Evaluation of the efficacy of monthly oral administration of afoxolaner plus milbemycin oxime (NexGard Spectra(®), Merial) in the prevention of adult Spirocerca lupi establishment in experimentally infected dogs.

The nematode Spirocerca lupi (Rudolphi, 1809) is widely distributed but mostly occurs sporadically with stable populations only in certain geographic areas. This helminth mainly infects dogs and wild canids. Primary pathology relates to migration of third stage larvae (L3) damaging the thoracic aorta and establishment of adults in nodules in the oesophagus. The objective of the present study was to evaluate the efficacy of milbemycin oxime in combination with afoxolaner (NexGard Spectra(®), Merial), administered monthly, in preventing establishment of adult worms after experimental infection. Two groups consisting of eight animals each were experimentally infected with 15 L3 on Days -28, -14 and -2, respectively (45 L3 per animal in total). Group 1 dogs served as untreated (negative) control, whereas animals in group 2 were treated with NexGard Spectra(®) at a minimum dose of 0.5mg/kg milbemycin oxime on Day 0 and from then onwards every 28 days up to Day 140 (six treatment occasions). Endoscopy was performed on Day 112 and for some animals also Day 140. Necropsy for worm recovery and nodule/lesion scoring was performed on Day 168. All eight animals in the control group (group 1) presented with 1-3 nodules and worm counts ranging from 9 to 41. Six animals in the NexGard Spectra(®) group presented with 1-4 nodules and worm counts ranging from 1 to 5. Significantly (p<0.05) fewer worms were collected from treated animals in the treated group (geometric mean 1.7) versus the negative control group (geometric mean 22.0) with 92.3% efficacy calculated. There was no significant (p>0.05) difference between groups with reference to number of nodules in the oesophagus. However, nodules in the control group were significantly (p<0.05) larger than those in the treated group. Number and size of lesions in the dorsal aorta did not differ statistically between groups 1 and 2. Because NexGard Spectra(®) was administered 28 days after onset of inoculation, migrating and developing L3 caused damage to the aorta wall of animals in the treated group. Milbemycin oxime (administered as NexGard Spectra(®)) demonstrated effectiveness in reducing infection with adult Spirocerca lupi worms in the oesophagus.

Mechanisms of vascular dysfunction in acute phase of Trypanosoma cruzi infection in mice.

Vascular disorders have a direct link to mortality in the acute phase of Trypanosoma cruzi infection. However, the underlying mechanisms of vascular dysfunction in this phase are largely unknown. We hypothesize that T. cruzi invades endothelial cells causing dysfunction in contractility and relaxation of the mouse aorta. Immunodetection of T. cruzi antigen TcRBP28 was observed in endothelial cells. There was a decreased endothelial nitric oxide synthase (eNOS)-derived NO-dependent vascular relaxation, and increased vascular contractility accompanied by augmented superoxide anions production. Endothelial removal, inhibition of cyclooxygenase 2 (COX-2), blockade of thromboxane A2 (TXA2) TP receptors, and scavenger of superoxide normalized the contractile response. COX-2, thromboxane synthase, inducible nitric oxide synthase (iNOS), p65 NFκB subunit and p22(phox) of NAD(P)H oxidase (NOX) subunit expressions were increased in vessels of chagasic animals. Serum TNF-α was augmented. Basal NO production, and nitrotyrosine residue expression were increased. It is concluded that T. cruzi invades mice aorta endothelial cells and increases TXA2/TP receptor/NOX-derived superoxide formation. Alongside, T. cruzi promotes systemic TNF-α increase, which stimulates iNOS expression in vessels and nitrosative stress. In light of the heart failure that develops in the chronic phase of the disease, to understand the mechanism involved in the increased contractility of the aorta is crucial.

A pilot study exploring the mechanisms involved in the longitudinal propagation of acute aortic dissection through computational fluid dynamic analysis.

