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Caputo, Francis J.; Rupani, Bobby; Watkins, Anthony C.; Barlos, Dimitrios; Vega, Dennis; Senthil, Maheswari; Deitch, Edwin A.

doi: 10.1097/shk.0b013e31804858f2
Basic Science Aspects

ABSTRACT: The studies of the mechanisms by which trauma-hemorrhagic shock leads to gut injury and dysfunction have largely ignored the nonbacterial factors contained within the lumen of the intestine. Yet, there is increasing evidence suggesting that intraluminal pancreatic proteases may be involved in this process. Thus, we tested the hypothesis that pancreatic proteases are necessary for the trauma-hemorrhagic shock-induced gut injury and the production of biologically active mesenteric lymph by determining the extent to which pancreatic duct ligation (PDL) would limit gut injury and mesenteric lymph bioactivity. To assess the effect of PDL on gut injury and dysfunction gut morphology, the mucus layer structure and the gut permeability were measured in the following four groups of male rats subjected to laparotomy (trauma) and hemorrhagic shock (pressure, 30 mmHg for 90 min): (1) rats subjected to trauma plus sham-shock (T/SS), (2) T/SS rats undergoing PDL (T/SS + PDL), (3) rats subjected to trauma and hemorrhagic shock (T/HS), and (4) rats subjected to T/HS + PDL. The ability of mesenteric lymph from these four rat groups to kill endothelial cells and activate neutrophils was tested in vitro. The PDL did not affect any of the parameters studied because there were no differences between the T/SS and the T/SS + PDL groups. However, PDL protected the gut from injury and dysfunction because PDL significantly abrogated T/HS-induced mucosal villous injury, loss of the intestinal mucus layer, and gut permeability. Likewise, PDL totally reversed the endothelial cell cytotoxic activity of T/HS lymph and reduced the ability of T/HS lymph to prime naive neutrophils for an augmented respiratory burst. Thus, it seems that intraluminal pancreatic proteases are necessary for the T/HS-induced gut injury and the production of bioactive mesenteric lymph.

Department of Surgery, New Jersey Medical School, Newark, New Jersey

Address reprint requests to Edwin A. Deitch, MD, Professor and Chairman, Department of Surgery, MSB G506, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07013. E-mail:

This study was supported by the National Institutes of Health (grant GM059841 [E.A.D.]) and grant T32GM069330 (E.A.D.).

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The loss of gut barrier function during trauma and hemorrhagic shock (T/HS) has been implicated as a major contributor to the development of distant organ injury and subsequent multiple-organ dysfunction syndrome (MODS) (1). This process of gut barrier failure-induced MODS seems to occur when the inflammatory mediators and the "toxic" factors generated in the ischemic/reperfused gut and contained in mesenteric lymph reach the systemic circulation and the distant organs (2). Although not fully characterized, the T/HS mesenteric lymph has been shown to have a wide array of detrimental biologic effects, including the induction of endothelial cell death and dysfunction, decreased red blood cell deformability, and neutrophil activation (3-5). Although our knowledge on the effects of the gut on distant organ injury after T/HS has increased during the last few years, the exact mechanisms and factors involved in the pathogenesis of gut barrier failure and the generation of biologically active T/HS mesenteric lymph remain to be fully elucidated. Although the shock-induced decreases in splanchnic blood flow resulting in a gut ischemia-reperfusion injury seems a necessary component of this process, our recent work and the work of other investigators suggest that intraluminal pancreatic serine proteases are also necessary components in the pathogenesis of gut-induced MODS (6-8). However, the mechanisms by which intraluminal pancreatic proteases contribute to gut injury and gut-induced MODS are unknown. Based on work indicating that the unstirred mucus layer is an important component of the gut barrier and that the mucus layer is damaged after T/HS (9-11), we investigated the hypothesis that pancreatic proteases contribute to gut injury and the production of biologically active T/HS mesenteric lymph, at least in part, by disrupting the mucus layer of the gut, thereby promoting the translocation of gut luminal contents, which, in turn, exacerbates gut injury and inflammation. If this hypothesis is true, then neutralization or elimination of pancreatic proteases from the gut lumen would preserve the mucus layer and thereby decrease the T/HS-induced gut permeability and the production of toxic mesenteric lymph. Consequently, the effect of pancreatic duct ligation (PDL) on T/HS-induced gut barrier function and on the production of biologically active mesenteric lymph was tested.

