Attenuated Semliki Forest virus for cancer treatment in dogs : safety assessment in two laboratory Beagles

Background: Dogs suffer from spontaneous tumors which may be amenable to therapies developed for human cancer patients, and dogs may serve as large-animal cancer models. A non-pathogenic Semliki Forest virus vector VA7-EGFP previously showed promise in targeting human tumor xenografts in mice, but the oncolytic capacity of the virus in canine cancer cells and the safety of the virus in higher mammals such as dogs, are not known. We therefore assessed the oncolytic potency of VA7-EGFP against canine cancer cells by infectivity and viability assays in two dog solid tumor cell lines. Furthermore we performed a 3-week safety study in two adult Beagles which received a single intravenous injection of similar to 2 x 10(5) plaque forming units of parental A7(74) strain. Results: VA7-EGFP was able to replicate in and kill both canine cancer cell lines tested. No adverse events were observed in either of the two virus-injected adult Beagles and no infective virus could be recovered from any of the biological samples collected over the course of the study. Neutralizing antibodies to Semliki Forest virus became detectable in the dogs at 5 days post infection and remained elevated until study termination. Conclusions: Based on these results, testing of the oncolytic potential of attenuated Semliki Forest virus in canine cancer patients appears feasible.Peer reviewe

Increased cross-education of muscle strength and reduced corticospinal inhibition following eccentric strength training

AIM: Strength training of one limb results in a substantial increase in the strength of the untrained limb, however, it remains unknown what the corticospinal responses are following either eccentric or concentric strength training and how this relates to the cross-education of strength. The aim of this study was to determine if eccentric or concentric unilateral strength training differentially modulates corticospinal excitability, inhibition and the cross-transfer of strength. METHODS: Changes in contralateral (left limb) concentric strength, eccentric strength, motor-evoked potentials, short-interval intracortical inhibition and silent period durations were analyzed in groups of young adults who exercised the right wrist flexors with either eccentric (N=9) or concentric (N=9) contractions for 12 sessions over 4weeks. Control subjects (N=9) did not train. RESULTS: Following training, both groups exhibited a significant strength gain in the trained limb (concentric group increased concentric strength by 64% and eccentric group increased eccentric strength by 62%) and the extent of the cross-transfer of strength was 28% and 47% for the concentric and eccentric group, respectively, which was different between groups (P=0.031). Transcranial magnetic stimulation revealed that eccentric training reduced intracortical inhibition (37%), silent period duration (15-27%) and increased corticospinal excitability (51%) compared to concentric training for the untrained limb (P=0.033). There was no change in the control group. CONCLUSION: The results show that eccentric training uniquely modulates corticospinal excitability and inhibition of the untrained limb to a greater extent than concentric training. These findings suggest that unilateral eccentric contractions provide a greater stimulus in cross-education paradigms and should be an integral part of the rehabilitative process following unilateral injury to maximize the response

Clinical manifestations and outcome in Staphylococcus aureus endocarditis among injection drug users and nonaddicts: a prospective study of 74 patients

BACKGROUND: Endocarditis is a common complication in Staphylococcus aureus bacteremia (SAB). We compared risk factors, clinical manifestations, and outcome in a large, prospective cohort of patients with S. aureus endocarditis in injection drug users (IDUs) and in nonaddicts. METHODS: Four hundred and thirty consecutive adult patients with SAB were prospectively followed up for 3 months. Definite or possible endocarditis by modified Duke criteria was found in 74 patients: 20 patients were IDUs and 54 nonaddicts. RESULTS: Endocarditis was more common in SAB among drug abusers (46%) than in nonaddicts (14%) (odds ratio [OR], 5.12; 95% confidence interval [CI], 2.65–9.91; P < 0.001). IDUs were significantly younger (27 ± 15 vs 65 ± 15 years, P < 0.001), had less ultimately or rapidly fatal underlying diseases (0% vs 37%, P < 0.001) or predisposing heart diseases (20% vs 50%, P = 0.03), and their SAB was more often community-acquired (95% vs 39%, P < 0.001). Right-sided endocarditis was observed in 60% of IDUs whereas 93% of nonaddicts had left-sided involvement (P < 0.001). An extracardiac deep infection was found in 85% of IDUs and in 89% of nonaddicts (P = 0.70). Arterial thromboembolic events and severe sepsis were also equally common in both groups. There was no difference in mortality between the groups at 7 days, but at 3 months it was lower among IDUs (10%) compared with nonaddicts (39%) (OR, 5.73; 95% CI, 1.20–27.25; P = 0.02). CONCLUSION: S. aureus endocarditis in IDUs was associated with as high complication rates including extracardiac deep infections, thromboembolic events, or severe sepsis as in nonaddicts. Injection drug abuse in accordance with younger age and lack of underlying diseases were associated with lower mortality, but after adjusting by age and underlying diseases injection drug abuse was not significantly associated with mortality

