Viral Reservoirs in Lymph Nodes of FIV-Infected Progressor and Long-Term Non-Progressor Cats during the Asymptomatic Phase.

BackgroundExamination of a cohort of cats experimentally infected with feline immunodeficiency virus (FIV) for 5.75 years revealed detectable proviral DNA in peripheral blood mononuclear cells (PBMCs) harvested during the asymptomatic phase, undetectable plasma viral RNA (FIV gag), and rarely detectable cell-associated viral RNA. Despite apparent viral latency in peripheral CD4+ T cells, circulating CD4+ T cell numbers progressively declined in progressor animals. The aim of this study was to explore this dichotomy of peripheral blood viral latency in the face of progressive immunopathology. The viral replication status, cellular immunophenotypes, and histopathologic features were compared between popliteal lymph nodes (PLNs) and peripheral blood. Also, we identified and further characterized one of the FIV-infected cats identified as a long-term non-progressor (LTNP).ResultsPLN-derived leukocytes from FIV-infected cats during the chronic asymptomatic phase demonstrated active viral gag transcription and FIV protein translation as determined by real-time RT-PCR, Western blot and in situ immunohistochemistry, whereas viral RNA in blood leukocytes was either undetectable or intermittently detectable and viral protein was not detected. Active transcription of viral RNA was detectable in PLN-derived CD4+ and CD21+ leukocytes. Replication competent provirus was reactivated ex vivo from PLN-derived leukocytes from three of four FIV-infected cats. Progressor cats showed a persistent and dramatically decreased proportion and absolute count of CD4+ T cells in blood, and a decreased proportion of CD4+ T cells in PLNs. A single long-term non-progressor (LTNP) cat persistently demonstrated an absolute peripheral blood CD4+ T cell count indistinguishable from uninfected animals, a lower proviral load in unfractionated blood and PLN leukocytes, and very low amounts of viral RNA in the PLN.ConclusionCollectively our data indicates that PLNs harbor important reservoirs of ongoing viral replication during the asymptomatic phase of infection, in spite of undetectable viral activity in peripheral blood. A thorough understanding of tissue-based lentiviral reservoirs is fundamental to medical interventions to eliminate virus or prolong the asymptomatic phase of FIV infection

The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies.

Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus disease of domestic cats. Recent studies of diseases caused by several RNA viruses in people and other species indicate that antiviral therapy may be effective against FIP in cats. The small molecule nucleoside analog GS-441524 is a molecular precursor to a pharmacologically active nucleoside triphosphate molecule. These analogs act as an alternative substrate and RNA-chain terminator of viral RNA dependent RNA polymerase. We determined that GS-441524 was non-toxic in feline cells at concentrations as high as 100 uM and effectively inhibited FIPV replication in cultured CRFK cells and in naturally infected feline peritoneal macrophages at concentrations as low as 1 uM. We determined the pharmacokinetics of GS-441524 in cats in vivo and established a dosage that would sustain effective blood levels for 24 h. In an experimental FIPV infection of cats, GS-441524 treatment caused a rapid reversal of disease signs and return to normality with as little as two weeks of treatment in 10/10 cats and with no apparent toxicity

Immunopathogenesis of canine chronic ulcerative stomatitis.

Canine Chronic Ulcerative Stomatitis is a spontaneously occurring inflammatory disease of the oral mucosa. An immune-mediated pathogenesis is suspected though not yet proven. We have recently reported on the clinical and histologic features, and identification of select leukocyte cell populations within the lesion. A clinical and histologic similarity to oral lichen planus of people was proposed. In the present study, these initial observations are extended by examining lesions from 24 dogs with clinical evidence of chronic ulcerative stomatitis. Because dogs with chronic ulcerative stomatitis often have concurrent periodontal disease, we wondered if dental plaque/biofilm may be a common instigator of inflammation in both lesions. We hypothesized that dogs with chronic ulcerative stomatitis would exhibit a spectrum of pathologic changes and phenotype of infiltrating leukocytes that would inform lesion pathogenesis and that these changes would differ from inflammatory phenotypes in periodontitis. Previously we identified chronic ulcerative stomatitis lesions to be rich in FoxP3+ and IL17+ cells. As such, we suspect that these leukocytes play an important role in lesion pathogenesis. The current study confirms the presence of moderate to large numbers of FoxP3+ T cells and IL17+ cells in all ulcerative stomatitis lesions using confocal immunofluorescence. Interestingly, the majority of IL17+ cells were determined to be non-T cells and IL17+ cell frequencies were negatively correlated with severity on the clinical scoring system. Three histologic subtypes of ulcerative stomatitis were determined; lichenoid, deep stomatitis and granulomatous. Periodontitis lesions, like stomatitis lesions, were B cell and plasma cell rich, but otherwise differed from the stomatitis lesions. Direct immunofluorescence results did not support an autoantibody-mediated autoimmune disease process. This investigation contributes to the body of literature regarding leukocyte involvement in canine idiopathic inflammatory disease pathogenesis