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Male Sprague Dawley rats weighing 300 to 450 g were housed under barrier-sustained conditions kept at a temperature of 25°C with 12-h light/dark cycle. The rats had free access to water and chow (Teklan 22/5 Rodent Diet W-8640; Harlan Teklad, Madison, Wis) for at least 5 days before the study. All rats were maintained in accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals. All animal protocols were approved by the New Jersey Medical School Animal Care Committee.

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Experimental design

The major goal of this study was to test the hypothesis that the pancreatic digestive enzymes produced during T/HS contribute to the increased gut permeability and to the production of biologically active mesenteric lymph and is associated with the disruption of the mucus layer. To accomplish this goal, we measured the effect of PDL before T/HS on the mucus layer of the gut, gut permeability, and biologic activity of lymph. Gut permeability was measured using both in vivo and ex vivo methodologies. The rats were divided into four groups: (1) trauma-sham shock (T/SS), (2) T/HS, (3) T/SS + PDL, and (4) T/HS + PDL. In the PDL groups, the pancreatic duct was ligated just before subjecting the rats to T/SS or T/HS. In addition, all the animals underwent cannulation of the main mesenteric lymph duct for mesenteric lymph collection before the induction of T/SS or T/HS.

In the T/HS groups, the rats underwent laparotomy followed by 90 min of hemorrhagic shock, after which they were resuscitated with their shed blood, as previously described (12). The T/SS groups had their vessels and mesenteric lymph duct cannulated and underwent a laparotomy, but they were not subjected to hemorrhagic shock. At 3 h after the end of the 90-min shock or sham-shock period and volume resuscitation, in vivo gut permeability was measured by placing the 4-kd fluorescent-labeled Dextran (FD-4) permeability probe into a segment of the gut. Subsequently, the animals were killed and the ileal samples were obtained for morphometric mucus analysis and gut histology and for assessment of ex vivo gut permeability using the everted gut sac methodology. The 3-h time point was selected on the basis of our previous T/HS studies, which showed maximum mucus disruption at this time point (9). In addition, all of the PDL rats had a biliary drain placed to optimize the permeability assay because the absorption spectra of FD-4 and bile overlap.

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Surgical procedures

The rats were weighed and anesthetized with i.p. sodium pentobarbital (dose, 50 mg/kg). Using aseptic techniques, the internal jugular vein and femoral artery were isolated and cannulated with polyethylene (PE-50) tubing or 50-gauge silicone catheter containing 0.1 mL heparinized saline solution (concentration, 10 units/mL), respectively. Both catheters (internal jugular vein and femoral artery) remained in situ for the duration of the experiment. Next, a 3-cm midline laparotomy (trauma) was performed, followed by the cannulation of the mesenteric lymph duct and by either ligation or sham ligation of the pancreatic duct, after which the abdomen was closed with a running 3-0 silk suture. The mesenteric lymph duct was cannulated as previously described (3). The main pancreatic duct, which also drains the extrahepatic bile ducts, was identified in the mesentery of the duodenum and ligated with a 4-0 silk suture. Next, the bile duct proximal to the ligated pancreatic duct was identified and a polyethylene (PE-10) tubing was placed in the duct and secured with a 4-0 silk suture. The total amount of bile drained during the experimental period averaged 4 to 5 mL.

After the closure of the abdomen, the femoral artery catheter was attached in line to a blood pressure monitor (BP-2 digital blood pressure monitor; Columbus Instruments, Columbus, OH) for continuous blood pressure monitoring. Blood was then withdrawn from the internal jugular vein and the mean arterial pressure was maintained at 30 to 35 mmHg for 90 min by withdrawing or infusing the shed blood. At the end of the shock period, the animals were resuscitated by reinfusing all the shed blood at a rate of 1 mL/min. The mean arterial pressure returned to normal level within a few minutes after the animals received their blood back and remained at that level for the duration of the experiment.

