosis in humans.25,26,27,28,29-30 However, available data make a less compelling case for a role for fXII in human thrombosis. Indeed, 2 large surveys reported the counterintuitive observation that plasma fXII levels are inversely correlated with risk of myocardial infarction26 and death from all causes.31 This suggests that the contribution of fXII to thrombus formation observed in rodents may not reflect processes in humans. To address this issue, we developed monoclonal antibodies to human fXII that inhibit fXII activation, specifically to determine whether blocking fXII in a primate thrombosis model produces an antithrombotic effect similar to the reported effects of antibodies that block fXI.
Materials and methods
Human fXII, fXIIa, PK, and high-molecular-weight kininogen (HK) were purchased from Enzyme Research Laboratories. Human fXI and fXIa were purchased from Haematologic Technologies.
Anti-fXII monoclonal antibodies
The murine fXII null genotype (C57Bl/6 background)7 was crossed onto the Balb-C background through 7 generations. fXII-deficient Balb-C mice were given 25 μg of a mixture of human fXII and fXIIa by intraperitoneal injection in Freund complete adjuvant on day 0 and Freund incomplete adjuvant on day 28. A 25-μg booster dose in saline was given on day 70. On day 73, spleens were removed and lymphocytes were fused with P3X63Ag8.653 myeloma cells using a standard polyethylene glycol–based protocol. Antibodies were tested for capacity to recognize human fXII by enzyme-linked immunosorbent assay (ELISA) and western blot, and to prolong the activated partial thromboplastin time (aPTT) of human plasma. Clones 9A2 and 15H8 were subcloned, expanded in a CL1000 bioreactor (Integra Biosciences), and purified by cation exchange and thiophilic agarose chromatography.
Expression of recombinant fXII and antibody mapping
The human fXII complementary DNA (cDNA) was inserted into vector pJVCMV.32 Sequence encoding individual domains from the fXII homolog hepatocyte growth factor activator (HGFA) were amplified from the human HGFA cDNA by polymerase chain reaction (PCR),33 and used to replace corresponding sequence in the fXII cDNA (Figure 1A and supplemental Tables 1-2, available on the Blood Web site). HEK293 fibroblasts (ATCC-CRL1573) were transfected with pJVCMV/fXII-HGFA constructs as described.32 Conditioned serum-free media (Cellgro Complete; Mediatech) from expressing clones were size-fractionated on 10% polyacrylamide–sodium dodecyl sulfate gels, and chemiluminescent western blots were prepared using 9A2, 15H8, or goat polyclonal–anti-human fXII immunoglobulin G (IgG) for detection.
aPTT assays were performed by mixing 65 μL of normal plasma (0.32% sodium citrate weight to volume ratio [w/v] with an equal volume of phosphate-buffered saline (PBS) with or without 8μM anti-fXII IgG. After 5 minutes at room temperature (RT), 65 μL of aPTT reagent (Diagnostica Stago) was added, followed by a 5-minute incubation at 37°C. CaCl2 (25 mM–65 μL) was added and time to clot formation determined on an ST4 fibrometer (Diagnostica Stago). In separate assays, 65 μL of fXIIa (50 nM) in PBS was incubated with an equal volume of antibody (1 µM) or vehicle for 15 minutes prior to addition of 65 μL of plasma. CaCl2 was added and time to clot formation determined.
Polyphosphate (75-100 phosphate units) was prepared by gel electrophoresis as described.9 fXII (100 nM) was incubated with aPTT reagent (2.5% of total volume) or polyphosphate (2 µM) at 37°C in the presence of 1 µM 9A2, 15H8, both antibodies, or vehicle in reaction buffer (50 mM Tris-HCl pH 7.4, 100 mM NaCl, and 1 mg/mL polyethylene glycol 8000). At various times, aliquots were removed into Polybrene (5 µM final). fXIIa activity was identified by adding chromogenic substrate S-2302 (500 μM; Diapharma) and following changes in optical density (OD) 405 nm on a microplate reader. Results were compared with a control curve prepared with pure fXIIa.
fXIIa (1 nM) was incubated with PK (50 nM) and HK (70 nM) in reaction buffer containing 250 μM CS-31(02) (Biophen) at RT, with or without aPTT reagent (5% volume to volume ratio [v/v]), and with or without anti-fXII IgG (100 nM). Changes in OD 405 nm reflecting conversion of PK to α-kallikrein were followed on a microplate reader.
Normal plasma (0.32% sodium citrate w/v) was supplemented with 415 μM Z-Gly-Gly-Arg-AMC, 5 μM phosphatidylcholine/phosphatidylserine vesicles, and 4 μM IgG anti-fXII IgG. Supplemented plasma (40 μL) was mixed with aPTT reagent (1% v/v) or type I fibrillar collagen (100 μg/mL; Chrono-Log). Ten microliters of 20 mM HEPES (N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid), pH 7.4, 100 mM CaCl2, 6% bovine serum albumin (BSA) was added and fluorescence (excitation λ 390 nm, emission λ 460 nm) was monitored at 37°C on a Thrombinoscope.34 In a separate experiment, fXII-deficient plasma (George King) was treated in a similar manner, except that 5 nM fXIIa was added with aPTT reagent (5% v/v). Each condition was tested 3 times in duplicate. Peak thrombin generation and endogenous thrombin potential (ETP) were determined (Thrombinoscope Analysis software, version 3.0).
Blood was collected from healthy volunteers (0.32% sodium citrate w/v), and platelets were labeled by adding 1,1′-dimethyl-3,3,3′,3′-tetramethylindodicarbocyanine iodide (DiIC15) (2 μM).13 Blood was supplemented with Alexa 594–labeled fibrinogen (20 μg/mL) and 4 μM anti-fXII IgG, and incubated for 30 minutes at 37°C prior to use. Glass capillary tubes (0.2 × 2.0 × 50 mm; VitroCom) were coated with 100 μg/mL type I fibrillar collagen (Chrono-Log) overnight at 4°C, then blocked with 0.5% BSA. Blood was perfused through tubes at an initial shear rate of 300 s−1 using a syringe pump. Prior to entering the capillary tube, blood was mixed with 20 mM Tris-HCl pH 7.4, 154 mM NaCl with 37.5 mM CaCl2, 19.8 mM MgCl2 via a second pump and passed through a coiled 12-cm mixing tube. Blood is diluted ∼20% by this step, with final free [Ca2+] and [Mg2+] ∼2.5 and 1.2 mM, respectively. Tubes were subsequently perfused with 3.5% formaldehyde/PBS solution and imaged by laser-scanning microscopy, using a Zeiss LSM 710 microscope.
Capillary occlusion assay
Glass35 capillary tubes (0.2 × 2 mm; VitroCom) were incubated for 1 hour at RT with fibrillar collagen (100 µg/mL), washed with PBS, blocked with 5 mg/mL denatured BSA for 1 hour, then placed in a vertical position. The top of the tube was connected to reservoir, and the bottom was immersed in PBS. Human blood (0.32% sodium citrate w/v) supplemented with 7.5 mM CaCl2 and 3.75 mM MgCl2 was added to the reservoir. Blood flows through the tube under the force of gravity. The height of the sample reservoir was maintained to produce an initial shear rate of 300 s−1.
Mouse thrombosis model
fXII-deficient (fXII−/−) C57Bl/6 mice were anesthetized with pentobarbital. PBS (100 μL) with or without 10 μg of human fXII, and with or without 100 μg of anti-fXII IgG, was infused into the right jugular vein. Thrombus formation was induced in the right carotid artery by applying 3.5% ferric chloride (FeCl3), as described.8 Arterial blood flow was monitored for 30 minutes using a Doppler flow probe (Model 0.5 VB; Transonic System). Studies with mice were approved by the Institutional Animal Care and Use Committee of Vanderbilt University.
Baboon thrombosis model
Nonterminal studies were performed on 2 male baboons (Papio anubis) with exteriorized femoral arteriovenous shunts, as described.8,12,13 Thrombus formation was initiated by deploying a thrombogenic graft (Figure 2) into the shunt for 60 minutes. The graft comprised a 20 × 4 mm ePTFE (Gortex) segment coated with collagen, a 20 × 4 mm silicon rubber linker, and a 20 × 9 mm silicon rubber expansion chamber. Flow through the shunt was restricted to 100 mL per minute, producing an initial wall shear rate in the graft of 265 s−1. Platelet deposition in the graft and expansion chamber was assessed in real time by quantitative imaging of 111In-labeled platelet accumulation using a GE-400T γ scintillation camera interfaced to a NuQuest InteCam computer system. Endpoint fibrin deposition was determined by direct measurement of 125I-labeled fibrinogen, as described.8,12,13 Plasma thrombin-antithrombin (TAT) complex levels were measured with an Enzygnost TAT ELISA (Siemens). Studies with baboons were approved by the Institutional Animal Care and Use Committee of Oregon Health and Sciences University.
Antibodies 9A2 and 15H8 recognize fXII in human and baboon plasma (Figure 1B) on western blots. The fXII gene arose from a duplication of the HGFA gene.33,36 fXII and HGFA have similar domain structures, except that fXII has a proline-rich region not found in HGFA (Figure 1A). We prepared fXII with individual domains replaced by corresponding HGFA domains. With the exception of the fXII/HGFA-fibronectin type II domain chimera, all proteins were secreted by a human fibroblast line (Figure 1C top). 9A2 and 15H8 recognize distinct epitopes on fXII, with 9A2 binding to the fibronectin type I and/or EGF2 domains (Figure 1C, middle), and 15H8 to the EGF2 /kringle domains (Figure 1C, bottom).
9A2 and 15H8 prolong the aPTT of human plasma (Figure 3A), with 15H8 having a greater effect. Antibodies at ∼2 to 3 times the plasma fXII concentration achieved maximum inhibition. Combining 9A2 and 15H8 produced a greater degree of inhibition (Figure 3B), consistent with the 2 antibodies recognizing distinct epitopes. The curve (open circles) in Figure 3C shows the relationship between fXII concentration and the aPTT. Using this curve for comparison, the effect of 15H8 on the aPTT of normal plasma corresponds to >95% inhibition of fXII activity, while 9A2 achieves ∼50% reduction. 15H8 prolonged the aPTT of baboon plasma (Figure 3D) to a greater degree than human plasma (Figure 3A). The curve with closed circles in Figure 3C was prepared by mixing baboon plasma with fXII-deficient human plasma. When data in Figure 3D are compared with this curve, it appears that 15H8 inhibits >99% of the fXII activity in baboon plasma. 9A2 did not prolong the aPTT of baboon plasma.
Effects of anti-fXII antibodies on fXII and PK activation in vitro
fXII undergoes autoactivation in the presence of a variety of surfaces and polymers.9,14,19 We tested the capacity of anti-fXII antibodies to inhibit fXII autoactivation in the presence of a silica-based aPTT reagent (Figure 4A) or polyphosphate (Figure 4B). Both antibodies reduced fXII activation with the aPTT reagent, with 15H8 having a greater effect, while both had roughly similar effects with polyphosphate.
When PK is incubated with fXIIa in solution, α-kallikrein is formed (Figure 4C, open circle). The rate of PK activation by fXIIa is enhanced slightly by adding HK (Figure 4C, open square) or aPTT reagent (Figure 4C, filled square), while adding both significantly increases activation (Figure 4C, filled triangle). This is consistent with the well-described surface-dependent cofactor effect of HK on PK activation by fXIIa. 9A2 has little effect on surface-dependent PK activation by fXIIa (Figure 4D, open triangle), while 15H8 reduced the rate of the reaction (Figure 4D, open diamond).
Effects of anti-fXII antibodies on thrombin generation in plasma
Addition of aPTT reagent to normal plasma leads to a burst of thrombin generation (Figure 5A, ETP 1805 nM × minutes) that is almost completely blocked by 15H8. 9A2 reduces ETP by ∼50% (961 nM × minutes), with a delay in peak thrombin generation. Similar results were obtained using collagen to induce coagulation (Figure 5B). In contrast, neither antibody blocks thrombin generation induced by adding fXIIa to fXII-deficient plasma supplemented with aPTT reagent (Figure 5C). These data indicate that 15H8 and 9A2 mostly inhibited fXII autoactivation to fXIIa while 15H8, but not 9A2, also reduces fXIIa activation of PK. Neither antibody affects surface-dependent fXI activation by fXIIa in plasma appreciably.
Anti-fXII antibodies in flow models
Anti-fXI antibodies inhibit fibrin formation in recalcified human blood perfused across collagen-coated surfaces.13 Figure 6A shows images from collagen-coated tubes perfused with human blood at a shear rate of 300 s−1. Platelet aggregates appear green and fibrin strands orange. The anti-fXI antibody O1A613 blocks fibrin generation in this system. 9A2 and 15H8 substantially reduce fibrin deposition, although some fibrin does form. These data indicate that the anti-fXII antibodies have an effect in flowing human blood that is similar to the effect reported for anti-fXI antibodies.13 9A2 and 15H8 also prolonged the time it takes for blood to occlude collagen-coated capillary tubes in which flow is induced by gravity (Figure 6B). At a concentration (1.3 μM) ∼3.5-fold higher than the plasma fXII concentration, 9A2 increased time to occlusion twofold, while 15H8 increased it nearly threefold.
Anti-fXII antibodies in a murine thrombosis model
Exposing blood vessels in mice to FeCl3 results in changes to the blood vessel endothelium that lead to thrombus formation in a fXII- and fXI-dependent manner.7,8,37 fXII-deficient C57Bl/6 mice do not develop carotid artery occlusion when exposed to 3.5% FeCl3, while wild-type mice reproducibly develop occlusion in 10 to 15 minutes.8 Infusing human fXII into fXII-deficient animals to raise the plasma level to ∼20% of normal restores the wild-type phenotype (n = 5, all with vessel occlusion). Coadministration of fXII and a 10-fold molar excess of 9A2 reduced the incidence of arterial occlusion to 50%, while 15H8 prevented arterial occlusion (n = 6 for each antibody).
Anti-fXII antibodies in a baboon thrombosis model