Intravenously Administered Alphavirus Vector VA7 Eradicates Orthotopic Human Glioma Xenografts in Nude Mice

VA7 is a neurotropic alphavirus vector based on an attenuated strain of Semliki Forest virus. We have previously shown that VA7 exhibits oncolytic activity against human melanoma xenografts in immunodeficient mice. The purpose of this study was to determine if intravenously administered VA7 would be effective against human glioma.In vitro, U87, U251, and A172 human glioma cells were infected and killed by VA7-EGFP. In vivo, antiglioma activity of VA7 was tested in Balb/c nude mice using U87 cells stably expressing firefly luciferase in subcutaneous and orthotopic tumor models. Intravenously administered VA7-EGFP completely eradicated 100% of small and 50% of large subcutaneous U87Fluc tumors. A single intravenous injection of either VA7-EGFP or VA7 expressing Renilla luciferase (VA7-Rluc) into mice bearing orthotopic U87Fluc tumors caused a complete quenching of intracranial firefly bioluminescence and long-term survival in total 16 of 17 animals. In tumor-bearing mice injected with VA7-Rluc, transient intracranial and peripheral Renilla bioluminescence was observed. Virus was well tolerated and no damage to heart, liver, spleen, or brain was observed upon pathological assessment at three and ninety days post injection, despite detectable virus titers in these organs during the earlier time point.VA7 vector is apathogenic and can enter and destroy brain tumors in nude mice when administered systemically. This study warrants further elucidation of the mechanism of tumor destruction and attenuation of the VA7 virus

Changes in corticospinal excitability during an acute bout of resistance exercise in the elbow flexors

Purpose Hypertrophic resistance exercise (HRE) induces central and peripheral fatigue. However, more detailed information about changes in corticospinal excitability remains to be elucidated. Methods Eleven volunteers participated in the upper arm HRE which included one repetition maximum (1 RM) control contractions and three sets of 13 RM (SET1–3). Transcranial magnetic stimulation (TMS) was applied during maximal isometric voluntary contraction (MVC) at the end of each set and during control contractions to study changes in corticospinal excitability. Electrical stimulation was used in order to measure peripheral changes. Results MVC decreased after each set when compared to control contractions. Motor evoked potential (MEP) were 138.7 ± 52.7 % (p < 0.05), 130.4 ± 44.7 and 113.1 ± 31.4 % after SET1, SET2 and SET3, respectively, when compared to pre-exercise value. A significant reduction in MEP area between SET1 and SET3 (p < 0.05) was observed while silent period (SP) duration increased (~151–165 ms, p < 0.05) simultaneously between these sets. TMS-evoked twitch force during MVC increased significantly following each set when compared to pre-exercise value. Simultaneously, a significant reduction was observed in resting twitch force over the sets. Conclusions The results of this study clearly support the existence of both central and peripheral fatigue during HRE of elbow flexors. However, changes in the MEP area and SP suggest that during HRE of the elbow flexors, the corticospinal excitability increases first, until at some point, supraspinal fatigue takes over.peerReviewe

Production and investigation of neutron-rich isotopes with and around N=126 using gas flow transport method

Neutron-rich isotopes of heavy nuclei are until now poorly studied. In this work we investigate neutron-rich osmium isotopes produced in multi-nucleon transfer reactions. The reaction 136Xe+208Pb at energy near Coulomb barrier is used for production of osmium isotopes. The CORSAR-V setup is used to record the characteristics of osmium isotopes. The separation of the reaction products is based on their respective volatility. Experimental results are presented and discussed.peerReviewe