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Measurement of ex vivo intestinal mucosal permeability

Intestinal ileal permeability was measured ex vivo using the everted gut sac method and the fluorescent tracer fluorescein isothiocyanate Dextran (molecular weight, 4 kd; FD-4), as described by Wattanasirichaigoon et al. (13). The ileal everted gut sacs were prepared in ice-cold modified Krebs-Henseleit bicarbonate buffer (KHBB; pH value, 7.4). One end of the gut segment was ligated with a 4-0 silk suture. The intestinal segment was then everted using a thin metal rod and secured to the grooved tip of a plastic syringe (capacity, 5 mL) containing KHBB by using a 4-0 silk tie. The everted gut sac was then distended gently by injecting 0.5 mL of KHBB. The gut sac was suspended in a beaker (capacity, 100 mL) containing 80 mL of KHBB to which FD-4 (concentration, 20 mg/mL) was added. The temperature of the solution in the beaker was maintained at 37°C using a water bath and was continuously oxygenated with a gas mixture containing 95% O2 and 5% CO2. A 1.0-mL sample was taken from the beaker before placing the everted gut sac to determine the initial external (mucosal surface) FD-4 concentration. The everted gut sacs were incubated for 30 min in the KHBB solution containing FD-4; then, the length and the volume of each gut sac was measured. The fluid inside the gut sac (serosal side) was aspirated into the syringe to determine the FD-4 concentration. The serosal and the mucosal samples were centrifuged for 10 min at an acceleration of 1,000 g and a temperature of 4°C, after which 100 μL of each sample was diluted with phosphate-buffered saline solution (volume, 900 μL). Fluorescence was measured by using a Perkin-Elmer LS-50 fluorescence spectrophotometer (Palo Alto, Calif) at an excitation wavelength of 492 nm (slit width, 510 nm) and an emission wavelength of 515 nm (slit width, 510 nm). Permeability was expressed as the mucosal-to-serosal clearance of FD-4 using the following equations:

where M is the mass (in nanograms) of FD-4 in the gut sac at the end of the 30-min incubation period; [FD4]serosal is the FD-4 concentration in the serosal fluid aspirated from the sac at the end of the 30-min incubation period; F is the flux of FD-4 (in nanograms per minute) across the mucosa; [FD4]mucosal is the FD-4 concentration measured in the beaker at the beginning of the 30-min incubation period; A = Π ld, which is the calculated area (in square centimeters) of the mucosal surface; and C is the clearance of FD-4 (in nanoliters per minute per square centimeter) across the mucosa (13).

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In vivo gut permeability

Ileal permeability was measured in vivo using FD-4 (Sigma, St. Louis, Mo) as follows: After the 3-h reperfusion period was complete, a repeat laparotomy was performed through the previous laparotomy incision. A loop of ileum was ligated 3 cm from the ileocecal valve; then, 20 cm of ileum was measured in a retrograde manner. At this point, the ileum was also ligated. Just distal to the proximal suture, an enterotomy was performed and the intestinal loop was flushed with 1 mL of isotonic sodium chloride solution, after which the enterotomy incision was closed. One milliliter of FD-4 (concentration, 25 mg/mL in 0.1 M phosphate-buffered saline solution; pH value, 7.2) was injected in a retrograde fashion into the lumen of the isolated bowel segment, then the bowel was returned into the abdomen. The abdominal incision was closed using 4-0 silk suture. After 30 min, a portal vein blood sample was collected. The blood sample was then centrifuged at an acceleration of 3000g and a temperature of 4°C for 10 min. The blood sample, along with the FD-4 standards, was analyzed in a BioTek Instruments FLx800 microplate fluorescence reader at an excitation of 485/20 and an emission of 528/20. Gut permeability is expressed as the amount of FD-4 found in portal vein plasma in micrograms per milliliter ± SD (14).

