Chronic Low-Level Vagus Nerve Stimulation Reduces Stellate Ganglion Nerve Activity and Paroxysmal Atrial Tachyarrhythmias in Ambulatory Canines

poster abstractIntroduction: Left sided low-level vagus nerve stimulation (LL-VNS) is used clinically for epilepsy and depression. We hypothesize that LL-VNS can suppress sympathetic outflow and reduce atrial tachyarrhythmias in ambulatory dogs. Methods: We implanted in 12 dogs a neurostimulator in left cervical vagus nerve and a radiotransmitter for continuous recording of left stellate ganglion nerve activities (SGNA), left thoracic vagal nerve activities (VNA) and electrocardiograms. The first 6 dogs (Group 1) underwent 1 week continuous LL-VNS. Another 6 dogs (Group 2) underwent intermittent rapid atrial pacing followed by active or sham LL-VNS on alternate weeks. Results: Integrated SGNA was significantly reduced during LL-VNS (7.8±0.9 mV-s vs. 9.4±0.9 mVs at baseline, P<0.05) in Group 1.The reduction was most apparent from 7 to 9 AM, (31% reduction, 10.8±2.5 mV-s versus 15.6±2.9 mV-s at baseline, P<0.01), along with a significantly reduced heart rate (P<0.05). SGNA-induced heart rate acceleration averaged 107.9±9.0 bpm during LL-VNS and 129.2±9.3 bpm at baseline (P<0.05). LL-VNS did not change VNA. The tyrosine hydroxylase-positive nerve structures in the left stellate ganglion were 99,684±22,257 µm2/mm2 in LL-VNS dogs and 186,561±11,383 µm2/mm2 (P<0.01) in normal control dogs. In Group 2, the frequencies of paroxysmal atrial fibrillation and atrial tachycardia during active LLVNS were 1.4±2.5/d and 8.0±5.8/d, respectively, significantly lower than during sham stimulation (9.2±6.2/d, P<0.01 and 22.0±4.4/d, P<0.001, respectively). Conclusion: LL-VNS suppresses SGNA and reduces the incidences of paroxysmal atrial tachyarrhythmias in ambulatory dogs. Significant neural remodeling of the left stellate ganglion is evident one week after cessation of chronic LL-VNS

The Tissue Microlocalisation and Cellular Expression of CD163, VEGF, HLA-DR, iNOS, and MRP 8/14 Is Correlated to Clinical Outcome in NSCLC

BACKGROUND: We have previously investigated the microlocalisation of M1 and M2 macrophages in NSCLC. This study investigated the non-macrophage (NM) expression of proteins associated with M1 and M2 macrophages in NSCLC. METHODS: Using immunohistochemistry, CD68(+) macrophages and proteins associated with either a cytotoxic M1 phenotype (HLA-DR, iNOS, and MRP 8/14), or a non-cytotoxic M2 phenotype (CD163 and VEGF) were identified. NM expression of the markers was analysed in the islets and stroma of surgically resected tumours from 20 patients with extended survival (ES) (median 92.7 months) and 20 patients with poor survival (PS) (median 7.7 months). RESULTS: The NM expression of NM-HLA-DR (p<0.001), NM-iNOS (p = 0.02) and NM-MRP 8/14 (p = 0.02) was increased in ES compared to PS patients in the tumour islets. The tumour islet expression of NM-VEGF, was decreased in ES compared to PS patients (p<0.001). There was more NM-CD163 expression (p = 0.04) but less NM-iNOS (p = 0.002) and MRP 8/14 (p = 0.01) expression in the stroma of ES patients compared with PS patients. The 5-year survival for patients with above and below median NM expression of the markers in the islets was 74.9% versus 4.7% (NM-HLA-DR p<0.001), 65.0% versus 14.6% (NM-iNOS p = 0.003), and 54.3% versus 22.2% (NM-MRP 8/14 p = 0.04), as opposed to 34.1% versus 44.4% (NM-CD163 p = 0.41) and 19.4% versus 59.0% (NM-VEGF p = 0.001). CONCLUSIONS: Cell proteins associated with M1 and M2 macrophages are also expressed by other cell types in the tumour islets and stroma of patients with NSCLC. Their tissue and cellular microlocalisation is associated with important differences in clinical outcome

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

Leishmaniasis represents a major international health problem, has a high morbidity and mortality rate, and is classified as an emerging and uncontrolled disease by the World Health Organization. The migration of population from endemic to nonendemic areas, and tourist activities in endemic regions are spreading the disease to new areas. Unfortunately, treatment of leishmaniasis is far from satisfactory, with only a few drugs available that show significant side-effects. Here, we show in vitro and in vivo evidence for the antileishmanial activity of the ether phospholipid edelfosine, being effective against a wide number of Leishmania spp. causing cutaneous, mucocutaneous and visceral leishmaniasis. Our experimental mouse and hamster models demonstrated not only a significant antileishmanial activity of edelfosine oral administration against different wild-type Leishmania spp., but also against parasites resistant to pentavalent antimonials, which constitute the first line of treatment worldwide. In addition, edelfosine exerted a higher antileishmanial activity and a lower proneness to generate drug resistance than miltefosine, the first drug against leishmaniasis that can be administered orally. These data, together with our previous findings, showing an anti-inflammatory action and a very low toxicity profile, suggest that edelfosine is a promising orally administered drug for leishmaniasis, thus warranting clinical evaluation