We tested the effects of 15H8 on platelet (Figure 7A) and fibrin (Figure 7B) deposition in thrombogenic devices deployed into arteriovenous shunts in 2 baboons (Figure 2). Thrombus formation is triggered in the collagen-coated segment of the graft where the initial wall shear rates is ∼265 s−1. A distal expansion chamber made of silicon rubber is incorporated to assess thrombus propagation under lower shear (<30 s−1; Figure 2). 15H8 (5-6 mg/kg IV) prolonged the aPTT from 29.5 to 50 seconds in 1 baboon, and from 33.5 to 78 seconds in a second animal. Based on the curve in Figure 3C (black circles), these results indicate substantial (∼99%) inhibition of fXII activity. The inhibitory effect lasted >24 hours. Results were obtained for 9 thrombogenic devices tested before, and 4 devices tested after, 15H8 administration. Devices were tested sequentially, and at least 30 minutes were allowed to lapse between removal of a device and placement of a new device. Data and means are shown in Figure 7, however, the design of the study is not conducive to a detailed statistical analysis.15H8 did not affect platelet deposition (Figure 7A) within the collagen-coated graft, had a modest effect in the linker downstream from the collagen, and caused a substantial reduction (∼80%) compared with control in the expansion chamber. 15H8 reduced fibrin deposition by 70% ± 5% in the collagen-coated portion of the graft (Figures 7B, left panel), and by 95% ± 1% in the linker-expansion chamber (Figure 7B, right panel). The grafts promote thrombin generation that is detectable in the systemic circulation as a TAT complex.8,13 15H8 reduced TAT levels by ∼50% (Figure 7C).
Anticoagulants currently used for treating or preventing thromboembolism directly inhibit thrombin or factor Xa activity, or limit production of their precursors. Although effective, this strategy increases bleeding risk because the targeted proteases are central to hemostasis. This places limits on the types of patients who can be treated safely with anticoagulants, and the clinical scenarios in which treatment is applied. The intuitive notion that thrombosis reflects “hemostasis in the wrong place” has been brought into question by data from rodent models demonstrating prothrombotic roles for the proteases fXIa and fXIIa.6,7,8,9-10,38,39-40 These observations suggest that it may be possible to develop therapies in which antithrombotic effects are largely or completely dissociated from antihemostatic effects.
Both fXIa and fXIIa have features that make them attractive therapeutic targets. There is substantial evidence supporting a role for fXI in human thrombosis. Plasma fXI levels at the upper end of the normal range increase risk for myocardial infarction,26 stroke,29 and venous thromboembolism (VTE)25,28 relative to the remainder of the population, while severe fXI deficiency reduces incidence of stroke27 and VTE.30 The major function of fXIa, activation of fIX, appears to serve a limited role in hemostasis, primarily directed at preventing excessive trauma-induced bleeding in tissues with high fibrinolytic activity such as the oropharynx and urinary tract.14,15 In patients with severe fXI deficiency, some types of surgery41 and normal child birth42 are associated with relatively low rates of excessive bleeding in the absence of factor replacement. Indeed, many fXI-deficient individuals do not experience abnormal hemostasis, and symptomatic patients rarely bleed spontaneously (with the exception of menorrhagia),14,15 indicating that drugs targeting fXIa would be associated with less bleeding than drugs that inhibit thrombin or fXa. The absence of a bleeding diathesis in fXII-deficient individuals suggests that drugs specifically targeting this protein would not compromise hemostasis, allowing them to be used in patients with the most restrictive contraindications for current anticoagulation therapies. Enthusiasm for developing fXIIa inhibitors, however, is tempered by 2 considerations. First, while numerous functions are attributed to fXIIa, the physiologic roles of the protease are incompletely understood. Perhaps as important, a clear link between fXII and thrombosis in humans is not established.
Anecdotal reports suggesting that fXII deficiency actually predisposes to VTE date back to the death of the first person identified with severe fXII deficiency from a pulmonary embolism.43 Subsequent investigation did not confirm an association between fXII levels and VTE,44,45 and an analysis of case reports concluded that most thrombotic events in fXII-deficient patients are unrelated to the deficiency.46 However, 2 recent studies have returned the issue of fXII and thrombotic risk to the forefront. Doggen et al reported an inverse relationship between plasma fXII levels and risk of myocardial infarction,26 with an odds ratio of 0.4 for individuals in the highest quartile for fXII level compared with those in the lowest quartile. This study examined fXII within the broad normal range, and not the consequences of severe fXII deficiency, which may be more relevant for anticipating effects of therapeutic fXII inhibition. Endler et al also observed an inverse relationship between plasma fXII and all-cause mortality,31 with participants with 10% to 20% of the normal fXII level having a hazard ratio of 4.7 compared with those with fXII >100% of normal. Curiously, there was no significant increase in mortality for subjects with fXII levels of 1% to 10% of normal, suggesting a fundamental difference between severe and moderate deficiency. Data from the studies from Doggen et al and Endler et al seem at odds with work showing that elevated plasma fXIIa is associated with an increased risk of coronary events.47,48 It is difficult to draw unifying conclusions from this data, but there seems to be grounds for concern that fXII may not contribute to thrombosis in humans and rodents in the same manner, or to the same extent.
The current study examined the contribution of fXII in human/primate models that require fXI for normal thrombus formation. An assumption here is that fXIIa contributes to thrombosis through fXI activation, and ultimately thrombin generation, although other fXIIa-mediated activities could be involved. For example, fXIIa can have direct effects on fibrin structure that could contribute to thrombus stability.49 Antibodies 9A2 and 15H8 recognize epitopes on the fXII heavy chain. They reduce fXII activity in plasma in which contact activation is triggered by inhibiting fXII activation, and not fXIIa activity, supporting work showing the fXII heavy chain is required for binding to polyanions.50,51-52 In baboons, 15H8 reduced fibrin deposition in thrombogenic grafts, and limited platelet-rich thrombus growth downstream from the collagen-coated graft segment. The antibody reduced thrombin-antithrombin complex levels induced by the grafts, consistent with the premise that a reduction in thrombin generation was behind the antithrombotic effect. It is illustrative to compare this performance to those of anti-fXI antibodies in this model. The antibody O1A6 is a potent inhibitor of factor IX activation by fXIa.13,32 O1A6 reduces systemic TAT levels by ≥80%, and significantly reduces platelet and fibrin accumulation within the collagen-coated segments of grafts. Platelets adhere to collagen in the presence of O1A6, but there is a defect in 3-dimensional thrombus growth,13 consistent with the thrombus instability observed in fXI- and fXII-deficient mice.7,8 The considerably greater effect of O1A6 compared with 15H8 may be explained by its larger effect on thrombin generation. The anti-fXI antibody 14E11 inhibits fXI activation by fXIIa, but does not affect fXIa activity.8 Similar to 15H8, 14E11 had relatively little effect on platelet accumulation in the collagen-coated graft segment, but did limit downstream platelet deposition. The performance of these antibodies in human blood in a collagen-based flow system are, in general, consistent with those for the baboon model. Taken as a whole, the data suggest that inhibiting fXI activation by fXIIa, either by inhibiting fXIIa generation (15H8) or by blocking fXIIa activation of fXI (14E11) can inhibit thrombus formation by reducing thrombin generation. The effect, however, is not as pronounced as the one produced by inhibiting fXIa activation of factor IX (O1A6). Interestingly, O1A6,13 14E118 and 15H8 prolong the aPTT to similar extents in treated baboons, demonstrating that it is the mechanism targeted, and not the absolute value of the aPTT, that determines the antithrombotic effect. The primate models used in this study (the baboon and human ex vivo flow models) are collagen-based. Although mechanistic details for the process(es) responsible for fXII activation cannot be definitively established in these models, collagen may contribute directly to fXII activation through a process similar or identical to contact activation. The findings of this study, therefore, may only be applicable to surface-induced thrombosis, such as a clot associated with an intravascular catheter, and may not be applicable to thrombus formation triggered by other stimuli. However, it should be noted that 15H8 is effective in preventing FeCl3-induced thrombosis in mice. Here, thrombus formation is initiated by changes in vascular endothelium that promote red blood cell and platelet adhesion,37 with exposure of subendothelial collagen probably playing a relatively minor role.
The results suggesting that fXII inhibition has a smaller antithrombotic effect than fXI inhibition in primates contrast with those obtained with mouse thrombosis models. We observed that fXII-deficient mice are somewhat more resistant to carotid artery thrombosis induced by FeCl3 or laser injury than are fXI-deficient mice.8 Thrombin-mediated feedback activation of fXI may explain the observation that fXII deficiency does not cause a hemorrhagic tendency.34 Perhaps this mechanism plays a more prominent role in thrombus formation in primates than in mice, accounting for the greater effectiveness of O1A6 compared with 15H8 and 14E11 in baboons. This scenario is consistent with the more modest reduction in TAT levels in baboons treated with 15H8 compared with O1A6.13 Alternatively, it appears that relatively small amounts of fXII have significant effects on the aPTT in primate plasmas. Therefore, a high degree of fXII inhibition (not easily obtained with an antibody) may be required to produce an antithrombotic effect. Indeed, while 15H8 reduced fXII activity in the aPTT, it did not block it completely. Consistent with this, Pixley and coworkers reported that an antibody that neutralized ∼60% of fXII activity in baboons did not affect endotoxin-induced disseminated intravascular coagulation.53 In contrast, reducing fXI levels in baboons by as little as 50% affects thrombus formation in the arteriovenous shunt model.54 Furthermore, inhibiting fXII with an antibody to produce a similar effect to total fXII deficiency is made difficult by the relatively high plasma fXII concentration (400 nM). The plasma fXI concentration is only 30 nM. These observations have implications for developing therapeutic fXII/XIIa inhibitors, which may need to inhibit a high percentage of protease activity to produce a therapeutic effect.
The online version of this article contains a data supplement.
There is an Inside Blood commentary on this article in this issue.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
We gratefully acknowledge Jennifer Greisel’s expert technical support with the primate studies, and Dr William Dupont for recommendations on the use of statistical analysis.
The authors acknowledge support from National Institutes of Health awards (Heart, Lung and Blood Institute) HL81326, HL58837 (D.G.), HL106919 (I.M.V.), HL047014 (J.H.M.), and HL101972 (A.G., O.J.T.M.); (National Institute of Allergy and Infectious Diseases) AI088937 (A.G., E.I.T.); (National Institute of Neurological Disorders and Stroke) NS077600 (P.Y.L.); UL1TR000128 to the Oregon Clinical and Translational Research Institute, and RR000163 to the Oregon National Primate Research Center from the National Institutes of Health.
Contribution: A.M. performed flow model studies, designed experiments for characterization of effects of antibodies on fXII, and contributed to the writing of the manuscript; P.Y.L. performed baboon studies and contributed to antibody development and to writing of the manuscript; A.E.G. and S.L.G. characterized the effects of antibodies on fXII activation and fXIIa activity in vitro; C.P. conducted capillary flow studies; Q.C. designed and conducted murine thrombosis studies; M-f.S. prepared the fXII/HGFA mutants and conducted studies to map the binding sites of 9A2 and 15H8 on fXII; O.J.T.M. contributed to design and interpretation of flow model experiments; E.I.T. contributed to antibody generation and characterization, and to baboon thrombosis studies; H.K. contributed to the design of XII/HGFA chimeras; T.R. contributed to the design of murine thrombosis models, and to the writing of the manuscript; J.H.M. contributed to the design of experiments with poly-P, and to the writing of the manuscript; A.G. oversaw studies involving baboons, generation of antibodies, and the writing of the manuscript; and D.G was responsible for oversight of the project and preparation of the final manuscript.
Conflict-of-interest disclosure: D.G. is a consultant, and receives consultant’s fees from several pharmaceutical companies. P.Y.L., E.I.T., and A.G. are employees of the company Aronora. A.M., P.Y.L., A.G., D.G., Oregon Health and Sciences University, and Vanderbilt University may have financial interest in the results of this study. The remaining authors declare no competing financial interests.
Correspondence: David Gailani, Hematology/Oncology Division, Vanderbilt University, 777 Preston Research Building, 2220 Pierce Ave, Nashville, TN 37232; e-mail: email@example.com.
A.M. and P.Y.L. contributed equally to the study and to manuscript preparation and should be considered cofirst authors.