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Villous injury

After killing the rats, a segment of the terminal ileum was excised and fixed in 10% buffered formalin. After processing, semithin (thickness, 2-4 μm) sections were cut and stained with toluidine blue. Five random fields with 100 to 250 villi from each animal were then analyzed in a blinded fashion using light microscopy at ×100 magnification as previously described (15). The overall incidence of villous damage was examined in a blinded fashion and expressed as a percentage of the number of injured villi to the total number of villi examined. To deem a villus injured, there must be a microscopic evidence of injury. This injury ranges from the submucosal edema at the villous tip to the frank necrosis of the villus.

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Ileal mucus thickness, appearance, and adherence

At the time of killing, a segment of the ileum was ligated with 4-0 silk tie distally at the terminal ileum. Then, while gently distending the ileum with 0.9% isotonic sodium chloride solution, a more proximal tie was placed, preventing the contact of adjacent walls. Next, the ileal specimen was snap-frozen in liquid nitrogen. Serial cryostat sections (thickness, 15-20 μm) of the ileum were stained using the modified periodic acid-Schiff-Alcian blue staining technique as described by Jordan et al. (16). The mucus thickness (original magnification, ×200), the percentage of mucus coverage of the ileal surface, and the qualitative changes (adherent versus loosely adherent to the mucosal surface) in the mucus layer were measured in a blinded fashion.

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Mesenteric lymph analysis

The mesenteric lymph collected at each time point was centrifuged (acceleration, 500g for 20 min at 4°C) to remove all cellular elements and obtain humoral cell-free lymph, after which the lymph samples were frozen at a temperature of −80°C.

The cytotoxic activity of the mesenteric lymph samples was tested on human umbilical vein endothelial cells (HUVECs; BioWhittaker, Walkersville, MD) using a mitochondrial cell viability assay (MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]; Sigma). In this assay, the HUVECs were seeded (distribution, 2 × 104 cells/well) on a 96-well tissue culture plate (Falcon) and grown to confluence at 37°C/5% CO2 in endothelial cell basal media (BioWhittaker). The media was supplemented with fetal bovine serum, bovine brain extract, heparin, endothelial cell growth medium, l-glutamine, hydrocortisol, and antibiotic-antimycotic solution (gentamicin and amphotericin B) as per the manufacturer's instructions. Only cells of low passage (3-5) were used for the assays. Toxicity was determined by incubating the cells with media and whole lymph (5% vol/vol) in a final volume of 100 μL. Cells incubated with media alone served as a negative control. After an 18-h incubation, the supernatant was removed and replaced with 90 μL of basal media (without phenol red) and 10 μL of MTT (5 mg/mL). The cells were then incubated for an additional 3 h. The fomazan crystals produced by viable cells were then solubilized as per the manufacturer's instructions. The plates were analyzed at a wavelength of 570 nm, and viability was calculated as a percentage of the cells incubated with media alone (3).

To determine the neutrophil-activating ability of the mesenteric lymph samples, heparinized whole blood samples (volume, 100 μL) were incubated with an equal volume of medium, after which the red blood cells were lysed. The white blood cell pellets were washed twice and then resuspended in 400 μL of Hanks medium. The lymph samples (final concentration, 5%) were then added and the tubes were placed in an incubator for 5 min, after which dihydrorhodamine (concentration, 15 ng/mL) was added to the tubes. Five minutes after the dihydrorhodamine was added, the polymorphonuclear neutrophils (PMNs) were stimulated with phorbol myristate acetate (concentration, 90 ng/mL). After 15 min at a temperature of 37°C, the PMN respiratory burst was measured by means of flow cytometry, as previously described (17).

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Statistical analysis

The results are expressed as mean ± SD. Continuous data was analyzed by means of one-way analysis of variance using the post hoc Tukey-Kramer test. Pairs of data were analyzed using a paired t test. Statistical significance was considered achieved at P < 0.05.