Parents’ experiences of health visiting for children with Down syndrome

© MA Healthcare Limited.Children with Down syndrome have an increased likelihoodof experiencing serious health conditions. Health visitors canhave an important role in monitoring and promoting healthand development for young children with Down syndrome.This study aimed to explore parents’ experiences of healthvisiting services for children with Down syndrome. Twentyfour parents of children with Down syndrome aged 0–5 yearscompleted a brief questionnaire about the number and natureof visits from health visitors in the previous 12 months andtheir support needs. Some parents commented that otherprofessionals met the needs of their child, whereas others saidthat they would like more advice and support from healthvisitors. A further exploration of broader health serviceprovision, including health visiting, for young children withDown syndrome is needed.Peer reviewedFinal Accepted Versio

Predictors of Hospitals with Endemic Community-Associated Methicillin-Resistant Staphylococcus aureus

OBJECTIVE: We sought to identify hospital characteristics associated with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) carriage among inpatients. DESIGN: Prospective cohort study. SETTING: Orange County, California. PARTICIPANTS: Thirty hospitals in a single county. METHODS: We collected clinical MRSA isolates from inpatients in 30 of 31 hospitals in Orange County, California, from October 2008 through April 2010. We characterized isolates by spa typing to identify CA-MRSA strains. Using California’s mandatory hospitalization data set, we identified hospital-level predictors of CA-MRSA isolation. RESULTS: CA-MRSA strains represented 1,033 (46%) of 2,246 of MRSA isolates. By hospital, the median percentage of CA-MRSA isolates was 46% (range, 14%–81%). In multivariate models, CA-MRSA isolation was associated with smaller hospitals (odds ratio [OR], 0.97, or 3% decreased odds of CA-MRSA isolation per 1,000 annual admissions; P < .001), hospitals with more Medicaid-insured patients (OR, 1.2; P = .002), and hospitals with more patients with low comorbidity scores (OR, 1.3; P < .001). Results were similar when restricted to isolates from patients with hospital-onset infection. CONCLUSIONS: Among 30 hospitals, CA-MRSA comprised nearly half of MRSA isolates. There was substantial variability in CA-MRSA penetration across hospitals, with more CA-MRSA in smaller hospitals with healthier but socially disadvantaged patient populations. Additional research is needed to determine whether infection control strategies can be successful in targeting CA-MRSA influx

Social Transmission of Avoidance Behavior under Situational Change in Learned and Unlearned Rats

BACKGROUND: Rats receive information from other conspecifics by observation or other types of social interaction. Such social interaction may contribute to the effective adaptation to changes of environment such as situational switching. Learning to avoid dangerous places or objects rapidly occurs with even a single conditioning session, and the conditioned memory tends to be sustained over long periods. The avoidance is important for adaptation, but the details of the conditions under which the social transmission of avoidance is formed are unknown. We demonstrate that the previous experience of avoidance learning is important for the formation of behaviors for social transmission of avoidance and that the experienced rats adapt to a change of situation determined by the presence or absence of aversive stimuli. We systematically investigated social influence on avoidance behavior using a passive avoidance test in a light/dark two-compartment apparatus. METHODOLOGY/PRINCIPAL FINDINGS: Rats were divided into two groups, one receiving foot shocks and another with no aversive experience in a dark compartment. Experienced and inexperienced rats were further divided into subjects and partners. In Experiment 1, each subject experienced (1) interaction with an experienced partner, (2) interaction with an inexperienced partner, or (3) no interaction. In Experiment 2, each subject experienced interaction with a partner that received a shock. The entering latency to a light compartment was measured. The avoidance behavior of experienced rats was inhibited by interaction with inexperienced or experienced partners in a safely-changed situation. The avoidance of experienced rats was reinstated in a dangerously-changed situation by interaction with shocked rats. In contrast, the inexperienced rats were not affected by any social circumstances. CONCLUSIONS/SIGNIFICANCE: These results suggest that transmitted information among rats can be updated under a situational change and that the previous experience is crucial for social enhancement and inhibition of avoidance behavior in rats

