A case of splenic artery pseudoaneurysm rupture presenting as rectal bleeding in a regional hospital.

Splenic artery pseudoaneurysm is a rare phenomenon most associated with chronic pancreatitis or previous trauma. Complications can include erosion and rupture into local structures, a situation that carries a reported mortality of 10-40%. A 58-year-old male with chronic alcoholic pancreatitis and a known splenic artery pseudoaneurysm presented to the emergency department of a regional hospital with rectal bleeding and sepsis. Computed tomography revealed a peri-splenic mass communicating with the splenic flexure. The patient was taken for an emergency splenectomy and left hemicolectomy and was confirmed to have rupture of the splenic artery aneurysm into the large bowel. This case presented with comparable features reported in the literature and demonstrates that access to emergency specialist surgical services in a regional setting offers the capability to manage rare, life threatening surgical emergencies.

The concentration of console surgeons: prospective evaluation of the loss of attention in robotic-assisted procedures.

To prospectively evaluate the possible loss of attention among console surgeons performing robotic-assisted procedures using a validated psychological test. The concentration of one console surgeon was assessed before and after 25 robotic-assisted procedures (radical prostatectomies) using the validated d2 attention test (computer-assisted, Hogrefe test systems, Germany). Error frequency, work rate, and accuracy of task performance were evaluated as parameters of the fluctuation in concentration. Data were correlated with clinical parameters, including console times, positive surgical margin rates and the use of a nerve-sparing procedure. Pre- and post-operative test results revealed no differences in the number of items performed, but a significant decline in the error-corrected performance between the pre- and post-operative tests was observed with increasing console time (p = 0.046; median console time 123 min.). No differences in the pre-operative tests for consecutive procedures (mean time between procedures 93 min.) were found, whereas the number of errors (missed items) increased in the post-operative tests (p = 0.0025). The measured differences in test results showed no association with the positive surgical margin rate. A planned nerve-sparing procedure tended to result in a lower level of concentration found in pre-operative testing (p = 0.07). Concentration decrease and loss of attention during robotic-assisted procedures can be measured validly using the d2 attention test. Longer console times lead to loss of attention but consecutive procedures do not decrease the test or surgical performance. Further studies need to address whether similar effects apply to the comparable open or other robotic procedures or to different levels of surgeons experience.

Deletion of p22phox-dependent oxidative stress in the hypothalamus protects against obesity by modulating ß3-adrenergic mechanisms.

A role for oxidative stress in the brain has been suggested in the pathogenesis of diet-induced obesity (DIO), although the underlying neural regions and mechanisms remain incompletely defined. We tested the hypothesis that NADPH oxidase-dependent oxidative stress in the paraventricular nucleus (PVN), a hypothalamic energy homeostasis center, contributes to the development of DIO. Cre/LoxP technology was coupled with selective PVN adenoviral microinjection to ablate p22phox , the obligatory subunit for NADPH oxidase activity, in mice harboring a conditional p22phox allele. Selective deletion of p22phox in the PVN protected mice from high-fat DIO independent of changes in food intake or locomotor activity. This was accompanied by ß3-adrenoceptor-dependent increases in energy expenditure, elevations in brown adipose tissue thermogenesis, and browning of white adipose tissue. These data reveal a potentially novel role for brain oxidative stress in the development of DIO by modulating ß3-adrenoceptor mechanisms and point to the PVN as an underlying neural site.

Adverse metabolic phenotype of female offspring exposed to preeclampsia in utero: a characterization of the BPH/5 mouse in postnatal life.