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As previously reported (8), T/HS was associated with a significant increase in villous injury as compared with the T/SS rats (Table 1). The ligation of the pancreatic duct did not seem to promote injury because the incidence of villous injury was similar between the T/SS and the T/SS + PDL groups (Table 1). In fact, although PDL did not completely prevent T/HS-induced villous injury, it did reduce the incidence of T/HS-induced villous injury by approximately 50% (P < 0.01). As shown in Figure 2, PDL essentially totally abrogated the T/HS-induced increases in gut permeability, whether measured by in vivo or ex vivo assays. Thus, PDL was more effective in preventing T/HS-induced changes in gut permeability than in preventing villous injury.

As hypothesized, the beneficial effects of PDL on T/HS-induced gut injury and dysfunction were associated with the preservation of the intestinal mucus layer (Fig. 1). Specifically, PDL totally prevented T/HS-induced mucus loss, whether measured as mucus thickness or as the percentage of the intestinal lumen covered with mucus. This ability of PDL to preserve the mucus layer after T/HS is readily apparent on the histological sections of the ileum (Fig. 1C).

As expected, the mesenteric lymph from the rats subjected to T/SS was not cytotoxic, whereas the T/HS lymph manifested significant endothelial cell cytotoxic activity, with only 11.2% of the HUVEC remaining alive after an 18-h incubation period (Fig. 3). In contrast, the mesenteric lymph collected from the T/HS rats subjected to PDL was not cytotoxic, and its endothelial cell cytotoxic biologic activity was similar to the T/SS rats (Fig. 3). Likewise, as compared with T/SS lymph, the mesenteric lymph collected after T/HS primed normal PMNs for an augmented respiratory burst. This PMN-priming ability of T/HS lymph was significantly abrogated by PDL (Table 2).

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The process of shock-induced splanchnic ischemia leading to gut and subsequent gut-induced distant organ injury has been implicated in the pathogenesis of systemic inflammatory response syndrome, acute respiratory distress syndrome, and MODS, and has thus been a major area of investigation (18, 19). However, the exact mechanisms by which the gut becomes injured and contributes to systemic inflammation and organ injury during shock and stress states remain to be fully clarified. The process of gut-origin sepsis can be divided into two major steps: the first is gut injury and the second is the generation/release of gut-derived factors that cause the adverse systemic consequences. Although the role of splanchnic ischemia and the systemic immunoinflammatory systems in the pathogenesis of gut injury have been extensively studied, the nonbacterial luminal side of the gut has been relatively ignored. However, there is evidence to suggest that nonbacterial factors on the luminal side of the gut may be important modulators of gut injury during shock states, with two of these being the intraluminal pancreatic proteases and the unstirred mucus layer. In this study, we tested the hypothesis that pancreatic proteases produced during T/HS contribute to increased gut permeability and to the production of biologically active mesenteric lymph and that this process is associated with disruption of the mucus layer. Our results, showing the abrogation by PDL of the T/HS-induced gut mucosal injury, the disruption of the mucus layer and loss of barrier function, and the prevention of the production of biologically active mesenteric lymph, support the notion that intraluminal pancreatic proteases are key components in the pathogenesis of gut injury/dysfunction, gut-origin distant inflammation, and tissue injury.

The concept that the pancreas plays an important pathological role in the development of organ failure observed after hemorrhagic or traumatic shock was initially proposed approximately 30 years ago (20-22). More recently, Kistler et al. (23) and Mitsuoka et al. (24), using a rat splanchnic arterial ischemia model, provided evidence that the pancreatic enzymes acting on the ischemic intestine are responsible for the production of factors leading to hypotension, neutrophil activation, and pulmonary injury. Since then, the results from them and from our laboratory have documented that the administration of serine protease inhibitors into the lumen of the gut decreases both lung and gut injury and neutrophil activation (7, 25, 26). Nevertheless, the exact mechanisms by which the pancreatic proteases interact with the ischemic gut to result in the generation of biologically active factors that contribute to gut and lung injury remain to be determined. Under normal conditions, the intact intestinal mucosal barrier prevents the pancreatic proteases within the intestinal lumen from reaching the submucosal space, where they could exert their enzymatic activities, whereas during the periods of gut ischemia, the gut barrier function fails and the intestinal permeability is increased (19). Thus, one possible explanation is that after a period of ischemia-reperfusion, the intestinal protective barrier is weakened, allowing the pancreatic proteases to exert their effect on or within the wall of the intestine. These observations would suggest that there are two distinct processes occurring simultaneously that contribute to gut injury during shock states, one systemically and the other at the luminal surface of the gut.

