Liposomes modulate human immunodeficiency virus infectivity

We have investigated the effects of the fusion of liposomes with human immunodeficiency virus type 1 (HIV-1(LVA)) on the ability of the virus to infect CD4+ and CD4- cells. Fluorescence dequenching measurements indicated that HIV-1 fuses with liposomes composed of either cardiolipin (CL) or N-[2,3-(dioleyloxy) propyl]-N,N,N-trimethyl ammonium chloride (DOTMA) but not appreciably with dioleoylphosphatidylcholine (DOPC) liposomes. Pre-incubation of HIV-1 with DOTMA liposomes enhanced virus production (measured by p24 gag antigen production in the culture medium and in situ) in CD4+ A3.01 and H9 cells in a concentration-dependent manner, but did not mediate the infection of the CD4- cell line, K562. Preincubation of HIV-1 with between 10 and 30 μM-DOTMA liposomes, and subsequent incubation with A3.01 cells, resulted in the production of about 30-fold greater levels of virus than controls. The presence of DOTMA liposomes during the incubation of A3.01 cells with HIV-1 enhanced the infectivity of the virus up to 90-fold compared to controls. Conversely, preincubation of HIV-1 with CL liposomes inhibited infection of A3.01 cells, dependent on the concentration of liposomes; DOPC liposomes did not alter the infectivity of the virus under any of the incubation conditions. Our results thus indicate that fusion of HIV-1 with liposomes alters the ability of the virus to infect its target cells

Enhanced effect of liposome-encapsulated amikacin on Mycobacterium avium-M. intracellulare complex infection in beige mice

We examined the therapeutic effects of free and liposome-encapsulated amikacin on Mycobacterium avium-M. intracellulare complex infection by using the beige-mouse model of the disease. In the first series of studies, intravenous administration of four weekly doses of 5 mg of amikacin per kg encapsulated in large (approximately 0.4-μm diameter), unilamellar liposomes arrested the growth of M. avium-M. intracellulare complex organisms in the liver, as measured by CFU counts. M. avium-M. intracellulare complex levels in untreated animals and in those treated with the same dose of free amikacin increased by several orders of magnitude over 8 weeks. Liposome-encapsulated amikacin was also effective against M. avium-M. intracellulare complex organisms in the spleens and kidneys, reducing the CFU counts by about 1,000-fold compared with those of both untreated controls and free-drug-treated mice. In the lungs, a slight reduction in CFU was observed in the liposome-encapsulated-amikacin-treated group, but only at the 8-week point. Neither free nor liposome-encapsulated amikacin reduced the colony counts in the lymph nodes compared with those of control animals. Reductions in CFU in all organs greater than those caused by the liposome preparation could be achieved by intramuscular administration of free amikacin, but only at a 10-fold-higher dose given 6 days a week for 8 weeks. In the second series of studies, we investigated the effects of (i) doubling the dose of liposome-encapsulated amikacin and (ii) increasing the size of the liposomes and prolonging the treatment to five injections. Administration of 10 mg of amikacin per kg in liposomes 2 to 3 μm in diameter was more effective in the liver than 5 or 10 mg of amikacin per kg in liposomes 0.2 μm in diameter. A slight reduction in the CFU levels in the lungs was observed with the higher dose, irrespective of liposome size. Our results indicate that liposome-based delivery of amikacin enhances its anti-M. avium-M. intracellulare complex activity, particularly in the liver, spleen, and kidney, and may therefore improve the therapy of this disease

Stacks and D-Brane Bundles

In this paper we describe explicitly how the twisted ``bundles'' on a D-brane worldvolume in the presence of a nontrivial B field, can be understood in terms of sheaves on stacks. We also take this opportunity to provide the physics community with a readable introduction to stacks and generalized spaces.Comment: 24 pages, LaTeX; v2: references adde

Precision atomic gravimeter based on Bragg diffraction

We present a precision gravimeter based on coherent Bragg diffraction of freely falling cold atoms. Traditionally, atomic gravimeters have used stimulated Raman transitions to separate clouds in momentum space by driving transitions between two internal atomic states. Bragg interferometers utilize only a single internal state, and can therefore be less susceptible to environmental perturbations. Here we show that atoms extracted from a magneto-optical trap using an accelerating optical lattice are a suitable source for a Bragg atom interferometer, allowing efficient beamsplitting and subsequent separation of momentum states for detection. Despite the inherently multi-state nature of atom diffraction, we are able to build a Mach-Zehnder interferometer using Bragg scattering which achieves a sensitivity to the gravitational acceleration of $\Delta g/g = 2.7\times10^{-9}$ with an integration time of 1000s. The device can also be converted to a gravity gradiometer by a simple modification of the light pulse sequence.Comment: 13 pages, 11 figure

Genome-Wide Association Analysis Identifies a Mutation in the Thiamine Transporter 2 (SLC19A3) Gene Associated with Alaskan Husky Encephalopathy

Alaskan Husky Encephalopathy (AHE) has been previously proposed as a mitochondrial encephalopathy based on neuropathological similarities with human Leigh Syndrome (LS). We studied 11 Alaskan Husky dogs with AHE, but found no abnormalities in respiratory chain enzyme activities in muscle and liver, or mutations in mitochondrial or nuclear genes that cause LS in people. A genome wide association study was performed using eight of the affected dogs and 20 related but unaffected control AHs using the Illumina canine HD array. SLC19A3 was identified as a positional candidate gene. This gene controls the uptake of thiamine in the CNS via expression of the thiamine transporter protein THTR2. Dogs have two copies of this gene located within the candidate interval (SLC19A3.2 – 43.36–43.38 Mb and SLC19A3.1 – 43.411–43.419 Mb) on chromosome 25. Expression analysis in a normal dog revealed that one of the paralogs, SLC19A3.1, was expressed in the brain and spinal cord while the other was not. Subsequent exon sequencing of SLC19A3.1 revealed a 4bp insertion and SNP in the second exon that is predicted to result in a functional protein truncation of 279 amino acids (c.624 insTTGC, c.625 C>A). All dogs with AHE were homozygous for this mutation, 15/41 healthy AH control dogs were heterozygous carriers while 26/41 normal healthy AH dogs were wild type. Furthermore, this mutation was not detected in another 187 dogs of different breeds. These results suggest that this mutation in SLC19A3.1, encoding a thiamine transporter protein, plays a critical role in the pathogenesis of AHE.University of California, Davis. School of Veterinary Medicine. Center for Companion Animal Healt

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation