Studies in the experimental pathology of louping-ill encephalitis

Aspects of the pathogenesis and neuropathology of louping-ill encephalitis have been investigated in rodents and sheep. In animals inoculated intraperitoneally virus was detected in the circulation before being isolated from nervous tissue. There was, however, no indication as to the means by which virus particles passed from blood to brain. Replication of virus within the central nervous system appeared to be confined to the cytoplasm of nerve cells. In infant hamster cerebellum virions were found within abnormal cytoplasmic membranes in both Purkinje cells and granule cells. Neurons containing these membranes were depleted of granular endoplasmic reticulum and showed loss of Nissl substance. Chromatolysis was seen also in ventral horn cells of moribund sheep but, although viral antigen was demonstrated in the majority of such cells by immunofluorescence, virus particles were not found on ultrastructural examination. Necrosis of ventral horn cells in sheep was accompanied by diminution in acid phosphatase activity and fragmentation of the Golgi apparatus. Onset of symptoms preceded obvious neuronal loss in 75 per cent, of C57 black mice inoculated intraperitoneally. However in most other experiments nerve cell necrosis could be correlated with neurological dysfunction. In infant hamsters and moribund sheep the distribution patterns of neuronal damage and cells containing virus particles and viral antigen were similar. It is concluded that the basic cause of louping-ill is damage of nerve cells by the virus. Neuronal damage in moribund sheep was most apparent in the vestibular nuclei, the motor nuclei, the Purkinje cells of the cerebellum and the ventral horns of the spinal cord. The telencephalon was relativelyunaffected. This distribution of lesions was seen in animals that were inoculated intracerebrally or subcutaneuosly, and in natural cases. Neuropathological changes were more generalized in mice inoculated intra¬ cerebrally, and were not obviously affected either by the strain of host or the presence of concurrent lesions of scrapie. Severe neuron necrosis was seen in infant hamsters and rats, but not in those more than 14 days old at inoculation. In sheep, however, the severity of lesions was similar in all age groups. No general principle can be formulated to explain the distribution of virus infected nerve cells in animals with louping-ill. Virus was detected in nervous tissue before inflammatory changes were apparent. Severe neuron necrosis was seen in all moribund sheep, and inflammatory changes were most marked in those with the longest incubation times. There were slight generalized inflammatory lesions, which were either perivascular or associated with effete neurons, in all surviving sheep and in subclinically affected hamsters and rats. Inflammation is essentially a secondary phenomenon, which occurs after nerve cells are infected with virus. The perivascular cuff was studied intensively in moribund sheep. Histologically most constituents of the cuff appeared to be of the lymphoid type, with a few classical plasma cells and monocytes. The majority were shown to contain globulin in their cytoplasm, when stained with a fluorescent conjugate prepared against sheep IgG. Electron microscopy showed that most of the perivascular inflammatory cells were plasmacytes. Infiltrating cells were also seen to be of the plasma cell type and were observed to enter nervous tissue without causing any obvious damage to either endothelial cells or their basement membranes. Thus perivascular cuffing in sheep with louping-ill results mainly from migration of circulating plasma cells, or plasma cell precursors, into the central nervous system and is a specific response to the presence of viral antigen in the tissues. The inflammatory reaction is a protective mechanism, and is not responsible for the development of symptoms. In this respect it is unlike the histologically similar delayed allergic reaction

Semiclassical theory of cavity-assisted atom cooling

We present a systematic semiclassical model for the simulation of the dynamics of a single two-level atom strongly coupled to a driven high-finesse optical cavity. From the Fokker-Planck equation of the combined atom-field Wigner function we derive stochastic differential equations for the atomic motion and the cavity field. The corresponding noise sources exhibit strong correlations between the atomic momentum fluctuations and the noise in the phase quadrature of the cavity field. The model provides an effective tool to investigate localisation effects as well as cooling and trapping times. In addition, we can continuously study the transition from a few photon quantum field to the classical limit of a large coherent field amplitude.Comment: 10 pages, 8 figure