domain: literature


A man was taken to hospital after a car and motorcycle collided by Hewitt's Farm in Orpington yesterday (March 16).
Police were called to Court Road at 11.40am following a crash involving a Honda Civic and Suzuki motorcycle.
A 58-year-old man, who was driving the motorcycle, was taken to a south London hospital with abdominal, chest and leg injuries.
His injuries are not believed to be life threatening.
Temporary road closures were put in place.
No arrests have been made.
- Bexleyheath Academy teacher 'appalled' by allegations of sex with pupil
- Mum and daughter attacked and pushed off Dartford-bound train at Welling
- Will Father Christmas arrive in an ambulance this year?
- VIDEO: Greenwich pupils feed hungry shoppers with 'mince flies'
- Woolwich listed building could be demolished for Crossrail square


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News and notes from our area, courtesy of Nora Mabery-Daniel. Do you have anything to report? Email email@example.com.
St. Joseph’s Women’s Club will host the movie “Wish Dragon” at 8:00 pm on Sunday. Families should bring their own chairs or blankets and social distance. Drinks and snacks are available for purchase.
Previve-Ogden Sixth graders hold potato Olympics They began by naming their potatoes and joining a group. Then each group brought a country name, flag, and anthem. Then they had to weigh and weigh. Each athlete wrote a biography in language arts. Finally, he competed in five different events and one team was selected as a gold medal.
Previve-Ogden hires Joe Emken as assistant baseball coach.
The stream at the natural playground is currently out of order, as a Champion County Forest Conservation worker approaches the problem.
Watseka Park Woreda Postgraduate Program celebrates “National Beach Day” by creating sand art.
Ryder Neahring has read 300 books at the Mahomet Public Library’s “1000 Books Before Library” program.
Rantoul High Greenhouse has received poinsettias for December sales. Vegetable classes sell four different varieties of poinsettias, including white, red, pink and multi-colored options.
Oakwood High Annual Swap Day – where parents attend classes on behalf of their students – will be held September 22. It was started in 1977 by former principal Glenn Louver.
On canvas: The beach boys’ festival will be held on September 23 at the Paris Art Center.
Negangard Pumpkin Patch will open on September 25.
Tuscola FAA meets with Governor JB Preszker at an agricultural development exhibition in Decatur.
Sicina Park has been named the FAA’s National Star 3 Star. This chapter is the highest award, and only 350 out of 8,000 chapters will receive it.
Arthur High School announces journalism editors for the 2021-22 school year: Josie Hale and Kylie Shrock are editors of Knightly News.
Bemen Anna hosts the fastest Saturday “Children’s Story Time” at the library on Saturday at 10:00 AM. Children of all ages are welcome. After reading, the library shows a movie and serves popcorn.
Work continued with the new Kathleen Bank. Meanwhile, the bank has set up a temporary ATM on the corner of Sandusky and Vermilion.
On September 2, Brad Halrock, a representative of Arcola Sunrise Rotary, welcomed the meeting.
Westville Labor Day Demonstration The Great Marshall is a longtime Westville School Board member and retired postmaster Shawn Bennett. Hon’ble Marshall has spent countless hours with Westville Senior Assistant Principal Michel Schumberg.
The Ministry of Victory Church has been providing Panera bread bags to local schools, including Tuscola, Heritage, Villa Grove, Oakland, Shiloh, Atwood and Arkola.
Sunrise Rotary at Y, Women’s Shelter, Crossroads with Bags. Rotary donated 20 bags of school supplies, hand sanitizers and toys. They also donated shoes, socks and underwear.
The September 11 annual Broadland Festival will feature vendors, live music, flexible, children’s games and parades.
The village will hold a golf cart and side-by-side march from Thomas Park on Sunday at 1 p.m.
WPXN Radio Dan Down and Joel Clover entered the 2021 Illinois Basketball Coaches Association at the Redford Arena Festival last weekend.
The Vermillion County Conservation District will host a free wool dye rally on September 18 in the cabin of the Glen Forest Reserve.
Giftford State Bank’s annual covered bridge bus trip to Bridgeton, Indy. October 14 (call 217-568-7311).
Bismarck-Henning / Rossville-Alvin students posed for a photo with Illinois State Police Trapper Lillar during the Agricultural Development Exhibition.

domain: news


UConn Trustees Adopt Budget, With State Budget Still UncertainUniversity of Connecticut trustees have approved a more than $1.3 billion budget for the Storrs and regional campuses for the fiscal year starting July 1-- largely flat compared to the current year.
After Criticism, Several UConn Administrators Give Up Some Pay HikesAfter criticism from state lawmakers, several UConn administrators are giving up a portion of their recent pay increases.
UConn Board Set To Vote On Closing Torrington Campus The University of Connecticut's Torrington campus is headed to the chopping block.
UConn Signs Space-sharing Deal With Hartford Public LibraryThe University of Connecticut has signed an agreement to spend $4 million to renovate and lease space inside the Hartford Public Library.
UConn Warns Cuts Could Lead To Closing Regional CampusesThe leaders of Connecticut's public colleges and universities asked lawmakers Wednesday to spare their schools major budget cuts, warning that more reductions could mean the elimination of academic and athletic programs and even shuttering some campuses.
UConn Breaks Ground On Engineering, Science Building
Herbst: Budget Would Cause Closures, Cuts
UConn Trustees Approve Herbst Contract Extension
UConn President Says Budget Cuts Won't Impact Tuition
New UConn Intiatives Aimed At Preventing & Responding To Sexual ViolenceThe president of the University of Connecticut on Thursday outlined for the campus community several new initiatives designed to better prevent and respond to sexual violence or harassment at the school.
$2.3 Million Gift For UConn Nursing School
Herbst Applauds Obama's Push To Stop Campus AssaultsUniversity of Connecticut President Susan Herbst is expressing support for a White House initiative to fight sexual assault on college campuses.