OBJECTIVE: This study sought to elucidate the underlying hemodynamic mechanisms involved in the longitudinal propagation of acute, type-B aortic dissections. METHODS: Three-dimensional patient-specific aortic geometry was reconstructed from computed tomography images of 3 cases, followed by computational fluid dynamic analysis using finite-element analysis modeling. Three models were reconstructed; the normal-aortic model (from a healthy volunteer), the visceral-involvement model (from a patient whose visceral arteries were involved) and the progression model (from a patient whose visceral arteries were intact at admission). Wall pressure distribution was analyzed in all three models. RESULTS: In the systolic phase of a cardiac cycle, the wall pressure dropped from the proximal to the distal aorta within the true lumen. This pressure gradient was observed in all three models. A milder pressure gradient was seen in the false lumen in the visceral-involvement model, whereas the pressure in the false lumen remained almost constant in the progression model. The dyssynchrony of the pressure gradients in the true and false lumens caused an imbalance in pressure between the two lumens. CONCLUSION: The interluminal pressure differential may be a contributing factor in the compression of the true lumen and the cleavage force of the aortic wall, leading to the longitudinal propagation of the dissection.

The efficacy of a topically applied imidacloprid 10 % / moxidectin 2.5 % formulation (Advocate®, Advantage® Multi, Bayer) against Immature and Adult Spirocerca lupi worms in experimentally infected dogs.

This study investigated the efficacy and safety of an imidacloprid 10 %/moxidectin 2.5 % spot-on combination (Advocate®, Advantage® Multi, Bayer) against immature and mature stages of Spirocerca lupi in experimentally infected dogs. 24 dogs were allocated to 3 groups and infected with approximately 10 L3 larvae of S. lupi orally on study day (SD) +2, +14, +28 and +42. Group 1 remained as untreated control group. Group 2 dogs were treated on SD ­28, 0, and thereafter monthly until Day 280 (12 treatments). Group 3 dogs were treated weekly on 19 occasions starting on SD +170. The dosage for all treatments was the licensed dose of 10­25 mg imidacloprid/2.5­6.25 mg moxidectin per kg body weight. All dogs were examined on SD +169 or +176 by endoscopy. Group 3 dogs were additionally examined approximately every two weeks up to Day 296. On Day +308 or +310, all dogs were necropsied to recover S. lupi worms and to quantify lesions in the thoracic aorta and oesophagus. Dogs in the control group were adequately infected with S. lupi, demonstrated by the extensive damage to the thoracic aorta, the nodules in the oesophagus and the large numbers of worms recovered. In total 144 worms were collected (geometric mean of 16.8 worms per dog). Dogs in group 2 had no or very slight damage to the thoracic aorta and no nodules or worms in the oesophagus, indicating 100 % efficacy of the monthly treatments. Dogs in group 3 were also adequately infected, showing nodules in the oesophagus before initiation of weekly treatment, and at necropsy extensive damage was seen in the thoracic aorta. After treatment, three dogs of 8 still had a few nodules and in total three worms (GM of 0.25 per dog) were recovered, demonstrating an efficacy of 98.5 % against adult S. lupi. All dogs tolerated the treatment well and no treatment- related adverse events occurred.

Rupture of the thoracic aorta associated with experimental Angiostrongylus vasorum infection in a dog.

This note describes the sudden death of a dog by the rupture of the thoracic aorta caused by the presence of Angiostrongylus vasorum. A female mongrel canine with a history of weight loss and exhaustion died two hours after clinical examination. At necropsy, performed one hour after death, showed the presence of clotted blood in the thoracic cavity. Haemothorax was diagnosed. The thoracic aorta wall was thin, congested and an abnormal hole in the wall was detected approximately 0.5 cm from the entrance to the diaphragm. From clotted blood collected from the thoracic cavity, 224 first stage larvae (L1) and 15 adults of Angiostrongylus vasorum were recovered alive. Also, from a blood clot found in the aorta, four adult females and 47 L1 larvae were recovered alive. Possibly, this parasite was responsible for the aortic rupture and death of the animal.