Preeclampsia (PE) is a devastating disorder of pregnancy that classically presents with maternal hypertension and proteinuria after 20 wk of gestation. In addition to being a leading cause of maternal and fetal morbidity/mortality, epidemiological and prospective studies have revealed long-term consequences for both the mother and baby of preeclamptic pregnancies, including chronic hypertension as well as other cardiovascular diseases and metabolic derangements. To better understand the effect of in utero exposure of PE on offspring, we utilized the BPH/5 mouse, a spontaneous model of the maternal and fetal PE syndrome. We hypothesized that young BPH/5 offspring would have altered metabolic and cardiovascular phenotypes. Indeed, BPH/5 growth-restricted offspring showed excess catch-up growth by early adulthood due to hyperphagia and increased white adipose tissue (WAT) accumulation, with inflammation markers isolated to the reproductive WAT depot only. Both excessive WAT accumulation and the inflammatory WAT phenotype were corrected by pair-feeding young BPH/5 female mice. We also found that young BPH/5 female mice showed evidence of leptin resistance. Indeed, chronic hyperleptinemia has been shown to characterize other rodent models of PE; however, the maternal metabolic profile before pregnancy has not been fully understood. Furthermore, we found that these mice show signs of cardiovascular anomalies (hypertension and cardiomegaly) and altered signaling within the reproductive axis in early life. Future studies will involve challenging the physiological metabolic state of BPH/5 mice through pair-feeding to reduce WAT before pregnancy and determining its causal role in adverse pregnancy outcomes.

Decidual Cox2 inhibition improves fetal and maternal outcomes in a preeclampsia-like mouse model.

Preeclampsia (PE) is a disorder of pregnancy that manifests as late gestational maternal hypertension and proteinuria and can be life-threatening to both the mother and baby. It is believed that abnormal placentation is responsible for the cascade of events leading to the maternal syndrome. Embryo implantation is critical to establishing a healthy pregnancy. Defective implantation can cause adverse "ripple effects," leading to abnormal decidualization and placentation, retarded fetal development, and poor pregnancy outcomes, such as PE and fetal growth restriction. The precise mechanism(s) of implantation defects that lead to PE remain elusive. BPH/5 mice, which spontaneously develop the cardinal features of PE, show peri-implantation defects including upregulation of Cox2 and IL-15 at the maternal-fetal interface. This was associated with decreased decidual natural killer (dNK) cells, which have important roles in establishing placental perfusion. Interestingly, a single administration of a Cox2 inhibitor (celecoxib) during decidualization restrained Cox2 and IL-15 expression, restored dNK cell numbers, improved fetal growth, and attenuated late gestational hypertension in BPH/5 female mice. This study provides evidence that decidual overexpression of Cox2 and IL-15 may trigger the adverse pregnancy outcomes reflected in the preeclamptic syndrome, underscoring the idea that Cox2 inhibitor treatment is an effective strategy for the prevention of PE-associated fetal and maternal morbidity and mortality.

Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension.

Recent studies have emphasized the role of perivascular inflammation in cardiovascular disease. We studied mechanisms of perivascular leukocyte infiltration in angiotensin II (Ang II)-induced hypertension and their links to vascular dysfunction. Chronic Ang II infusion in mice increased immune cell content of T cells (255 ± 130 to 1664 ± 349 cells/mg; P < 0.01), M1 and M2 macrophages, and dendritic cells in perivascular adipose tissue. In particular, the content of T lymphocytes bearing CC chemokine receptor (CCR) 1, CCR3, and CCR5 receptors for RANTES chemokine was increased by Ang II (CCR1, 15.6 ± 1.5% vs. 31 ± 5%; P < 0.01). Hypertension was associated with an increase in perivascular adipose tissue expression of the chemokine RANTES (relative quantification, 1.2 ± 0.2 vs. 3.5 ± 1.1; P < 0.05), which induced T-cell chemotaxis and vascular accumulation of T cells expressing the chemokine receptors CCR1, CCR3, and CCR5. Mechanistically, RANTES(-/-) knockout protected against vascular leukocyte, and in particular T lymphocyte infiltration (26 ± 5% in wild type Ang II vs. 15 ± 4% in RANTES(-/-)), which was associated with protection from endothelial dysfunction induced by Ang II. This effect was linked with diminished infiltration of IFN-γ-producing CD8(+) and double-negative CD3(+)CD4(-)CD8(-) T cells in perivascular space and reduced vascular oxidative stress while FoxP3(+) T-regulatory cells were unaltered. IFN-γ ex vivo caused significant endothelial dysfunction, which was reduced by superoxide anion scavenging. In a human cohort, a significant inverse correlation was observed between circulating RANTES levels as a biomarker and vascular function measured as flow-mediated dilatation (R = -0.3, P < 0.01) or endothelial injury marker von Willebrand factor (R = +0.3; P < 0.01). Thus, chemokine RANTES is important in the regulation of vascular dysfunction through modulation of perivascular inflammation.-Mikolajczyk, T. P., Nosalski, R., Szczepaniak, P., Budzyn, K., Osmenda, G., Skiba, D., Sagan, A., Wu, J., Vinh, A., Marvar, P. J., Guzik, B., Podolec, J., Drummond, G., Lob, H. E., Harrison, D. G., Guzik, T. J. Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension.