On the basis of our results and a review of the literature, we think that injury to the mucus layer (Fig. 4) is a critical link in the pathogenesis of T/HS-induced gut injury and the locus where the systemic factors leading to gut injury interact with intraluminal pancreatic proteases. This concept is supported by studies showing that the mucus layer is an important protective barrier in the stomach where stress- or ischemia-related loss of the gastric mucus layer contributes to gastric mucosal injury caused by intraluminal acid (27, 28). Furthermore, the mucus layer seems to function also as a physical and chemical barrier that prevents luminal bacteria, toxins, and other factors, such as digestive enzymes, within the intestine from getting into contact with the intestinal epithelium (10). In fact, our recent studies showing that T/HS was associated with the loss of the mucus layer and that the changes in the mucus layer correlated with increased gut permeability after T/HS support the concept that the mucus layer is an important component of the gut barrier that is lost after T/HS (9). Furthermore, the results of the current study documenting that PDL prevents T/HS-induced mucus layer disruption implicate the pancreatic proteases in this process. Although the mechanisms by which T/HS and luminal pancreatic proteases contribute to the disruption of the mucus layer remain to be fully determined, several facts are known. First, it has been reported that under conditions of oxidant stress, the mucins lose their viscoelastic properties, reducing their barrier properties (29), and that the lysosomes of exfoliated epithelial cells can degrade mucus (30). Because the conditions associated with intestinal ischemia are associated with oxidant production and enterocyte exfoliation, these processes might contribute to T/HS-induced injury to the mucus layer. Furthermore, it has been reported that the ability of pancreatic enzymes to cleave and degrade mucins in vivo is significantly augmented when the mucins have been chemically modified, as may occur under conditions of oxidant stress (30, 31). On the basis of this information, our working hypothesis for the mechanisms by which T/HS increases gut permeability is as follows: The T/HS induces a gut ischemia-reperfusion injury, which, in turn, causes an oxidant-mediated injury to the mucus layer, which by itself is not sufficient to completely disrupt the mucus layer. However, the subsequently chemically modified mucus loses enough of its hydrophobic and other normal properties to allow further mucin degradation by the intraluminal, water-soluble pancreatic proteases.

On the basis of our results showing that PDL abrogated the ability of T/HS to induce the production of biologically active mesenteric lymph, it seems that pancreatic enzymes are also involved in this process. The extent to which pancreatic enzymes are directly or indirectly involved in the production of the biologically active factors in T/HS lymph that injure endothelial cells and activate neutrophils cannot be determined from this study (i.e., it is not possible to determine whether it is the ability of the pancreatic enzymes to potentiate gut injury that is important in the production of biologically active T/HS lymph or whether the pancreatic enzymes, through their enzymatic activity, are involved directly in the production of these lymph factors). On the other hand, these PDL studies do suggest that the T/HS-induced gut ischemia-reperfusion insult, in the absence of pancreatic enzymes, is not sufficient by itself to generate the biologically active factors contained in mesenteric lymph.

In conclusion, the current study supports the notion that the pathogenesis of gut ischemia-reperfusion-mediated injury involves luminal pancreatic proteases. Although the mechanisms by which the ischemic gut becomes susceptible to pancreatic enzymatic injury will require further study, it seems that the loss of the mucus layer is likely to be involved. In addition, these studies indicate that the components acting on the luminal and on the systemic side of the gut are important in the pathogenesis of gut barrier failure and gut-origin sepsis.

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Bacterial translocation; ischemia-reperfusion; multiple-organ dysfunction syndrome; unstirred mucus layer; villous injury

©2007The Shock Society