Schistosomiasis differentially affects vasoconstrictor responses: up-regulation of 5-HT receptor-mediated aorta contraction.

Schistosomiasis, classified by the World Health Organization as a neglected tropical disease, is an intravascular parasitic disease associated to a chronic inflammatory state. Evidence implicating inflammation in vascular dysfunction continues to mount, which, broadly defined, reflects a failure in the control of intracellular Ca2+ and consequently, vascular contraction. Therefore, we measured aorta contraction induced by 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1), two important regulators of vascular contraction. Isometric aortic contractions were determined in control and Schistosoma mansoni-infected mice. In the infected animals, 5-HT induced a 50% higher contraction in relation to controls and we also observed an increased contraction in response to Ca2+ mobilisation from sarcoplasmic reticulum. Nevertheless, Rho kinase inhibition reduced the contraction in response to 5-HT equally in both groups, discarding an increase of the contractile machinery sensitivity to Ca2+. Furthermore, no alteration was observed for contractions induced by ET-1 in both groups. Our data suggest that an immune-vascular interaction occurs in schistosomiasis, altering vascular contraction outside the mesenteric portal system. More importantly, it affects distinct intracellular signalling involved in aorta contraction, in this case increasing 5-HT receptor signalling.

Hydatid cyst involving the aortic arch.

We report a very rare case of primary mediastinal hydatid cyst which invaded the ascending aorta and the aortic arch which initially presented as a cranial mass. Aortic wall is a very unusual site for the hydatid cysts. To the best of our knowledge, this is the first reported case of hydatid cyst located within the aortic arch lumen. Patient underwent ascending aortic and hemiarch replacement under hypothermic circulatory arrest and removal of the cyst. Patient had an uneventful recovery and has been on follow-up. Although the literature data are very limited, we believe that the aortic procedure of choice should be graft interpositon rather than patch repair.

Noradrenaline-induced contraction of mice aorta is enhanced in schistosomiasis.

Schistosomiasis, an intravascular parasitic disease caused by Schistosoma mansoni, is related to alterations of murine vascular reactivity in the mesenteric bed, characterized by an impairment of the l-arginine/NO pathway and an increased potency of 5-hydroxytryptamine. The current study was performed to test the hypothesis that a similar alteration of reactivity also occurs in the aorta and to identify the mechanism behind such an increase. We found that aorta from mice infected with male S. mansoni exhibited an enhanced contraction in response to noradrenaline and 100 mM KCl. The inhibition of nitric oxide synthase increased aortic maximal contraction in response to noradrenaline in both groups, but the effect was less pronounced in infected mice than in control mice. Endothelium-dependent relaxation induced by acetylcholine was also smaller in infected mice compared to control mice, while endothelial-independent relaxation induced by sodium nitroprusside and forskolin was similar in both groups. The inhibition of voltage-dependent L-type Ca(2+) channels reduced the maximal contraction in response to noradrenaline more effectively in infected than in control mice. Conversely the inhibition of K(ATP) channels had a smaller effect in the infected group. As a conclusion, our data indicate that schistosomiasis also alters murine vascular reactivity outside the mesenteric bed, due to a partial impairment of NO signaling, a reduced contribution of K(ATP) channels and an increased Ca(2+) influx through L-type Ca(2+) channels.

Is it justified to classify patients to Stage IIIC epithelial ovarian cancer based on nodal involvement only?