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Fudgy brownies with plenty of caramel and pecans!
Position a rack in the center of the oven and preheat the oven to 350°F. Spray the bottom and sides of a 9x13-inch baking pan with nonstick spray.
Put the butter and chocolate in a medium saucepan over low heat and stir constantly until melted and smooth. Remove from heat and set aside.
In a medium bowl, whisk the eggs until well blended. Gradually whisk in the sugar and then whisk vigorously until well blended. Whisk in the melted chocolate mixture, vanilla extract, and salt. Whisk in the flour and cocoa powder until blended. Stir in the pecans, and then scrape the batter into the prepared pan, smoothing it into an even layer with a spatula.

domain: food


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INTRODUCTION - Chronic Prostatitis/chronic pelvic pain syndrome (CP/CPPS) and interstitial cystitis/bladder pain syndrome collectively referred to as urologic CPPS (UCPPS) is defined by Difficulty Urinating the absence of identifiable bacterial infection as a cause for the chronic pain and urinary symptoms Prostatitis Treatment .
METHODS - A PubMed search of all recent relevant articles using the keywords/phrases: CPPS, CPPS , and male pelvic pain, Painful ejaculation was conducted.
RESULTS - prostatitis CPPS has a high worldwide prevalence Frequent Urination and its negative impact on quality of life compares with or exceeds common chronic morbidities. Triggers include certain comestibles as well as psychosocial chronic Pelvic Pain Syndrome
factors that Blood in the Urine promote catastrophizing and illness focused behavior. Several validated tools are currently available to help diagnose and direct targeted therapy. Burning While Urinating Treatment should begin with the most simple and least invasive BPH based on the presenting clinical Pain While Urinating phenotype.
CONCLUSIONS - Prostatitis Symptoms Although no gold-standard treatment exists, a multidisciplinary Blood in the semen approach with multimodal therapy gives the UCPPS patient the best chance of symptom relief.

domain: medical


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This hike begins at Fort la Latte, a 14th century castle built on a rocky promontory offering a beautiful view of the bay of Saint-Malo and the Emerald Coast. There is a charge for its visit.
The trail then runs along impressive cliffs overlooking the sea to the famous Cape Fréhel lighthouse, itself in the heart of unspoiled moors. The return is made by small paths inland.
BACK TO START
Parking du fort la Latte.

domain: travel


Tablet Testing Area
This the area for Manual and Semi-Automated Tablet Hardness Testing Products. Please read more next to the images for more information about performance, accessoires, calibration tools and consumables.
All PHARMA TEST Hardness tablet Testing Instruments meet the latest requirements of the USP monograph and EP
Tablet Tester Series
The PTB311E “3-in-1” is doubtless one of our most popular instruments for measuring Thickness, Diameter and Hardness. A variety of tablet Thickness Jaws are available for tablet different diameters or shapes.
The PTB302 is the latest version of the very first electronical Tablet Hardness Tester world-wide. Its main features are: Built-in Printer, RS-232 interface, operation mode for linear force increase, simple to operate, no change of jaws required.
The PT-MT3 instrument, the new Magentic Tablet with built-in calibrated load cell, is used to qualify and calibrate the maximum hardness result detection and speed/force increase rate of most Tablet Hardness Test Instruments in the field.
Request a quote or more information
Would you like to request a quote or more information?
Phone: +31 (0)162 383100
or use our contactform
Standard Hardness Test Instrument
To test Hardness of any solid sample up to 300 or alternatively 500 N (Newton) the PTB111E is designed for. The PTB111E is equipped with a COM port for data transfer and a Pinter port to record the results. The test result is immediately displayed at the LED Display of the unit. It offers load cell adjustment and 3-point calibration menus.
Depending on the tablet hardness you can manually test between 5 to 8 samples per minute. The user has to enter a nominal hardness and push the START key. When all data have been collected simply push the STOP key and get the results including statistical information printed at the attached or integrated Printer. The Auto-Restart option allows a faster test and higher throughput of samples compared with a manual Start procedure.
3 in 1 Hardness, Diameter and Thickness Tester
The PTB311E “3-in-1” Tester is doubtless one of the most popular instruments for measuring thickness up to 15mm, Diameter (or Length) up to 40mm (optional 70 mm), and Hardness up to 300N with an option to increase this to 500N. It is designed in compliance with the USP and EP monographs.
A variety of Tablet Thickness Test Jaws are available for different shaped tablets. Connect a DOT Matrix Printer to get a Force Curve Print or use the optional PTB32 software for result presentation. Full calibration and validation program included.
Tablet Hardness Tester
The PTB300 was very first electronical Tablet Hardness Tester and so the oldest member of the hardness tester team, but still the PTB302 is a very popular instrument. The PTB 302 is manufactured and supplied with an inox housing and built-in thermo-printer. It is designed in compliace to the USP and EP monographs.
Sample throughput is around 6 – 10 per minute. Standard instrument has a load cell up to 300N, but can be upgraded to 500N. Display results in N, Sc or Kp. Linear Force increase mode selection, built-in printer and RS-232 interface. No change of the Test Jaws required, design made to suit all sizes and shapes. This unit can be supplied for larger tablets up to 70 mm, too.
Ampoule Breakpoint Tester
The PTBA211E is an Ampoule Hardness (or Breakpoint) Tester. It is a special adaptation of the PTB311E series to allow the determination of ampoule break point. Ampoules with a volume of 1 to 30 ml may be tested. Up to 250 tests per series for statistical evaluation are possible. Easy calibration and validation possible with full calibration report.
The PTBA211E is probably the most used Ampoule Breakpoint Test Instrument world-wide. Its stainless steel design, easy to operate features, and the design in compliance to the DIN/ISO 9187 are highlight of the popular Instrument.
Magnetic Tablet for Hardness Test Qualification
The PT-MT3 Magnetic Tablet, is the sucsessor of the PT-MT2 used to qualify and calibrate correct hardness detection and force/speed increase rate of most Hardness Test Instruments, like PTB 311E/511E, PTB 411/411-500, PTB 301/302/501/502/320, PTBA211E, WHT and WHTME, 4M, 8M series.
Similar to the breaking behaviour of a tablet or ampoule the test jaw “breaks” when a selected force is applied to the test handle in which a calibrated load cell is placed. Any test range can be selected within the range of 10 to 500N. In order to use the instrument for all PHARMATEST and other make Hardness Test Instruments special instrument adaptors (supports) are available. The PT-MT3 is calibrated using certified weights.


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At the Florida Spine Institute, we offer more than 80 treatments to help people overcome spine and joint pain. Use the list below to explore our treatment options.
An anterior cervical discectomy and fusion is an anterior approach to removing a cervical...Learn More
Decompression is a surgical procedure to relieve pressure and alleviate pain caused by...Learn More
A laminectomy is a surgical procedure typically undertaken when back pain continues after other less...Learn More
Minimally invasive spine surgery—often abbreviated as MISS—uses advanced...Learn More
Scoliosis is an abnormal curvature of the spine that affects approximately seven million people...Learn More
Spinal cord decompression is a general term that refers to a variety of surgical procedures...Learn More
Spinal fusion is surgery to permanently join together two or more bones (vertebrae) in the spine so there is no movement between them.Learn More


WWE Raw women’s champion Rhea Ripley recently spoke to TalkSport about a variety of subjects including the extra times he got to spend in NXT ahead of her main roster call-up, and why the creative in WWE is always on top of their game. Highlights are below.
On the extra time she got to spend in NXT:
“I didn’t really know what the whole plan was for the rest of the year, but I thought it would last a lot longer than it did. I thought I’d be, in my mind, having matches with Charlotte for the majority of the year then possibly going to RAW or SmackDown and continuing things there. But, it didn’t happen and I’m still really thankful I got that extra time in NXT because I got to do so much cool stuff. Like I got to wrestle one of my best friends, Raquel Gonzalez, and have epic matches. I’m still really thankful I got to stay and do my work there, but I definitely thought it was going to lead somewhere different.”
On WWE creative:
“Yeah, it’s wild! You just got to trust the process because even if you don’t know what’s going on, they always do. It’s wild to think we’re back to where I was a year ago and I’m back into something with Charlotte Flair. And it’s cool to have Asuka there too. I think that’s going to be magic.”