Women’s experiences of coping with the sexual side effects of antidepressant medication

A growing body of evidence has highlighted the sexual side effects of selective serotonin reuptake inhibitor (SSRI) medication. Whilst most of the research has focused on the prevalence and treatment of sexual difficulties, little is known about how patients cope with the SSRI-related sexual side effects. The objective of this study was to explore women’s experiences of coping with the sexual side effects of SSRI medication and interpretative phenomenological analysis was employed for an in-depth exploratory study of a sample of 10 women. Four broad themes emerged which are discussed under the following headings: searching, suffering in silence, trying to resolve and accepting what is. The themes provide an insight into the different strategies used by women to cope with the sexual side effects of SSRI medication and highlight the importance of contextualising these difficulties as part of an overall approach to improve the management and treatment of SSRI-related sexual side effects

Fast spin exchange between two distant quantum dots

The Heisenberg exchange interaction between neighboring quantum dots allows precise voltage control over spin dynamics, due to the ability to precisely control the overlap of orbital wavefunctions by gate electrodes. This allows the study of fundamental electronic phenomena and finds applications in quantum information processing. Although spin-based quantum circuits based on short-range exchange interactions are possible, the development of scalable, longer-range coupling schemes constitutes a critical challenge within the spin-qubit community. Approaches based on capacitative coupling and cavity-mediated interactions effectively couple spin qubits to the charge degree of freedom, making them susceptible to electrically-induced decoherence. The alternative is to extend the range of the Heisenberg exchange interaction by means of a quantum mediator. Here, we show that a multielectron quantum dot with 50-100 electrons serves as an excellent mediator, preserving speed and coherence of the resulting spin-spin coupling while providing several functionalities that are of practical importance. These include speed (mediated two-qubit rates up to several gigahertz), distance (of order of a micrometer), voltage control, possibility of sweet spot operation (reducing susceptibility to charge noise), and reversal of the interaction sign (useful for dynamical decoupling from noise).Comment: 6 pages including 4 figures, plus 8 supplementary pages including 5 supplementary figure

Pathogenesis of Murine Gammaherpesvirus-68 Infection in Interleukin-6-Deficient Mice

AbstractMurine gammaherpesvirus-68 (MHV-68) induces high levels of interleukin (IL)-6 production in both naive and primed lymphocyte populations. Mice that are homozygous (−/−) for deletion of the IL-6 gene were used to investigate the role of this cytokine in MHV-68 infection. The results showed that IL-6 is not essential for clearance of infectious MHV-68 from the lung or for the establishment, or control, of viral latency. Both IL-6 +/+ and −/− mice eliminated replicating virus from the respiratory tract within 15 days of infection, and their lungs remained clear of infectious virus for ≥150 days. Interestingly, the IL-6 −/− mice had both increased numbers of natural killer (NK)1.1+ cells and higher levels of NK cell activity than the +/+ controls at 10–15 days after infection. However, there was no difference in the cytotoxic T cell activity between the two groups of mice. Levels of latent virus were comparable in IL-6 +/+ and −/− mice over the time course studied. Furthermore, analysis of the numbers, types, and activation status of the various leukocyte subsets (other than NK cells) in the bronchoalveolar lavage population, lymph nodes, and spleens of +/+ and −/− mice revealed no striking differences. Apart from the expected lack of IL-6, cytokine profiles were not dramatically altered in IL-6 −/− mice. Thus, there is no evidence for an obligatory role for IL-6 in T cell activation during infection with MHV-68

Consequences of immunodominant epitope deletion for minor influenza virus-specific CD8+-T-cell responses