Effect of Sucralfate on the Relative Bioavailability of Enrofloxacin and Ciprofloxacin in Healthy Fed Dogs.

BACKGROUND: Sucralfate impairs absorption of ciprofloxacin and other fluoroquinolones in humans, but no sucralfate-fluoroquinolone interaction has been reported in dogs. Veterinary formularies recommend avoiding concurrent administration of these medications, which might impact compliance, therapeutic success, and resistance selection from fluoroquinolones. OBJECTIVES: To determine whether a drug interaction exists when sucralfate is administered to fed dogs concurrently with ciprofloxacin or enrofloxacin, and whether a 2 hour delay between fluoroquinolone and sucralfate affects fluoroquinolone absorption. ANIMALS: Five healthy Greyhounds housed in a research colony. METHODS: This was a randomized crossover study. Treatments included oral ciprofloxacin (C) or oral enrofloxacin (E) alone, each fluoroquinolone concurrently with an oral suspension of sucralfate (CS, ES), and sucralfate suspension 2 hours after each fluoroquinolone (C2S, E2S). Fluoroquinolone concentrations were evaluated using liquid chromatography with mass spectrometry. RESULTS: Drug exposure of ciprofloxacin was highly variable (AUC 5.52-22.47 h µg/mL) compared to enrofloxacin (AUC 3.86-7.50 h µg/mL). The mean relative bioavailability for ciprofloxacin and concurrent sucralfate was 48% (range 8-143%) compared to ciprofloxacin alone. Relative bioavailability of ciprofloxacin improved to 87% (range 37-333%) when sucralfate was delayed by 2 hours. By contrast, relative bioavailability for enrofloxacin and concurrent sucralfate was 104% (94-115%). CONCLUSIONS AND CLINICAL IMPORTANCE: A possible clinically relevant drug interaction for the relative bioavailability of ciprofloxacin with sucralfate was found. No significant difference in bioavailability was documented for enrofloxacin with sucralfate. Further research is warranted in fasted dogs and clinical cases requiring enrofloxacin or other approved fluoroquinolones in combination with sucralfate.

Transurethral versus suprapubic catheter at robot-assisted radical prostatectomy: a prospective randomized trial with 1-year follow-up.

OBJECTIVE: To evaluate urethral catheter (UC) versus suprapubic tube (SPT) without stenting the anastomosis at robot-assisted radical prostatectomy (RALP) regarding surgical outcome and catheter-associated discomfort. One year after surgery, continence and patient satisfaction were evaluated. MATERIALS AND METHODS: Sixty-two patients undergoing RALP were prospectively randomized to urinary drainage with UC or with SPT. Functional results were assessed with standardized questionnaires (IPSS, IPSS Bother Score, IIEF and Visual Analogue Scale) preoperatively, after catheter removal and 1 year after surgery. Moreover, bother by the catheter as well as pain due to the catheter was assessed. RESULTS: At personal hygiene, SPT was significantly less bothersome on the day of surgery as well as POD 1-6. Pain caused by the catheter did not differ significantly between the two groups except for POD 5 and 6, when the SPT performed significantly better. Differences regarding voiding parameters after catheter removal did not reach statistical significance. One year after surgery, no significant difference between the two groups was found regarding urinary function and IPSS. Though not statistically significant either, the need for the incision of bladder neck contracture (BNC) in two patients in the UC group is of note, as in the SPT group, no BNC occurred. CONCLUSION: Draining the bladder with SPT only is a feasible option in patients undergoing RALP. Patients with SPT are significantly less bothered by the catheter at personal and genital hygiene compared to UC. The risk of BNC seems to be reduced in the SPT group.