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The Williams Martini Racing team locked out the third row of the grid in Bahrain, with Valtteri Bottas ahead of Felipe Massa, with the Finn out-qualifying the Brazilian by just over three-tenths of a second.
Bottas felt that fifth on the grid was representative of where the Williams is at present, and was happy to finally have a clean qualifying session this season. He knows the race will be tougher, but is hoping for a strong performance on Sunday.
“I’m not unhappy to get P5 as it is representative of our pace,” said Bottas. “The race is long and will be tougher than today, the start will be especially important considering Turn One can produce problems.
“As a team we did a good job, we got the best out of the tyres and it is refreshing to finally get a clean qualifying session.”
Team-mate Massa will start sixth, and the Brazilian agreed with Bottas that fifth and sixth is where the Williams’ are where they should be on the grid with the pace of the cars as they are right now. He feels there could be opportunity to overtake during the race, and hopes for a positive result on Sunday.
“I did a great lap in Q2, so was upset not to replicate this in Q3 after a few mistakes,” said Massa. “The best position I could have achieved today was P5 and Valtteri has that, so the cars are where they should be.
“Overtaking is possible here so we can have a good race, but tyre management and strategy will be important. I am not unhappy, we are not out of position and there is a long race ahead tomorrow.”

domain: sports


Following on the success of the AUTO-MATE swing gate system which has been in service since 1988 and installed in applications around the world including the UK, New Zealand and Canada, Centurion has developed the R3 operator.
The R3 uses a rotary arm principle. This combined with a new generation of electronics with ramp control, provides for a rapid yet smooth opening and closing of the gates. Each operator incorporates a high torque geared 12 V d.c. motor for safe low voltage and whisper quiet operation. The output shaft is linked to the gate via an articulated arm secured by a padlock. The drive units are self-locking preventing the gates from being forced open.
The linkage system is fully adjustable and its design makes installation quick and easy. The R3 system can be driven by a traditional 220 V transformer-rectifier or directly from a 12 V battery for power failure protection and various low voltage power supply options including solar charging, etc.
The operators can be mounted on steel pillars, which are firmly concreted into the ground adjacent to each gate leaf. Alternatively for a quick installation, sturdy brackets are available allowing for the operator to be mounted directly to the gate pillar.
Adding further to the ease of installation of the system the electronic controller, charger and maintenance free battery are housed inside the main operator of each system. For added reliability the controller is fitted with advanced lightning protection designed and tested in conjunction with the CSIR (South African Centre for Scientific and Industrial Research).
The drive units use an internal position control system which constantly monitors the movement of the gate to provide sensitive anti-crushing control protection and pin point stopping. Centurion's products are marketed through an extensive network of qualified installers. The equipment is manufactured to the ISO9001 quality standard and is CE certified.
For more information contact Centurion Systems, 011 699 2400.
© Technews Publishing (Pty) Ltd. | All Rights Reserved.


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Steve the Vietnamese micro potbellied pig was reunited with Brian Maguire and Bernadette Broadhurst on Friday. Broadhurst says a Ridley Township commissioner personally delivered the stray swine, days after he'd been taken to a farm by police.
Maguire said Steve had apparently escaped from his yard for a stroll and disappeared. When he checked with police to see if Steve had been spotted, Maguire said he was told the animal was found but sent to a farm because of a ban on keeping farm animals.
Maguire said feared for the 6-pound, 10-week-old pig's safety in a farm setting.
A Facebook group the couple set up following Steve's disappearance garnered about 2,000 supporters.


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The 9th U.S. Circuit Court of Appeals is no doubt one of the more controversial federal courts in the United States. It’s commonly referred to as the “Nutty 9th” or the “9th Circus Court.”
Currently, the 9th Circuit has appellate jurisdiction over Alaska, Arizona, California, Hawaii, Idaho, Montana, Nevada, Oregon and Washington.
When it comes to federal courts, the 9th Circuit has among the highest percentage of sitting judges appointed by democratic presidents.
The fact is the numbers speak for themselves when it comes to the court’s rulings. From 2010–2015, around 79% of the cases accepted for review by the 9th Circuit were reversed — one of the highest rates in the country.
However, recently, the typically liberal-leaning 9th Circuit has handed down rulings surprising people from both sides of the aisle…
Size Doesn’t Matter
Last year, the state of California passed a law that made it illegal to possess a rifle magazine that can hold more than 10 rounds, essentially turning thousands of lawful gun owners into criminals.
According to the law, any person who possesses a legally purchased magazine capable of holding more than 10 rounds of ammunition must either remove the magazine from the state, sell it to a licensed firearm dealer or hand it over to law enforcement.
Citizens who retained their magazines after the law went into effect could be fined or sentenced up to a one year in a county jail.
This law ignores the fact that gun owners who purchase large capacity magazines do it for the same reason police carry large capacity magazines.
If you’re involved in a shooting, the amount of ammunition you have can mean the difference between life and death.
I imagine that many California gun owners didn’t willingly give up their magazines, leading people to be concerned that California would simply create another law to seize them.
In a ruling that shocked many folks, the judges in this case relied on the historical intention of the Second Amendment to have a “well-regulated militia” as written by our Founding Fathers.
When the Second Amendment was written, most gun owners owned a single-shot musket. The authors of the Constitution didn’t anticipate a day when Americans would be able to purchase magazines that could hold 30 rounds.
So obviously, they didn’t include anything about magazines because they weren’t available during that time.
Open Carry Controversy
In another recent judgment from the 9th Circuit, the court ruled that the Second Amendment protects the right to openly carry a gun in public for self-defense.
This ruling stemmed from a case where Hawaiian officials violated George Young’s rights by denying him a permit to openly carry a loaded gun in public.
As you probably know, Hawaii has some of the most restrictive gun laws in the country. The state currently employs a “may issue” gun-carry law, meaning state officials may deny permits to applicants even if they’ve passed a background check and training requirements.
To put this into perspective, in 2016 and 2017, ZERO civilians were issued permits to carry a concealed weapon in Hawaii.
According to Judge Diarmuid O’Scannlain, who wrote the ruling, “For better or for worse, the Second Amendment does protect a right to carry a firearm in public for self-defense.”
The thing is I believe that both California and Hawaii will fight both of these rulings. In the end, there is a chance these cases could reach the Supreme Court.
That being said, the latest nomination for the Supreme Court, Brett Kavanaugh, has a history of ruling in favor of the Second Amendment.
Even though the 9th Circuit will probably remain a controversial court, it’s encouraging to see the judges making decisions based on the Second Amendment as it was written.


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Back to entry: melchior_ib | Show links black
(1917-2015) Danish-born actor, screenwriter and director, in the USA since World War Two, whose short story "The Racer" (October 1956 Escapade) – about car-racing as a gorily extreme spectator sport (see Games and Sports) – was adapted for Cinema as the cult classic Death Race 2000 (1975). This was in turn remade as Death Race (2008). Melchior scripted or co-scripted the mostly low-budget sf films The Angry Red Planet (1959; vt Invasion of Mars), Reptilicus (1962), Journey to the Seventh Planet (1962), Robinson Crusoe on Mars (1964), The Time Travelers (1964) and Terrore Nello Spazio (1965; vt Planet of the Vampires); of these, Angry Red Planet and Time Travelers were directed by Melchior solo, and Journey to the Seventh Planet co-directed with Sidney W Pink. Most of his work as director was however in non-genre Television. For the small screen he wrote two episodes of Men into Space (1959-1960) and one script for The Outer Limits (1963-1965): "The Premonition" (9 January 1965), which deals suspensefully with Time Distortion effects. His 1960 outline for a never-made television series to be called Space Family Robinson, which became a 1963 Comic book from Gold Key Comics, was arguably (as Melchior himself insisted) the seed of Lost in Space (1965-1968).
In 1976, the Academy of Science Fiction, Fantasy and Horror Films awarded Melchior its Golden Scroll for lifetime achievement in screenwriting. [DRL]
born Copenhagen, Denmark: 17 September 1917
died West Hollywood, Los Angeles, California: 13 March 2015
about the filmmaker
Entry from The Encyclopedia of Science Fiction (2011-current) edited by John Clute and David Langford.
Accessed 10:10 am on 3 October 2022.

domain: library


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Volkswagen on Tuesday stated it will release an entry-level JETTA brand in China in the third quarter in 2019, as a measure to grab first-time buyers in the world’s largest car market which has begin to sputter.
Car sales in China dropped for a seventh straight month in January, the country’s top auto industry association stated previously this month.
A third of the Chinese auto market is in a segment which is positioned below the core volume segment, where the Volkswagen brand is market leader, VW stated.
To grab market share in the entry-level segment, where 80 percent of clients are first-time car buyers, VW is making the JETTA brand, the automaker stated.
Chinese joint venture partner FAW Volkswagen is going to use JETTA to offer a limousine and two sports utility vehicle that can be purchased through JETTA dealerships and mobile sales trucks in shopping malls. By the end of 2019, there will be around 200 dealers providing cars under the JETTA brand, VW stated.


Bluetooth Bathroom Scale Body Fat Scales BMI Bone Weighing Smart App iOS Android
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- Connect your smartphone to the scale's Bluetooth with the capability to store multiple users' data
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automatically turn on after weighing, not automatically use after about 5-10 seconds after weighing.
- High-quality tempered glass, said gravity is strong -700 °C high temperature tempering, sturdy and durable, anti-pressure, strong wear-resistant and compressive, can weigh 180kg.
- High-elastic foot pad, non-slip wear-resistant, fit, more stable and effective to prevent rollover, safe double.