The extent to which CD8+ T cells specific for other antigens expand to compensate for the mutational loss of the prominent DbNP366 and DbPA224 epitopes has been investigated using H1N1 and H3N2 influenza A viruses modified by reverse genetics. Significantly increased numbers of CD8+ KbPB1703+ , CD8+ KbNS2114+, and CD8+ DbPB1-F262+ T cells were found in the spleen and in the inflammatory population recovered by bronchoalveolar lavage from mice that were first given the -NP-PA H1N1 virus intraperitoneally and then challenged intranasally with the homologous H3N2 virus. The effect was less consistent when this prime-boost protocol was reversed. Also, though the quality of the response measured by cytokine staining showed some evidence of modification when these minor CD8+-T-cell populations were forced to play a more prominent part, the effects were relatively small and no consistent pattern emerged. The magnitude of the enhanced clonal expansion following secondary challenge suggested that the prime-boost with the -NP-PA viruses gave a response overall that was little different in magnitude from that following comparable exposure to the unmanipulated viruses. This was indeed shown to be the case when the total response was measured by ELISPOT analysis with virus-infected cells as stimulators. More surprisingly, the same effect was seen following primary challenge, though individual analysis of the CD8+ KbPB1703+ , CD8+ KbNS2114+, and CD8+ DbPB1-F262+ sets gave no indication of compensatory expansion. A possible explanation is that novel, as yet undetected epitopes emerge following primary exposure to the -NP-PA deletion viruses. These findings have implications for both natural infections and vaccines.<br /

Natural history of radiographic first metatarsophalangeal joint osteoarthritis: A nineteen‐year population‐based cohort study

Objective: To assess the long-term prevalence, natural history, progression and incidence of 73 radiographic first metatarsophalangeal joint (1st MTPJ) osteoarthritis (OA). Methods: A longitudinal, cohort design was used in which radiographic OA at the 1st MTPJ was 75 investigated in participants at year 6 (1995) and year 23 (2013-2015) from the Chingford 1000 76 Women study. Radiographic features of osteophytes (OPs) and/or joint space narrowing (JSN) at the 77 1st MTPJ were scored according to a validated foot atlas. Natural history was determined by the 78 change in prevalence, incidence, progression and worsening of OA in the 1st MTPJ. Results: Complete case matched foot radiographic data were available for 193 of the women 80 currently enrolled in the study, mean age: 75.7 years (SD: 5.2; range 69-90). At the level of the 1st 81 MTPJ, prevalence of OA at year 6 was 21.76% in the left and 24.35% in the right and at year 23 was 82 23.83% in the left and 32.64% in the right. Over the 19-year period, 13.5% of women developed 83 incident OA in the right 1st MTPJ and 8.3% in the left. Both progression and worsening of OA were 84 more evident for OPs and in the right 1st MTPJs. Conclusion: In this longest study of the natural history of radiographic 1st MTPJ OA to date, the 86 prevalence and incidence of 1st MTPJ OA increased over a 19-year period. Progression and/or 87 worsening of 1st MTPJ OA over time appears to be driven by OP development rather than JSN 88 suggestive of a biomechanical cause

An Early CD4+ T Cell–dependent Immunoglobulin A Response to Influenza Infection in the Absence of Key Cognate T–B Interactions

Contact-mediated interactions between CD4+ T cells and B cells are considered crucial for T cell–dependent B cell responses. To investigate the ability of activated CD4+ T cells to drive in vivo B cell responses in the absence of key cognate T–B interactions, we constructed radiation bone marrow chimeras in which CD4+ T cells would be activated by wild-type (WT) dendritic cells, but would interact with B cells that lacked expression of either major histocompatibility complex class II (MHC II) or CD40. B cell responses were assessed after influenza virus infection of the respiratory tract, which elicits a vigorous, CD4+ T cell–dependent antibody response in WT mice. The influenza-specific antibody response was strongly reduced in MHC II knockout and CD40 knockout mice. MHC II–deficient and CD40-deficient B cells in the chimera environment also produced little virus-specific immunoglobulin (Ig)M and IgG, but generated a strong virus-specific IgA response with virus-neutralizing activity. The IgA response was entirely influenza specific, in contrast to the IgG2a response, which had a substantial nonvirus-specific component. Our study demonstrates a CD4+ T cell–dependent, antiviral IgA response that is generated in the absence of B cell signaling via MHC II or CD40, and is restricted exclusively to virus-specific B cells