Differential effects of sertraline in a predator exposure animal model of post-traumatic stress disorder.

Serotonin (5-HT), norepinephrine (NE), and other neurotransmitters are modulated in post-traumatic stress disorder (PTSD). In addition, pro-inflammatory cytokines (PIC) are elevated during the progression of the disorder. Currently, the only approved pharmacologic treatments for PTSD are the selective-serotonin reuptake inhibitors (SSRI) sertraline and paroxetine, but their efficacy in treating PTSD is marginal at best. In combat-related PTSD, SSRIs are of limited effectiveness. Thus, this study sought to analyze the effects of the SSRI sertraline on inflammation and neurotransmitter modulation via a predator exposure/psychosocial stress animal model of PTSD. We hypothesized that sertraline would diminish inflammatory components and increase 5-HT but might also affect levels of other neurotransmitters, particularly NE. PTSD-like effects were induced in male Sprague-Dawley rats (n = 6/group × 4 groups). The rats were secured in Plexiglas cylinders and placed in a cage with a cat for 1 h on days 1 and 11 of a 31-day stress regimen. PTSD rats were also subjected to psychosocial stress via daily cage cohort changes. At the conclusion of the stress regimen, treatment group animals were injected intraperitoneally (i.p.) with sertraline HCl at 10 mg/kg for 7 consecutive days, while controls received i.p. vehicle. The animals were subsequently sacrificed on day 8. Sertraline attenuated inflammatory markers and normalized 5-HT levels in the central nervous system (CNS). In contrast, sertraline produced elevations in NE in the CNS and systemic circulation of SSRI treated PTSD and control groups. This increase in NE suggests SSRIs produce a heightened noradrenergic response, which might elevate anxiety in a clinical setting.

Functional comparison of staple line reinforcements in lung resection.

PURPOSE: Staple line reinforcement with bovine pericardium and expanded polytetrafluoroethylene during lung resections has shown reduction in air leak incidence and duration. Small intestinal submucosa and polyglycolic acid-trimethylene carbonate, have been introduced as new reinforcements for nonpulmonary staple lines. We hypothesize that reinforcement of staple lines in lungs with commercially available materials will decrease staple line leak at increased pressures. DESCRIPTION: We evaluated 8 staple lines per reinforcement material (4 groups) and a control group (n = 40) in healthy living pigs. After resections (up to four per animal), the lungs were tested sequentially using hand ventilation to increasing pressures (5-75 cm H2O). The occurrence of pressure at which leaks was recorded. EVALUATION: All reinforced staple lines exhibited higher mean leak threshold when compared with the controls; however only small intestinal submucosa achieved significance when compared with the controls. CONCLUSIONS: Commercially available reinforcements allow pulmonary staple lines to tolerate higher intrabronchial pressures without demonstrating air leak. In addition, reinforcement with small intestinal submucosa imparts a significant advantage to the other reinforcements in terms of pulmonary staple line leak rate.

Functional assessment of a new staple line reinforcement in lung resection.

BACKGROUND: A major complication of lung resection is prolonged leaking at the staple line. Staple-line reinforcement is performed routinely during these procedures using bovine pericardium (peri-strips) and expanded polytetrafluorethylene. Both materials have been shown previously to increase staple-line durability and reduce the overall incidence of prolonged air leaking after lung resection, specifically in lung volume-reduction surgery. Small intestinal submucosa (SIS) has had many applications in human tissues consequent to its absorption and healing profile, which are well documented in human and animal models. However, it had not been studied in reinforcement of pulmonary staple lines. MATERIALS AND METHODS: We hypothesized that SIS reinforcement of staple lines in healthy lung tissue would increase durability, as determined by leak rates at increased airway pressures as compared to nonreinforced staple lines. Eight healthy juvenile Yorkshire-cross pigs were subjected to bilateral apical lung resections; one side was reinforced with SIS. The lungs were then inflated to sequentially increase intrabronchial pressures (5-75 cm H2O) for 60-second intervals while the chest was filled with saline under direct visualization monitoring for air leak. RESULTS: Staple lines reinforced with porcine small intestinal submucosa had significantly better durability as determined by Kaplan-Meier survival calculations with respect to leak rate as a function of pressure. CONCLUSION: Reinforcement of staple lines with SIS allows pulmonary staple lines to tolerate significantly higher intrabronchial pressures without demonstrating air leak at the staple line.

Increased burst pressure in gastrointestinal staple-lines using reinforcement with a bioprosthetic material.

BACKGROUND: Leakage at an anastomosis is a major and often catastrophic complication of gastrointestinal (GI) surgery. Staple-line reinforcement with one of the several materials commercially available has been utilized to reduce the incidence of this complication. The bioprosthetic material, small intestinal submucosa (SIS, Surgisis((R)); Cook, Inc., Bloomington, IN) has found widespread applications in surgery. However, its ability to improve the durability of staple-lines in GI surgery in terms of burst pressure has not been documented. We hypothesized that SIS reinforcement of staple-lines in healthy living GI tissue would increase durability, as determined by leak rates at increased intraluminal pressures, compared to unreinforced staple-lines. METHODS: Two healthy Yorkshire-Cross pigs were subjected to midline laparotomy and underwent small intestinal division (n=28) with GIA stapling devices. Half of the staple-lines were reinforced with SIS. The staple-lines were then exposed to increased intraluminal pressures by means of a constant-rate dye solution infusion, until staple-lines exhibited visible leakage of the dye solution. The intraluminal pressure was recorded at the time of visible leakage. RESULTS: Staple-lines reinforced with SIS had significantly better durability as determined by analysis of variance and Kaplan-Meier survival calculations, with respect to leak rate as a function of intraluminal pressure (P<0.003). The mean burst pressure of the unreinforced staple-lines was 53 mmHg, while those staple-lines reinforced with SIS had a mean burst pressure of 83 mmHg. CONCLUSION: Reinforcement of stapled GI anastomoses with SIS significantly increases anastomotic burst pressure. These findings suggest a role for this material in GI surgery.