Role of decidual natural killer cells, interleukin-15, and interferon-γ in placental development and preeclampsia.

Preeclampsia is a hypertensive, proteinuric disease that affects 5-10% of all pregnancies and is a leading cause of maternal and perinatal morbidity/mortality (Soto et al., J Matern Fetal Neonatal Med 25: 498-507, 2011). The primary treatment for preeclampsia still is delivery of the fetus and placenta. The underlying mechanisms remain elusive. One possibility is inadequate uterine angiogenesis/vascularity (decidualization) at the time of implantation (Torry et al., Am J Reprod Immunol 51: 257-268, 2004). Here, we review evidence for dysregulation of decidual natural killer (dNK) cells, which secrete important angiogenic factors during decidualization, as a contributing factor in preeclampsia.

Effect of sucralfate on oral minocycline absorption in healthy dogs.

Sucralfate and minocycline may be administered concurrently to dogs. The relative bioavailability of tetracyclines may be reduced if administered with sucralfate, but studies confirming these interactions in dogs are not available. This study evaluated the pharmacokinetics of oral minocycline in dogs (M), determined the effects of concurrent administration of sucralfate and minocycline (MS) on minocycline pharmacokinetics, determined the effects of delaying sucralfate administration by 2 h (MS+2) on minocycline pharmacokinetics, and established dosing recommendations based on pharmacodynamic indices. Oral minocycline (300 mg) and sucralfate suspension (1 g) were administered to five greyhounds in a randomized crossover design. Minocycline plasma concentrations were evaluated using liquid chromatography with mass spectrometry. The maximum plasma concentration (CMAX ) and area under the curve (AUC) of minocycline were 1.15 µg/mL and 8.0 h* µg/mL, respectively. The CMAX and AUC were significantly lower (P < 0.05) in the MS group (CMAX  = 0.33 µg/mL, AUC 3.0 h*µg/mL) compared with M or MS+2 (CMAX = 0.97 µg/mL, AUC 10.3 h*µg/mL). Delaying sucralfate by 2 h did not decrease oral minocycline absorption, but concurrent administration significantly decreased minocycline absorption. A dose of 7.5 mg/kg p.o. q12 h achieves the pharmacodynamic index for a bacterial minimum inhibitory concentration (MIC) of 0.25 µg/mL (AUC:MIC≥33.9).

Role of vascular oxidative stress in obesity and metabolic syndrome.

Obesity is associated with vascular diseases that are often attributed to vascular oxidative stress. We tested the hypothesis that vascular oxidative stress could induce obesity. We previously developed mice that overexpress p22phox in vascular smooth muscle, tg(sm/p22phox), which have increased vascular ROS production. At baseline, tg(sm/p22phox) mice have a modest increase in body weight. With high-fat feeding, tg(sm/p22phox) mice developed exaggerated obesity and increased fat mass. Body weight increased from 32.16 ± 2.34 g to 43.03 ± 1.44 g in tg(sm/p22phox) mice (vs. 30.81 ± 0.71 g to 37.89 ± 1.16 g in the WT mice). This was associated with development of glucose intolerance, reduced HDL cholesterol, and increased levels of leptin and MCP-1. Tg(sm/p22phox) mice displayed impaired spontaneous activity and increased mitochondrial ROS production and mitochondrial dysfunction in skeletal muscle. In mice with vascular smooth muscle-targeted deletion of p22phox (p22phox(loxp/loxp)/tg(smmhc/cre) mice), high-fat feeding did not induce weight gain or leptin resistance. These mice also had reduced T-cell infiltration of perivascular fat. In conclusion, these data indicate that vascular oxidative stress induces obesity and metabolic syndrome, accompanied by and likely due to exercise intolerance, vascular inflammation, and augmented adipogenesis. These data indicate that vascular ROS may play a causal role in the development of obesity and metabolic syndrome.

Arterial stiffening precedes systolic hypertension in diet-induced obesity.