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The consequences of the widespread power outages in Texas have been beyond devastating to the state who has endured unrelenting winter weather made worse by an inferior infrastructure. Power and water outages have raged across the state last week as a result of an unusual deep freeze that has pushed many into survival mode.
Sadly, while Texas is beginning to receive relief, the Nguyen family has been faced with the unimaginable.
Jackie Pham Nguyen is the only survivor of a house fire that killed her three children and grandmother.
Nguyen was with her three children in their home in the Houston suburb of Sugar Land, Texas when the power went out at her mother Loan Le’s house. That Monday, Nguyen welcomed her mother into her home, located just five miles away, and where she and her children Olivia, 11, Edison, 8, and Colette, 5, still had power.
“We thought we were really lucky because we still had power until the early evening,” Nguyen said in an interview with CNN. After losing power just a few hours later, Nguyen says she and her family members settled down, lit their fireplace, and played board and card games. When 9:30 p.m. rolled around, everyone headed to sleep.
“Tucked my kids into bed and really the next thing I know I’m in the hospital,” Nguyen told CNN. “A few hours later the fireman and police officer came and said that no one else made it.”
Nguyen says she has little recollection of what happened but remembers being unable to get upstairs to her children’s bedrooms.
Nguyen’s room, which was located on her first floor where her bedroom is and yelled for her kids. “I was just standing there screaming and screaming and screaming their names hoping they would come out of their rooms and basically jump over so that we could get out,” she explained. “I just remember feeling like it was so dark and I can still kind of hear everything crackling around me.”
Coco, Edison and Olivia Nguyen all died in the fire.
Nguyen said she doesn’t remember much more of what happened but Doug Adolph, a spokesperson for the city of Sugar Land, told CNN that she “had to be physically restrained from running back into the house.”
According to Adolph, Nguyen’s neighborhood was without power for at least eight hours. The fire department arrived around 2 a.m. Tuesday and it took nearly an hour to get the fire fully under control.
“The family had posted on social media that they were attempting to stay warm by using a fireplace inside the home,” Adolph said, adding that the cause of the fire has not yet been determined and may never be. “We can’t say for sure that was the cause of the fire. We just don’t know yet,” he explained. “It’s possible that the investigation may never identify an exact cause.”
Nguyen suffered burns on her hands, but explained in an interview that the loss of her children and her mother is devastating
“My heart is broken,” she explained to CNN. “I’m never gonna be the same… I’m in this crisis tactical mode now and I’m just really focused on all these final arrangements because this is the last sort of thing I’m going to do for my kids.”
Speaking about her children, Nguyen describes them as having big personalities and hearts.
“My kids were such phenomenal, amazing, little badass humans,” she said of her children. “Colette is just a little firecracker and she has so much charisma… she also, as a 5-year-old, had that level of confidence. She was never afraid, totally unapologetic, not intimidated.”
“Obviously I mourn losing them,” Nguyen told CNN. “But I feel like it’s honestly a tragic loss for the world that these kids don’t get to like live up to their potential and contribute to society in the way that they could have.”
A GoFundMe page for the family has already brought in $342,387 in donations. Nguyen says she hopes to use the money to build an organization or foundation.
“I want to do something lasting for them,” Nguyen said. “I really want to be thoughtful about it because I want it to be lasting and meaningful. … I owe it to everybody’s support and their intentions to not be hasty about how those resources are used.”
It seems like Ted Cruz can’t stay away from the spotlight. On the heels of a very public* scandal, Cruz is now drumming up some more controversy for himself. But now he’s inserting himself into some pre-existing drama.
This time, Rafael Cruz decided to share his opinion on a recent dispute in the Star Wars universe. Yes, you read that right.
Ted Cruz–who has had his fair share of celebrity feuds— decided to pick a fight with Star Wars actress, Daisy Ridley.
The drama started when Cruz tweeted about the ongoing conflict between Disney and “The Mandalorian” actress, Gina Carano.
As background, Disney fired Carano from the hit show after she shared various controversial, far-right opinions on social media. Her posts included anti-mask rhetoric, Q-Anon conspiracies, and promoting false election fraud rumors. Oh, and she also compared being a conservative in Hollywood to being a Jew in Nazi Germany.
Since Carano’s firing, many conservative figures have publicly come to her defense. One of them being Ted Cruz.
Recently, Rafael tweeted out: “Texan Gina Carano broke barriers in the Star Wars universe: not a princess, not a victim, not some emotionally tortured Jedi. She played a woman who kicked ass & who girls looked up to. She was instrumental in making Star Wars fun again. Of course Disney canceled her.”
For those who aren’t well versed in the Star Wars universe, Cruz’s tweet seemed to be throwing subtle shade at the character of Rey–a female Jedi in the most recent Star Wars trilogy. Sure, you could call Rey “emotionally tortured”…or you could call her a normal person who expresses normal feelings. *Shrug*
Anyway, Daisy Ridley–the actress who played Rey–soon caught wind of the diss when an interviewer brought it to her attention.
I’m so confused why emotional depth is supposed to be a bad sign for a character?
The interviewer than asked if Ridley had any response to her character being classified as an “emotionally tortured Jedi”.At first, Ridley seemed visibly surprised that Cruz shaded her character. But she quickly regained her composure–as well as her wit.
“I am very happy to be an emotionally tortured Jedi who doesn’t leave their state when it’s having a terrible time,” she quipped.
Looks like Cruz had to learn the hard way not to mess with the Force.
So often as women, we find ourselves forced into the position of feeling as if we have to accommodate the feelings and desires of other people. We say “yes” to things when we want to actually say “no.” We smile when we feel sad or upset in order to make others feel comfortable. And more often than not we find ourselves contorting ourselves into being smaller to make others feel big.
Women on Reddit recently addressed the moment they realized they no longer had to do this in order to make others feel better.
The stories were pretty surprising! Check them out below.
“It’s become more clear as I’ve gotten older (hitting 30). Being forceful gets shit done. I don’t need people to like me, but I do need them to do their jobs. It’s worked for slumlord landlords (reporting code violations) and shitty coworkers (refusal to participate in busywork projects).
Being excessively agreeable wastes your time and costs you money. No, I’m not attending wedding or baby showers for acquaintances. No, I’m not buying whatever multilevel marketing crap acquaintances are pushing. No, I do not want to hold your baby.
It also sets you up for shitty, unsatisfying relationships. Potential partner, I am not a maid nor the fun director of the cruise ship that is your life. Handle your own shit.
“YES. I turned 30 last year and I started becoming less concerned about being “nice.” When you’re used to being agreeable and a people pleaser, it’s a tough transition, but I’m staying the course.”-
“Being agreeable and having boundaries can happen at the same time. I feel like I’m constantly evaluating the opportunity cost of saying yes/ being agreeable. Sometimes it’s really no big deal to be agreeable and it doesn’t make you a doormat. Sometimes it’s important to take a stand for yourself and speak up.”- Potential_Sea_832
“Actually when I got cancer. I just started giving no fucks about dumb shit. I cut out toxic people like it was nothing. Wanna be dramatic? Block. Wanna demand i do something for you? Block. It was so freeing and easy. No regrets at all.” –SilentSiren39
“When I was about 9 and my parents divorced, (mid 80’s so this was unheard of), my little friend group thought something was wrong with me and they decided to ostracize me. I vividly remember being on the playground and thought ‘fuck that shit’ and walked off to find new friends. From then on I give no fucks and take no shit.”- McWonderWoman
“100% agree. Honestly I think today was the first time I really truly had an authoritative vibe going on during a meeting. I’ve been at my job for almost 4 years and I’m 30 years old. When I first started, I sat in the meetings taking notes and just listening. Now I’m able to call out people on their shit while still being likable at the end of the day. I think either of the two extremes aren’t as useful as being friendly AND direct. Sad that it took me this long to feel comfortable in these shoes though!”- stripedbathmat
“I thought that I was being “nice” and “cool” and “a good friend” by never having an opinion on anything and always saying “I want to do whatever you want to do!” and “I want to eat whatever you want to eat!”
I would visit friends and I honestly thought I was being “cool” and “easygoing” by having zero plans for what to do while I’m there and making the host make all the decisions.
At some point it began to dawn on me how fucking ANNOYING it was to be around someone who goes out of their way to avoid having an opinion on things. I realized it was a defense mechanism I had built up over decades of living in a house where if you answered a question “wrong” you were harassed and taunted for the next year over it.
Once I realized that healthy, good people who ask you “Do you prefer tacos or Chinese for dinner tonight?” are ACTUALLY asking you and they are not laying in wait, ready to pounce on you and call you an piece of shit for answering the question “wrong” my life changed dramatically.
A person who has no opinion and only agrees with the group is not being “cool” and “easygoing” they are being a freaking door mat!! Probably because of some trauma or low self esteem (a mix of both for me).
Now if asked an honest question, I give an honest answer, and if someone freaks out then I realize that THEY are the one with issues, not me.”- FuckTon_of_Frosting
“For me, this moment happened when I was listening to a podcast called My Favorite Murder. Two women comedians telling stories of murder/crimes and talking about it respectfully the way you would talk to your friends. One episode they say “fuck politeness” in terms of you don’t have to be nice to strangers because you’re scared of seeming rude. It’s how a lot of women end up as victims of violent crime. Now I understand fuck politeness and it has made me so much more aware of my own self preservation and made me realize that people who react negatively to that are not people I want around me anyway. It’s been liberating and has helped my anxiety tremendously!”- Statistical-outlier1
“I’ve always been labeled as “challenging” by most people, especially teachers growing up. It’s gotten me in hot water a few times but the majority of the time, you gain respect. I stand up for myself and those around me that need it and don’t take crap. I don’t have time for toxic people or those who don’t treat me with any respect and it makes life so much easier without the drama. I still care deeply for the people in my life and make an effort to be well liked. But being a doormat doesn’t do you any favours.”- Scotty_Blues
“I never understood why i have to be agreeable to be honest… I was really bad at understanding social norms as a kid and it impacted my life in a lot of bad ways but there’s a lot of silver lining too… I realized a lot about myself and what im willing to put up with purely by Questioning things a lot, and the whole be a lady, be as small as possible, don’t be stubborn, that’s not how girls act, youll change your mind when youre older etc etc thing never made sense to me… It all seemed like it was made up to either stop me from having fun or to excuse people mistreating me (i was called stubborn a lot and i took it as a compliment every time cause it always happened when someone tried stomping a boundry for instance).
Then I grew up and realized it’s all stupid made up rules that exist to hold women down anyway. so yeah, im still dumb sometimes but at least i have enough confidence to not think misogyny is normal and i should put up with it…”- AvocadoBounty
“When it wasn’t about me. For some reason, I find it way easier to step up and say no when it was about other people. Like in college, when we were all out dancing and some creepy guy would start dancing up on me, I’d just go with it. But if a friend of mine was being creeped on, I’d cut in, tell him “no, she’s not interested” and move on. When I started work as a nurse, I realized this was even more important. I had to advocate for my patients because they can’t talk, or because I have information about the patient that the doctors making decisions didn’t. It didn’t matter if I was going against what the rest of the team or the patient’s family thought/wanted. My job was to uphold what the patient wanted.
As far as not being agreeable when it comes to myself, I’d say it was when I had a horrible breakup with my ex. He was the guy I thought I was going to marry, start a family with, and grow old together because he loved me. Turns out I was wrong. And after that, I had this horrible realization that no one (besides family) had my back…which was definitely depressing. but then I realized I could just have my own back, lol. So I started doing things that I wanted to do. I traveled to places I wanted to see. I went back to school for the degree I wanted. I invested and picked up the hobbies I wanted. and I never hesitate to spend money on myself, because fuck it. I’m worth it!”- lexi7171
“When my therapist gave me permission to hate the woman my ex completely destroyed me to be with – as long as I never actually acted on it (which I never have and never will because she didn’t do anything wrong that I can prove, I just fucking hate how her entire life has been perfect and full of money even though she’s basic af, unlike my ex or I). Hating her without reservation let me just…be. It almost gave me a sense of peace. I was never going to get closure from that donkey of an ex and the anonymous hate messages I used to get were definitely from this woman but allowing myself to stop saying “well I don’t want to hate on another woman since he’s the one who was a monster to me” and stopping giving her all these allowances let me see who he really was and how he treated me like shit compared to the way he is with her.”- FragrantEscape20