The effects of intraoperative fenoldopam on renal blood flow and tubular function following suprarenal aortic cross-clamping.

This study evaluated the effect of fenoldopam, a selective dopamine (DA1) agonist, on renal blood flow and renal tubular function following renal ischemia induced by suprarenal aortic cross-clamping. Twenty anesthetized research pigs received either fenoldopam (10 micro g/kg/min; n = 10) or saline ( n = 10) beginning 20 min before suprarenal aortic cross-clamping and continuing for 20 min after clamp release, for a total infusion time of 160 min (120-min cross-clamp). Recordings of renal blood flow, mean arterial pressure, and heart rate were taken at baseline, during cross-clamping, and immediately postclamp. Ischemic renal injury was evaluated by serum creatinine and by histologic grading of acute tubular necrosis. Treatment with fenoldopam increased renal blood flow in comparison to that in the control group ( p = 0.03). The mean creatinine increase from baseline at 6 hr and 18 hr after cross-clamp removal for the fenoldopam-treated group was significantly less than that in the control group ( p < 0.001). On histologic evaluation, the mean score for the degree of tubular necrosis was significantly higher in the control group ( p = 0.02), indicating less derangement of tubular morphology in the fenoldopam group. This study demonstrated that the intraoperative use of a continuous infusion of fenoldopam during suprarenal aortic cross-clamping results in increased renal blood flow, less postoperative rise in creatinine, and better preservation of tubular histology in the pig model.

Variable susceptibility of the owl monkey (Aotus nancymae) to four serotypes of dengue virus.

The goal of this study was to determine, for each of four dengue serotypes, whether owl monkeys (Aotus nancymae) become viremic and develop antibody responses in patterns similar to those seen in humans and whether any behavioral parameters are reliably associated with immunologic responses. A secondary goal was to investigate effects of chronic blood sampling on hematologic parameters in this genus. We inoculated 20 owl monkeys with 2 x 10(4) plaque-forming units of one of four dengue serotypes. Blood samples ranging from 0.4 to 0.7 ml per animal were taken each day for 12 consecutive days after inoculation, as well as on days 21, 28, and 60 post-inoculation. The total amount of blood taken per monkey was 8.0 ml during the first 12 days and 9.5 ml during the first 30 days of the study (i.e., up to 17% total blood volume per week and up to 20% total blood volume per month). Detailed behavioral assessments of all animals were made twice daily on every day of sample collection. The dengue-1 group were viremic for an average of 3.75 days. Dengue-2, -3, and -4 groups had average viremias of 1.00, 1.25, and 1.33 days, respectively. All animals demonstrated appropriate antibody responses as determined by enzyme-linked immunosorbency assay (ELISA). Animals tolerated repeated phlebotomy well, as all animals remained within clinically normal hematocrit (HCT) reference ranges, and no lasting effects on HCT occurred in any monkey. Final HCT for most animals was greater than 45% (mean final hematocrit, 45%). The maximum decrease in HCT ranged from 3.5 to 19 (mean, 8.9) percentage points. No consistent correlation of any behavioral disease parameters with viremia and antibody status was demonstrated, although overt illness did occur in two animals. Aotus can be an affordable and safe model for testing dengue vaccine efficacy; further testing with higher doses of dengue-2, -3 and -4 viruses is warranted.

Protection of rhesus macaques against lethal Plasmodium knowlesi malaria by a heterologous DNA priming and poxvirus boosting immunization regimen.

We tested a cytokine-enhanced, multiantigen, DNA priming and poxvirus boosting vaccine regimen for prevention of malaria in the Plasmodium knowlesi-rhesus macaque model system. Animals were primed with a mixture of DNA plasmids encoding two preerythrocytic-stage proteins and two erythrocytic-stage proteins from P. knowlesi and combinations of the cytokines granulocyte-macrophage colony-stimulating factor, interleukin-4, and tumor necrosis factor alpha and were boosted with a mixture of four recombinant, attenuated vaccinia virus strains encoding the four P. knowlesi antigens. Two weeks after boosting, the geometric mean immunofluorescence titers in the immunized groups against sporozoites and infected erythrocytes ranged from 160 to 8,096 and from 1,810 to 5,120, respectively. The geometric mean anti-P. knowlesi circumsporozoite protein (PkCSP) titers ranged from 1,761 to 24,242. Peripheral blood mononuclear cells (PBMC) from the immunized monkeys produced gamma interferon (IFN-gamma) in response to incubation with pooled peptides from the PkCSP at frequencies of 10 to 571 spot-forming cells/10(6) PBMC. Following challenge with 100 infectious P. knowlesi sporozoites, 2 of 11 immunized monkeys were sterilely protected, and 7 of the 9 infected monkeys resolved their parasitemias spontaneously. In contrast, all four controls became infected and required treatment for overwhelming parasitemia. Early protection was strongly associated with IFN-gamma responses against a pool of peptides from the preerythrocytic-stage antigen, PkCSP. These findings demonstrate that a multistage, multiantigen, DNA priming and poxvirus boosting vaccine regimen can protect nonhuman primates from an otherwise lethal malaria sporozoite challenge.