Stiffening of conduit arteries is a risk factor for cardiovascular morbidity. Aortic wall stiffening increases pulsatile hemodynamic forces that are detrimental to the microcirculation in highly perfused organs, such as the heart, brain, and kidney. Arterial stiffness is associated with hypertension but presumed to be due to an adaptive response to increased hemodynamic load. In contrast, a recent clinical study found that stiffness precedes and may contribute to the development of hypertension although the mechanisms underlying hypertension are unknown. Here, we report that in a diet-induced model of obesity, arterial stiffness, measured in vivo, develops within 1 month of the initiation of the diet and precedes the development of hypertension by 5 months. Diet-induced obese mice recapitulate the metabolic syndrome and are characterized by inflammation in visceral fat and aorta. Normalization of the metabolic state by weight loss resulted in return of arterial stiffness and blood pressure to normal. Our findings support the hypothesis that arterial stiffness is a cause rather than a consequence of hypertension.

Effect of cefovecin on the fecal flora of healthy dogs.

Cefovecin is an extended-spectrum long-acting third generation cephalosporin used to treat canine infections. The study objective was to determine the effect of cefovecin on the absolute number and antimicrobial susceptibility of fecal enteric bacteria in healthy dogs. Fourteen Beagles were randomly assigned to a treated (n=7, 8 mg/kg cefovecin subcutaneously on day 1) or untreated (n=7) group. LC/MS was used to determine plasma cefovecin concentration on day 14. E. coli, enterococci, and Salmonella were isolated and enumerated from fecal samples collected on days 0, 3, 7, 14, and 28. Antimicrobial resistance was determined using disc diffusion, MIC, and detected using PCR for the blaCMY-2 gene on select isolates. Mean plasma concentration of cefovecin on day 14 was 9.59 µg/mL in treated dogs; untreated dogs had no measurable plasma cefovecin. The absolute number of E. coli was lower in treated dogs on day 3 (P ≤ 0.0001), and the absolute number of cefovecin-resistant E. coli was higher in treated dogs on days 7 (P=0.002), 14 (P=0.004) and 28 (P ≤ 0.0001), compared to untreated dogs. Enterococci increased and were higher in the treatment group on day 7 (P=0.0226). Isolation of Salmonella was rare. After cefovecin treatment, beta-lactam resistance was more common in fecal E. coli from treated dogs than untreated dogs, while resistance of enterococci was not altered. On day 28, treated dogs were 3.25 times more likely to carry the blaCMY-2 gene than untreated dogs (95% CI 1.27 - 8.35). The implications of these findings in clinically ill patients require further research.

Role of the NADPH oxidases in the subfornical organ in angiotensin II-induced hypertension.

Reactive oxygen species and the NADPH oxidases contribute to hypertension via mechanisms that remain undefined. Reactive oxygen species produced in the central nervous system have been proposed to promote sympathetic outflow, inflammation, and hypertension, but the contribution of the NADPH oxidases to these processes in chronic hypertension is uncertain. We therefore sought to identify how NADPH oxidases in the subfornical organ (SFO) of the brain regulate blood pressure and vascular inflammation during sustained hypertension. We produced mice with loxP sites flanking the coding region of the NADPH oxidase docking subunit p22(phox). SFO-targeted injections of an adenovirus encoding cre-recombinase markedly diminished p22(phox), Nox2, and Nox4 mRNA in the SFO, as compared with a control adenovirus encoding red-fluorescent protein injection. Increased superoxide production in the SFO by chronic angiotensin II infusion (490 ng/kg min(-1) × 2 weeks) was blunted in adenovirus encoding cre-recombinase-treated mice, as detected by dihydroethidium fluorescence. Deletion of p22(phox) in the SFO eliminated the hypertensive response observed at 2 weeks of angiotensin II infusion compared with control adenovirus encoding red-fluorescent protein-treated mice (mean arterial pressures=97 ± 15 versus 154 ± 6 mm Hg, respectively; P=0.0001). Angiotensin II infusion also promoted marked vascular inflammation, as characterized by accumulation of activated T-cells and other leukocytes, and this was prevented by deletion of the SFO p22(phox). These experiments definitively identify the NADPH oxidases in the SFO as a critical determinant of the blood pressure and vascular inflammatory responses to chronic angiotensin II, and further support a role of reactive oxygen species in central nervous system signaling in hypertension.