BACKGROUND: Stage IIIC epithelial ovarian cancer is generally associated with upper abdominal tumor implants of greater than 2 cm and carries a grave prognosis. A subset of patients is upstaged to Stage IIIC because of lymph node metastases, in which prognosis is not well defined. We undertook this study to describe the clinical behavior of occult Stage IIIC. METHODS: All consecutive patients found to have Stage IIIC epithelial ovarian cancer during a 9-year period (1994-2002) were analyzed for surgical procedures, pathology, and disease-free (DFS) and overall survival (OS). RESULTS: Thirty-six patients were upstaged to Stage IIIC by virtue of positive nodes. Nine had small volume upper abdominal disease (IIIA/B before upstaging), 15 had disease limited to the pelvis and 12 had disease confined to the ovaries. 32/36 patients had no gross residual disease at the conclusion of surgery. The 5-year DFS and OS survivals were 52% and 76% respectively, for all patients. We observed no significant difference in outcomes between patients upstaged from IIIA/B versus I-II stage disease. The outcomes were superior to a control group of patients cytoreduced to either no gross RD or RD<1 cm, who had large volume upper abdominal disease at beginning of surgery (p<0.001). CONCLUSIONS: Patients upstaged to Stage IIIC epithelial ovarian cancer for node involvement have an excellent 5-year OS relative to all patients with Stage IIIC disease. These data demonstrate the necessity for stratifying patients classified as having Stage IIIC disease based solely on nodal disease when comparing outcomes. This information is particularly valuable when counseling patients regarding prognosis.

Dirofilaria immitis: do filarial cyclooxygenase products depress endothelium-dependent relaxation in the in vitro rat aorta?

Endothelial cells modulate the function of their underlying smooth muscle. Thus, altered endothelial behavior could be important in the pathogenesis of vascular and lymphatic diseases, including human and animal filariasis. Endothelium-dependent relaxation is depressed in both in vivo canine femoral artery of dogs infected with Dirofilaria immitis and in vitro rat aorta exposed to adult D. immitis. The experiments reported here were designed to determine if filarial cyclooxygenase products could depress endothelium-dependent relaxation in vitro. Pretreatment of the parasites, but not the vascular ring, with either indomethacin or aspirin, prevented filarial-induced depression of relaxation. Analysis of heartworm-conditioned medium by gas chromatography--mass spectrometry revealed two peaks in the biologically active medium that were not present in the control. One peak had a retention time and chromatographic profile characteristic of derivatized PGD2 standard, and the other was not identified. Incubation of the vascular ring with PGD2 mimicked filarial-induced depression of endothelium-dependent relaxation at low, but not high, concentrations of acetylcholine. Thus, filarial PGD2 may be involved in altered endothelium-dependent relaxation seen in heartworm-infected dogs.

Bovine onchocerciasis caused by Onchocerca armillata and O. gutturosa.

Onchocerca armillata was found in 284 (28%) of 1,016 aortas, and O. gutturosa in 82 (28.87%) of 284 nuchal ligaments and in 11 (7.85%) of 140 rumenosplenic areas in specimens from cattle slaughtered during a 12-month period. Adult parasites were not found in 600 hides. Gross lesions included parasitic tunnels, nodules, roughening and calcification in the aortic walls. The connective tissue of nuchal ligaments and rumenosplenic areas was increased in amount, was gelatinous and brown and had afew nodules, Microscopically there were acute changes with oedema, haemorrhages and cellular infiltrations predominatly by eosinophils. There were chronic granulomatous reactions characterized by accumulation of macrophages, lymphocytes, plasma cells, giant cells, calcification and fibrosis around degenerate and dead parasites. Neutral fat was in parasites and surrounding cells. Both changes often occurred in the same specimen and many samples had parasites but no tissue reaction. Hypersensitivity, foreign-body reactions and parasitic toxins apparently were involved in the genesis of these lesions.

An epizootic among knots (Calidris canutus) in Florida. II. Ultrastructure of the causative agent, a Besnoitia-like organism.

Multinucleated cysts near the luminal surface of the thoracic aortas of diseased knots (Calidris canutus) were similar to besnoitia cysts. Ultrastructurally, the cyst had four distinct layers. The central area included a vacuole that contained a sporozoan with a conoid, polar ring, micronemes, rhoptries, nucleus, mitochondria, dense bodies, a lipid-like vacuole and endoplasmic reticulum. External to the vacuole was a layer with organelles typical of vertebrate cells. The wall of the cyst was irregular in thickness and was bound by a strongly osmiophilic membrane. There was a loose, acellular area of intertwined strands between the cysts wall and layer of organelles.