Effects of ecstasy/polydrug use on memory for associative information

Rationale Associative learning underpins behaviours that are fundamental to the everyday functioning of the individual. Evidence pointing to learning deficits in recreational drug users merits further examination. Objectives A word pair learning task was administered to examine associative learning processes in ecstasy/polydrug users. Methods After assignment to either single or divided attention conditions, 44 ecstasy/polydrug users and 48 non-users were presented with 80 word pairs at encoding. Following this, four types of stimuli were presented at the recognition phase: the words as originally paired (old pairs), previously presented words in different pairings (conjunction pairs), old words paired with new words, and pairs of new words (not presented previously). The task was to identify which of the stimuli were intact old pairs. Results Ecstasy/ploydrug users produced significantly more false-positive responses overall compared to non-users. Increased long-term frequency of ecstasy use was positively associated with the propensity to produce false-positive responses. It was also associated with a more liberal signal detection theory decision criterion value. Measures of long term and recent cannabis use were also associated with these same word pair learning outcome measures. Conjunction word pairs, irrespective of drug use, generated the highest level of false-positive responses and significantly more false-positive responses were made in the divided attention condition compared to the single attention condition. Conclusions Overall, the results suggest that long-term ecstasy exposure may induce a deficit in associative learning and this may be in part a consequence of users adopting a more liberal decision criterion value

Prospective memory functioning among ecstasy/polydrug users: evidence from the Cambridge Prospective Memory Test (CAMPROMPT)

Rationale: Prospective memory (PM) deficits in recreational drug users have been documented in recent years. However, the assessment of PM has largely been restricted to self-reported measures that fail to capture the distinction between event-based and time-based PM. The aim of the present study is to address this limitation. Objectives: Extending our previous research, we augmented the range laboratory measures of PM by employing the CAMPROMPT test battery to investigate the impact of illicit drug use on prospective remembering in a sample of cannabis only, ecstasy/polydrug and non-users of illicit drugs, separating event and time-based PM performance. We also administered measures of executive function and retrospective memory in order to establish whether ecstasy/polydrug deficits in PM were mediated by group differences in these processes. Results: Ecstasy/polydrug users performed significantly worse on both event and time-based prospective memory tasks in comparison to both cannabis only and non-user groups. Furthermore, it was found that across the whole sample, better retrospective memory and executive functioning was associated with superior PM performance. Nevertheless, this association did not mediate the drug-related effects that were observed. Consistent with our previous study, recreational use of cocaine was linked to PM deficits. Conclusions: PM deficits have again been found among ecstasy/polydrug users, which appear to be unrelated to group differences in executive function and retrospective memory. However, the possibility that these are attributable to cocaine use cannot be excluded

Advancing Tests of Relativistic Gravity via Laser Ranging to Phobos

Phobos Laser Ranging (PLR) is a concept for a space mission designed to advance tests of relativistic gravity in the solar system. PLR's primary objective is to measure the curvature of space around the Sun, represented by the Eddington parameter $\gamma$, with an accuracy of two parts in $10^7$, thereby improving today's best result by two orders of magnitude. Other mission goals include measurements of the time-rate-of-change of the gravitational constant, $G$ and of the gravitational inverse square law at 1.5 AU distances--with up to two orders-of-magnitude improvement for each. The science parameters will be estimated using laser ranging measurements of the distance between an Earth station and an active laser transponder on Phobos capable of reaching mm-level range resolution. A transponder on Phobos sending 0.25 mJ, 10 ps pulses at 1 kHz, and receiving asynchronous 1 kHz pulses from earth via a 12 cm aperture will permit links that even at maximum range will exceed a photon per second. A total measurement precision of 50 ps demands a few hundred photons to average to 1 mm (3.3 ps) range precision. Existing satellite laser ranging (SLR) facilities--with appropriate augmentation--may be able to participate in PLR. Since Phobos' orbital period is about 8 hours, each observatory is guaranteed visibility of the Phobos instrument every Earth day. Given the current technology readiness level, PLR could be started in 2011 for launch in 2016 for 3 years of science operations. We discuss the PLR's science objectives, instrument, and mission design. We also present the details of science simulations performed to support the mission's primary objectives.Comment: 25 pages, 10 figures, 9 table