Novel neurological and immunological targets for salicylate-based phytopharmaceuticals and for the anti-depressant imipramine.

Inflammatory processes are increasingly recognised to contribute to neurological and neuropsychatric disorders such as depression. Thus we investigated whether a standardized willow bark preparation (WB) which contains among other constituents salicin, the forerunner of non-steroidal antiphlogistic drugs, would have an effect in a standard model of depression, the forced swimming test (FST), compared to the antidepressant imipramine. Studies were accompanied by gene expression analyses. In order to allocate potential effects to the different constituents of WB, fractions of the extract with different compositions of salicyl alcohol derivative and polyphenols were also investigated. Male Sprague Dawley rats (n=12/group) were treated for 14 days (p.o.) with the WB preparation STW 33-I (group A) and its fractions (FR) (groups FR-B to E) in concentrations of 30 mg/kg. The FRs were characterized by a high content of flavone and chalcone glycosides (FR-B), flavonoid glycosides and salicyl alcohol derivatives (FR-C), salicin and related salicyl alcohol derivatives (FR-D) and proanthocyanidines (FR-E). The tricyclic antidepressant imipramine (20 mg/kg) (F) was used as positive control. The FST was performed on day 15. The cumulative immobility time was significantly (p<0.05) reduced in group A (36%), group FR-D (44%) and by imipramine (16%) compared to untreated controls. RNA was isolated from peripheral blood. RNA samples (group A, group FR-D, and imipramine) were further analysed by rat whole genome microarray (Agilent) in comparison to untreated controls. Quantitative PCR for selected genes was performed. Genes (>2 fold, p<0.01), affected by WB and/or FR-D and imipramine, included both inflammatory (e.g. IL-3, IL-10) and neurologically relevant targets. Common genes regulated by WB, FR-D and imipramine were GRIA 2 ↓, SRP54 ↓, CYP26B ↓, DNM1L ↑ and KITLG ↓. In addition, the hippocampus of rats treated (27 d) with WB (15-60 mg/kg WB) or imipramine (15 mg/kg bw) showed a slower serotonin turnover (5-hydroxyindol acetic acid/serotonin (p<0.05)) depending on the dosage. Thus WB (30 mg/kg), its ethanolic fraction rich in salicyl alcohol derivatives (FR-D) (30 mg/kg) and imipramine, by being effective in the FST, modulated known and new targets relevant for neuro- and immunofunctions in rats. These findings contribute to our understanding of the link between inflammation and neurological functions and may also support the scope for the development of co-medications from salicylate-containing phytopharmaceuticals as multicomponent mixtures with single component synthetic drugs.

[A 38-year-old patient with gastroenteritis and unusual liver lesions]. / 38-jährige Patientin mit Gastroenteritis und ungewöhnlichen Leberherden.

A 38-year-old female presented with symptoms of gastroenteritis including fatigue and epigastric pain. An abdominal ultrasound indicated on the basis of raised liver values showed multiple liver lesions. However, additional imaging using contrast-enhanced ultrasound (CEUS), computer tomography (CT) as well as a magnetic resonance tomography (MR) failed to clarify the diagnosis. A fine needle biopsy revealed the histological diagnosis of peliosis hepatis. After discontinuing oral contraceptive medication, follow-up showed a steady state with clinical well being for at least 24 months.Peliosis hepatis is a rare hepatic disorder involving "bloody cysts" in the liver. Aetiology and pathogenesis remain unclear, but medication or toxins as possible triggering factors are discussed. Different clinical courses have been reported, including total asymptomatic state, unspecific fatigue, epigastric pain, as well as fulminant cases with liver rupture and bleeding complications.

T lymphocytes and vascular inflammation contribute to stress-dependent hypertension.