domain: sociology


text:
A new piece of legislation on Gov. Gretchen Whitmer's desk would clear records for first-time first-time operating while intoxicated (OWI) offenders.
The legislation, which has been passed by the Michigan House and Senate, is an amendment to Clean Slate Michigan, the marijuana criminal record expungement reform signed by Whitmer
The original bill package allows a person to apply to set aside one or more marijuana offenses if it would not have been a crime if committed after the 2018 recreational legalization of marijuana in Michigan. It also expands expungement eligibility for select traffic offenses and allows multiple felonies or misdemeanors from the same 24-hour period to be treated as one conviction for expungement.
“These bipartisan bills are a game-changer for people who are seeking opportunities for employment, housing, and more, and they will help ensure a clean slate for hundreds of thousands of Michiganders,” Whitmer said after signing the Clean Slate reform bills. “This is also an opportunity to grow our workforce and expand access to job training and education for so many people.”
First-time drunk driving convictions, however, were not among those convictions eligible for forgiveness.
Enter Senate Bill 1254
. Introduced by Republican state Sen. Ed McBroom, the proposed amendment would allow eligible individuals with first-time OWI convictions to apply to clear their records through the courts and would require a judge to sign off on the request. The bill was introduced to Whitmer on Dec. 21 and could take effect starting April 11, 2021.
“This is the right thing to do for people who have made a one-time mistake and earnestly want to move past it,” Republican House Speaker Lee Chatfield said in a statement earlier this month. “But this is also the right thing to do for their family, friends, and neighbors who benefit from having people back on the job and parents able to drive their kids to school all around the state.”
Currently, there are an estimated 200,000 Michiganders with OWI convictions on their records who are likely eligible for the expungement program. Michigan residents with more than one OWI, or whose drunk driving resulted in physical harm, death, serious injury, or a felony conviction, would not be expunged under the legislation.
As per the original Clean Slate legislation, expungement of select misdemeanors only affect public records and the visibility of those convictions. Courts and law enforcement will still be able to access prior OWI/DUI conviction history.
Under current Michigan law, drunken driving offenses remain on an individual's record for life.
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domain: law


New tactical vests complement Muleshoe Police Department’s safety gearwebmaster October 31, 2019 0 COMMENTS
By Gail M. Williams
Muleshoe Journal Correspondent
The Muleshoe Police Department recently purchased tactical vests that officers can wear in the event of a critical incident or response.
“We were able to purchase the vests with some cost savings found in last year’s budget,” said Muleshoe Chief of Police Gary McHone.
McHone pointed out that officers already wear body armor every day.
“This is additional protection on top of that,” he said.
At about $300 each, McHone says the department got the vests at a good price. Each individual officer will be issued one to carry in the back of the squad car.
“The vests will complement other equipment including everything in their duty belts as well as well as in their patrol vehicles, such as first aid kits and traffic cones,” McHone said.
Equipped with tactical plates front and back, the vests weigh about 30 pounds. The department plans to hold extra training sessions so that officers can get used to wearing the vests.
“It’s an additional piece to keep the officers and their community safe,” McHone said. “We’re thankful to be able to provide it. It’s better to have it and not need it than it is to not have it and need it.”


text:
Adding product to your cart
Our Nursery- Baby-Announcement -Name -Keepsake is 6". Made of 1/8th wood. Is the perfect way to say "I am here!"
Our items are left natural wood. This particular piece is engraved and 3D. The sides will be darker due to the cutting process.

domain: artistic


Stoeger Condor Supreme - need parts for safety
I got a Condor Supreme on a trade and it seemed to work pretty good for a while. It had had the safety auto-reset bar removed but didn't have any other mods to it. First time I took it out, it seemed OK but after a few rounds, I noticed the safety selector wanted to pop out. I disassembled the gun to fnd that someone had tried to install a roll pin but there was no pin. I also found the safety selector to be bent slightly not allowing it to move freely - which is why I didn't notice it at first, it would stick in place when I moved it. How do I go about getting a new safety selector and possibly the correct auto-safety linkage? I don't think I can straighten the selector without breaking it at this point.
Well, I was able to get the selector straightend out and a pin installed so it's set up like the Competition guns. Took some fitting to get it all together with what the PO had done but it's good to go now, I think. I'll take it to shoot soon and find out.


text:
Lottery is a process that is run when there is high demand for something that is limited in supply. Some examples include kindergarten placements at a reputable public school or units in a subsidized housing block. It is a system that is designed to make the process fair for everyone involved. It can also be used to dish out large cash prizes to paying participants in sports or financial games.
It is a very popular way to raise money. The first recorded lotteries were held in the Low Countries in the 15th century. These were conducted in various towns to raise funds for town fortifications, poor relief, and other community needs. The results were often in the form of articles such as dinnerware, although this was not a requirement of participation.
A large percentage of lottery revenues go to the winners, with prizes ranging from small prizes to jackpots that can be millions of dollars. Retailers receive commissions for selling tickets in general and bonuses for selling jackpot-winning tickets. The rest of the revenue is spent on administrative costs and overhead such as advertising, staff salaries, legal fees, ticket printing, and other necessities.
Lottery money can be used to help students from poor families pay for their tuition fees. This will enable them to pursue their long-term objectives. It can also be used to provide teaching tools that are useful in improving the quality of learning. In addition, this money can be used to help the homeless and address the issue of substance abuse.

domain: finance


Erlton school land will likely go back to City of Calgary
Inn from the Cold has expressed an interest, but the city gets first dibs for a dollar
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A parcel of land in Erlton that's being eyed by a women's shelter as a possible new location has a long way to go before it's available to build on.
The land is currently owned by the Calgary Board of Education (CBE), but Inn from the Cold has expressed an interest in relocating its downtown operations to the site.
That expression of interest has sparked concern from local residents.
Although there are no concrete ideas or designs as to what Inn from the Cold would like to see, residents and the community association have said the 50,000 square foot estimate means it would be too big for Erlton's area redevelopment plan (ARP).
Danny Breton, superintendent of facilities and environmental services with CBE, said they're making plans to move operations currently offered at the Erlton school location to other high schools in the area.
He said once Chinook Learning Services is out, there will be an assessment of the property and a recommendation made to elected school trustees about what can and should happen with the land.
"It's property that's zoned as special purpose community service district, so (…) it’s a designation that's for education and community uses that can accommodate a small scale of recreation facilities," he said.
Breton said they're not closing the door on holding onto the land for future CBE use, but noted that most of the city's growth is in outer parts of the city, where younger families are moving into new builds.
Breton said if the trustees and the education minister sign off on divesting of the land, the school board is legally required to offer the land to the City of Calgary for a dollar.
If they were to refuse that offer, the CBE could then put the land on the market.
Breton confirmed that in July he was approached by former city councillor John Mar, who spoke with him about Inn from the Cold's interest in the land.
"That's as far as that discussion went," said Breton. "Certainly for us, we're not even at the point where we can say that land is surplus."
Area Coun. Jeromy Farkas said there was a lot of interest and questions about the school site at Erlton Community Association's monthly meeting on Tuesday night.
"That sort of matched what we've been hearing at our office," said Farkas. "We've been fielding a lot of questions from people curious about the proposal, and what are some of the next steps."
Farkas said the discussion about what to do with the land is still in very early stages.
"At this point there is no application or even a proposal – there's just an expression of interest from Inn from the Cold, and my understanding is they haven't even drilled down into the specifics of that because it's so premature at this stage," he said.


text:
Latest research shows that decline of the brain is not inevitable. While the brain volume shrinks slightly, it continues to make new neurons and fine tune connections as long as we live. Anti-aging studies show we still can learn as we age.
The best way to reduce brain loss and deep cognitive abilities sharp is aerobic exercise, which slashes the lifetime risk of Alzheimer's disease in half and the risk of dementia by 60%.
Exercise boosts the flow of blood to the brain, releasing what's been called "Miracle-Gro for the brain" - brain derived neurotrophic factor (BDNF). This chemical stimulates the formation of new neurons in the hippocampus, the area involved in memory, learning and the ability to plan and make decisions. BDNF also repairs cell damage and strengthens the synapses which connects brain cells.
Studies over the last few years show that everyone, young or old, can increase brain power by aerobic exercising regularly. Exercising aerobically, even in late adulthood and even if you have not been active before, is not futile. Dementia is not inevitable.
Bare Skin Care has the best creams for the face. Skin care for men and women, our products are unsurpassed.

domain: biology


text:
McIntosh Properties is pleased to welcome the Original De Dutch Pannekoek House to Orchard Plaza Shopping Centre.
Like many great stories throughout history, theirs starts with a mistake. The year was 1955 and John Dys was living in the Netherlands. At some point John had a great idea. Join the army. However; shortly after joining, John wanted “out.” Luckily the Dutch army provided three convenient options: die, retire, or leave the country. Option three seemed nice. So he packed his bags and left for Canada.
While in Vancouver, John armed with an understanding of the restaurant business, opened his own place in 1970. He called it the “Frying Dutchman” and his hamburger sales became famous for predicting elections.
“Pannekoeken are served for lunch and dinner”
On a trip home to the Netherlands, his father took him to a traditional Dutch restaurant where pannekoeken are served for lunch and dinner. Not breakfast. John decided then and there he would bring the pannekoek back to Canada. And so, the first “Original Dutch Pannekoek House” opened July of 1975 on the corner of Knight Street and 25th Avenue in Vancouver. This location is still in operation today.
Timeless Breakfast Food at De Dutch
By the time the third one opened on Main Street and Terminal, John had created a unique breakfast restaurant with an emphasis on quality food. People couldn’t pronounce the “P Word,” but they sure loved to eat it. Right around this time John met Bill Waring. Soon after meeting, Bill bought a Frying Dutchman franchise in 1979.
As they grow and become a part of more neighbourhoods they never forget that our success has been built one customer at a time.
Since 1975, De Dutch has been offering our guests genuine Dutch cuisine and West Coast favourites prepared with a subtle, yet original twist! Their Mission Statement is: “We earn tomorrow’s guests today.” Join them for a meal experience that is simply de licious and simply de best!
2080a Springfield Rd.
Find More Here

domain: history


Philippe Coutinho could be in line for a possible return to the English Premier League, as Barcelona is ready to listen to offer him to Arsenal or Newcastle united.
The Brazilian spent the 2019/2020 season on loan at FC Bayern Munich, having faced limited playing time with Barcelona within his one and half year stay.
Coutinho Linked up with Barcelona in January 2018 following protracted transfer speculations and was placed with a heavy burden of replacing his compatriot Neymar Jnr at the Camp Nou.
The Ride wasn’t as successful as expected notwithstanding commanding a vibrant reputation with sparkling performances for Liverpool and Inter Milan where He spent some successful Years.
Barcelona is in the hunt for Inter’s Lautaro Martinez and would be able to fund the transfer if they could recoup some of the funds spent on Coutinho in order to balance their books.
Arsenal is seen as a worthy destination as the gunners seek attacking reinforcements while Newcastle united could attract Coutinho if they could land their potential new Mega-rich owners.
Picture credit: Twitter


text:
Ex-Real Madrid President Reveals Why Antonio Conte Will Not Be Club's Next Manager
Julen Lopetegui was sacked by Real Madrid after they were thrashed by Barcelona.
Ex-Real Madrid president reveals list of Conte's demands
Ramon Calderon feels Real Madrid will not accept Conte's demands
Julen Lopetegui was sacked by Real Madrid after loss to Barcelona
Antonio Conte was being touted as the next manager of Real Madrid well before Julen Lopetegui was sacked by the Spanish giants. However, following the Spaniard's sacking as Real Madrid manager, talk of Conte taking over has somewhat cooled with Belgium manager Roberto Martinez emerging as the surprise favourite. According to former Real Madrid president Ramon Calderon, the reason for Conte not becoming the Real Madrid manager is the Italian's list of incredible demands that are unlikely to be met by the Spanish football club.
"He's asked for three years and to come in with five people and have hands free for signings and transfers," Calderon was quoted as saying by BBC Radio 5 live's Football Daily Euro Leagues Show.
"But that's something the president (Florentino Perez) isn't willing to accept."
Calderon, who was Real president from 2006 to 2009, does not think the former Juventus and Italy boss would be a popular choice.
"I don't think Antonio Conte will be the coach the Bernabeu is expecting. He's like Jose Mourinho - a defensive coach with normally three centre-backs playing counter-attacking football.
"That's not what Real Madrid expect to see. The president tried this before with Mourinho. They didn't win the Champions League and he left the club in a bad situation."
Conte is a demanding coach, meticulous in his tactical preparation and unrelenting when it comes to defensive organisation. And this stance was what in the end cost him job at Chelsea.
Conte's excessive disciplinarian approach alienated his players and his constant tussle with the board over transfer dealings were enough to get the sack despite taking Chelsea to the Premier League title the previous season.
In all the talk regarding the next Real Madrid manager, Santiago Solari, who is currently in charge of the Spanish club, has gone under the radar. The former Castilla coach, the Real Madrid B team, came through the dress rehearsal with flying colours.
Real Madrid's stroll past Melilla from Spain's third tier in the Copa del Rey was a particularly kind opening assignment.
Already Solari is being discussed as a realistic option for longer than the 15 days that regulations allow a provisional coach to work.
With every success, and without a clear alternative, his status will be enhanced.


text: We have stayed at the Liola at least 4 times, why, because it's the best place to stay. The people there are super. The breakfast is very good. The rooms are very, very clean especially the bathroom! Great location between Rome & Naples, just off the Pontecorva exit Great value for the price. The outside grounds are beautiful!


text:
The National, Monday, May 2, 2011
THE Autonomous Bougainville Government does not pay and will not pay armed groups in Bougainville, acting President Patrick Nisira says.
Nisira stressed this after media reports last Wednesday claimed rebel Damien Koike warned the ABG to help the Me’ekamui Defence Force settle outstanding claims.
It reported Koike wanted the issues handled by the United Nations.
In a statement yesterday, the ABG “wholeheartedly welcomed UN intervention in the Konnou area”.
Another report quoted a chief from Wissai alleging that criminal activities in the Konnou constituency of South Bougainville were being funded by the ABG.
The ABG strongly denied that.
“The ABG does not believe that the barrel of the gun will solve anything in South Bougainville especially criminal groups causing instability and disunity among the peace loving people of Wisai and in the Konnou area,” Nisira said.
He said the ABG would not pay compensation for any deaths which may have occurred recently in the Konnou area as a result of violence and lawlessness.
Nisira said the ABG “is committed to the peace agreement and will ensure that peace remains a priority and will prevail to enhance the livelihood of Bougainvilleans who abide by this agreement”.
“The ABG condemns in the strongest possible term the manner in which two men had been killed by armed groups before the Easter break. These murderous acts must stop,” he said.
He said the people of Bougainville had had enough of this type of activities and were fed up of everyone found with arms on Bougainville.
“The sale of ammunition and guns to those who have the potential to derail and cause a big set-back to the peace process must stop now.
“If anyone is in this illegal trade, he is responsible for the deaths caused by guns or ammunition that he supplies,” Nisira said.
He called on the chiefs, community leaders, church groups and right thinking citizens throughout the region to respect the peace process in Bougainville.


text:
Three hundred and fifty hospital technicians, respiratory therapists, dieticians, and clerical workers began a five-day strike yesterday at a Sutter Health hospital in Antioch, California, in the San Francisco Bay Area, after voting down the company’s “last, best, and final offer.” These workers join more than 700 Kaiser Permanente stationary and biomedical engineers across 24 Northern California locations who have been on strike since September 18.
Sutter workers are fighting against understaffing and overwork during the COVID-19 pandemic, as well as below-inflation pay proposals in one of the most expensive areas in the country. Sutter’s proposal includes a 3 percent wage increase for the first three years of the contract, with a 4 percent raise in the fourth year. Inflation is currently over 5 percent, making the company’s proposal an effective pay cut. Contract highlights provided by Sutter to the media do not mention any increases in staffing to reduce workloads, workers’ primary demand.
Kaiser Permanente is offering only a 2 percent wage increase, supplemented with bonuses that will not accrue into base pay, and is similarly demanding that its existing engineers make up for staffing shortfalls. Stationary engineers and biomedical engineers service and maintain the hospital’s mechanical systems including heating, air-conditioning and ventilation equipment, boilers, electrical and emergency generators, and the hospital’s medical equipment. Kaiser’s proposal would allow the company to force workers to travel to other counties to work on other Kaiser medical buildings, further allowing the company to cut personnel and costs.
In both cases, the union gave management ample warning to allow it to hire scabs, which have been brought in in both cases. The SEIU gave Sutter 10 days’ notice. In an October 1 announcement, Kaiser stated that it has made “extensive preparations” to minimize the impact of an engineers’ strike by bringing in scabs from Kaiser Permanente facilities across the country and supplementing with contracted “equipment specialists.” Continued operation of the hospital would not be possible if the nurses’ unions and other health care unions were not ordering their members to cross the picket lines. Thus, all health care unions involved are conspiring with the companies to ensure the strike has as little effect as possible on the hospital’s operations.
Health care unions have a long history of utilizing isolated stunt strikes to wear down militant workers and force through pro-company contracts. Such was the case with the Sutter nurses’ struggle of 2011–2013, which began with a one-day strike by 23,000 workers in February 2011. By November 2012, the California Nurses Association had already forced through a sellout contract at most locations, calling out only 3,200 nurses in a one-day strike at seven Northern California Sutter Health facilities. Each time, the union gave the company advance notice to ensure it could acquire the necessary scabs, sometimes for periods substantially longer than the actual duration of the strike. In May 2013, 3,100 remaining nurses were called out for a weeklong strike before ultimately accepting the concessions demanded by the company.
Today, the SEIU has already pushed through the Sutter contract for over 3,000 other workers, leaving the Antioch workers isolated.
Health care workers must not let their struggle be left in the hands of the SEIU and the IUOE, run by well-paid, pro-company bureaucrats that run them. They must adopt a new strategy to break out of the unions’ stranglehold, based on mobilizing the independent strength of the working class as a whole.
Powerful battalions of health care workers are entering into struggle after fighting for a year and a half on the front lines against COVID-19 without adequate support. Twenty-four thousand California Kaiser Permanente workers in the United Nurses Associations of California/Union of HealthCare Professionals union, including nurses, pharmacists, rehab therapists, midwives and optometrists, will vote on strike authorization this week. Additionally, roughly 3,400 nurses and other health care workers at Kaiser Permanente in Oregon, under the Oregon Federation of Nurses and Health Professionals (OFNHP), could vote to strike as soon as next week.
Elsewhere in the country, more than 2,000 nurses and other health care workers struck Friday in Buffalo, New York, joining Worcester, Massachusetts, nurses, who have been on strike for more than 28 weeks in their fight for safe staffing.
Health care workers are confronted with the need to unify and coordinate their struggles on a national scale, something the unions are doing everything possible to prevent. In response, Sutter Health and Kaiser Permanente health care workers must follow the example of autoworkers at Volvo and Dana and form democratically controlled rank-and-file committees, completely independent of the pro-company trade unions, to fight for their demands and build up lines of communication with other workers. These demands should include increases in staffing, substantial raises, no cuts to benefits, and full provision of necessary personal protective equipment.
These committees should make appeals to other health care workers, at their workplaces, in other health care systems in Northern California, and to their brothers and sisters across the country and internationally.
Such appeals will get a response. In Oakland, California, waste management employees refused to cross the picket line at at least one Kaiser facility. If nurses or doctors did the same, the multibillion-dollar “non-profit” health care companies would be brought to their knees.
Health care workers should make appeals to workers in other sectors, including and especially educators. The current policy of Democrats and Republicans alike is to force open schools and businesses, resulting in mass infection of the population and forcing health care workers and educators to conduct damage control.
In opposition to the Democrats and Republicans, the Socialist Equality Party calls for an eradication strategy to fight the COVID-19 pandemic. With a lockdown of just two months, transmission could be brought down to traceable levels that could be identified and quarantined with sufficient surveillance testing.
The World Socialist Web Site stands ready to assist workers in building rank-and-file committees. For more information, visit wsws.org/workers.