BACKGROUND: Psychological stress is a significant risk factor for hypertension and also directly affects the immune system. We have previously reported that T lymphocytes are essential for development of hypertension and that the central nervous system contributes to peripheral T-lymphocyte activation and vascular inflammation in this disease; however, the role of T-cell activation in stress-related hypertension remains unclear. METHODS: Wild-type and T-cell-deficient (RAG-1(-/-)) mice were subjected to daily episodes of stress and blood pressure was measured. Circulating T-cell activation markers and vascular infiltration of immune cells were analyzed, as were stress hormone levels and gene expression changes in the brain. The effects angiotensin II infusion in the presence of chronic stress was also studied. RESULTS: Repeated daily stress contributed to acute elevations in blood pressure that were associated with increased activation of circulating T cells and increased vascular infiltration of T cells. Repeated stress increased blood pressure in wild-type but not RAG-1(-/-) mice. Adoptive transfer of T cells to RAG-1(-/-) mice restored blood pressure elevation in response to stress. Stress-related hypertension and vascular infiltration of T cells was markedly enhanced by angiotensin II. Moreover, angiotensin II-infused mice exposed to chronic stress exhibited greater blood pressure reactivity to an episode of acute stress. CONCLUSIONS: These data demonstrate that stress-dependent hypertension triggers an inflammatory response that raises blood pressure at baseline and augments the hypertension caused by angiotensin II. These data provide insight as to how psychological stress contributes to hypertension.

Role of vascular extracellular superoxide dismutase in hypertension.

Previous studies indicate that superoxide is important in the modulation of blood pressure but have not specifically identified the cell types or organs involved. We created mice with loxP sites flanking the extracellular superoxide dismutase (SOD3) gene. These mice were crossed with mice expressing inducible Cre-recombinase driven by the smooth muscle myosin heavy chain promoter allowing tissue-specific deletion of SOD3. Deletion of SOD3 increased vascular superoxide and reduced vascular NO levels as detected by electron spin resonance. Despite these changes in NO and superoxide, we did not observe increases in vascular inflammation caused by angiotensin II. Moreover, deletion of vascular SOD3 did not augment hypertension in response to angiotensin II. In additional studies, we also deleted SOD3 from the circumventricular organs by intracerebroventricular injection of an adenovirus encoding Cre-recombinase. Although this raised blood pressure and augmented the hypertension caused by angiotensin II, these responses were not further increased by vascular deletion of SOD3. These data suggest that the extracellular superoxide dismutase in vascular smooth muscle is not involved in the genesis of angiotensin II-induced hypertension and further emphasize the role of central SOD3 in the modulation of blood pressure.

Role of interleukin 17 in inflammation, atherosclerosis, and vascular function in apolipoprotein e-deficient mice.

OBJECTIVE: Interleukin 17A (IL17A) is involved in many inflammatory processes, but its role in atherosclerosis remains controversial. We examined the role of IL17A in mouse and human atherosclerosis. METHODS AND RESULTS: Atherosclerosis was induced in apolipoprotein E (ApoE)(-/-) and IL17A/ApoE(-/-) mice using high-fat feeding, angiotensin II infusion, or partial carotid ligation. In ApoE(-/-) mice, 3 months of high-fat diet induced interferon-γ production by splenic lymphocytes, and this was abrogated in IL17A/ApoE(-/-) mice. IL17A/ApoE(-/-) mice had reduced aortic superoxide production, increased aortic nitric oxide levels, decreased aortic leukocyte and dendritic cell infiltration, and reduced weight gain after a high-fat diet compared with ApoE(-/-) mice. Despite these favorable effects, IL17A deficiency did not affect aortic plaque burden after a high-fat diet or angiotensin II infusion. In a partial carotid ligation model, IL17A deficiency did not affect percentage of stenosis but reduced outward remodeling. In this model, neutralization of the related isoform, IL17F, in IL17A/ApoE(-/-) mice did not alter atherosclerosis. Finally, there was no correlation between IL17A levels and carotid intima-media thickness in humans. CONCLUSIONS: IL17 contributes to vascular and systemic inflammation in experimental atherosclerosis but does not alter plaque burden. The changes in plaque composition caused by IL17 might modulate plaque stability.