Infectiousness in a Cohort of Brazilian Dogs: Why Culling Fails to Control Visceral Leishmaniasis in Areas of High Transmission

The elimination of seropositive dogs in Brazil has been used to control zoonotic visceral leishmaniasis but with little success. To elucidate the reasons for this, the infectiousness of 50 sentinel dogs exposed to natural Leishmania chagasi infection was assessed through time by xenodiagnosis with the sandfly vector, Lutzomyia longipalpis. Eighteen (43%) of 42 infected dogs became infectious after a median of 333 days in the field (105 days after seroconversion). Seven highly infectious dogs (17%) accounted for >80% of sandfly infections. There were positive correlations between infectiousness and anti-Leishmania immunoglobulin G, parasite detection by polymerase chain reaction, and clinical disease (logistic regression, r2 = 0.080.18). The sensitivity of enzyme-linked immunosorbent assay to detect currently infectious dogs was high (96%) but lower in the latent period (<63%), and specificity was low (24%). Mathematical modeling suggests that culling programs fail because of high incidence of infection and infectiousness, the insensitivity of the diagnostic test to detect infectious dogs, and time delays between diagnosis and culling

Detection of Leishmania infantum by PCR, serology and cellular immune response in a cohort study of Brazilian dogs

The sensitivity and specificity of PCR, serology (ELISA) and lymphoproliferative response to Leishmania antigen for the detection of Leishmania infantum infection were evaluated in a cohort of 126 dogs exposed to natural infection in Brazil. For PCR, Leishmania DNA from bone-marrow was amplified with both minicircle and ribosomal primers. The infection status and time of infection of each dog were estimated from longitudinal data. The sensitivity of PCR in parasite-positive samples was 98%. However, the overall sensitivity of PCR in post-infection samples, from dogs with confirmed infection, was only 68%. The sensitivity of PCR varied during the course of infection, being highest (78–88%) 0–135 days post-infection and declining to around 50% after 300 days. The sensitivity of PCR also varied between dogs, and was highest in sick dogs. The sensitivity of serology was similar in parasite-positive (84%), PCR-positive (86%) and post-infection (88%) samples. The sensitivity of serology varied during the course of infection, being lowest at the time of infection and high (93–100%) thereafter. Problems in determining the specificity of serology are discussed. The sensitivity and specificity of cellular responsiveness were low. These data suggest that PCR is most useful in detecting active or symptomatic infection, and that serology can be a more sensitive technique for the detection of all infected dogs

Tissue Cytokine Responses in Canine Visceral Leishmaniasis

To elucidate the local tissue cytokine response of dogs infected with Leishmania chagasi, cytokine mRNA levels were measured in bone marrow aspirates from 27 naturally infected dogs from Brazil and were compared with those from 5 uninfected control animals. Interferon-γ mRNA accumulation was enhanced in infected dogs and was positively correlated with humoral (IgG1) but not with lymphoproliferative responses to Leishmania antigen in infected dogs. Increased accumulation of mRNA for interleukin (IL)4, IL-10, and IL-18 was not observed in infected dogs, and mRNA for these cytokines did not correlate with antibody or proliferative responses. However, infected dogs with detectable IL-4 mRNA had significantly more severe symptoms. IL-13 mRNA was not detectable in either control or infected dogs. These data suggest that clinical symptoms are not due to a deficiency in interferon-γ production. However, in contrast to its role in human visceral leishmaniasis, IL-10 may not play a key immunosuppressive role in dogs

Glycemic Control Protocol Comparison using Virtual Trials

DTM2011 handbook/programme is given in files and also available as a hard copyBackground: Several accurate glycemic control (AGC) protocols for critical care patients exist but making comparisons is very hard. Objective: This study uses clinically validated virtual patient methods to compare safety and performance for several published AGC protocols. Method: Clinically validated virtual trials were run on 371 patients (39,481 hours, 26,646 measurements) created from the SPRINT AGC cohort. For protocols that do not modulate feed rates enteral nutrition was held at 100% of ACCP goal (25kcal/kg/day) when the patients were clinically fed, and parenteral nutrition rates were matched to clinical data. Performance was defined as %BG within glycemic bands and BG measurement frequency. Safety was defined as the incidence of severe (number patients with BG<40mg/dL) and moderate (%BG<72mg/dL) hypoglycemia. Clinical data from SPRINT is also compared. Results: Clinical SPRINT performance data matched re-simulated SPRINT with 86% vs. 86% BG in 80-145mg/dL, 2.00% vs. 2.07% BG above 180mg/dL and 7.83% vs. 7.29% BG below 72mg/dL, with 14 measurements (over 8 patients) of BG<40mg/dL. Yale results were 83.5%, 3.20%, 5.18%, with 6 severe hypoglycemic patients, using 37,961 measurements (23.0/day). Glucontrol had 75.2%, 3.70%, 9.45%, 52 cases and 26,199 measurements (15.8/day). Braithwaite had 84.2%, 3.00%, 4.22%, 19 cases and 24,396 measurements (14.8/day). The STAR (Stochastic TARgeted) model-based method had 90.6%, 1.67%, 1.33%, 5 cases and 20,591 measurements (12.3/day). Conclusions: Virtual trials provided an effective comparison across protocols with different target bands/values and different clinical cohorts. The model-based STAR protocol provided the best management of patient variability yielding the best performance and safety

SRSF1-dependent nuclear export of C9ORF72 repeat-transcripts: targeting toxic gain-of-functions induced by protein sequestration as a selective therapeutic strategy for neuroprotection

Microsatellite repeat expansions cause several incurable and lethal neurodegenerative disorders including ataxias, myotonic dystrophy, Huntington's disease and C9ORF72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Abnormal repeat transcripts generated from the expanded loci are substrates of repeat-associated non-AUG (RAN) translation, an unconventional form of translation leading to the production of polymeric repeat proteins with cytotoxic and aggregating properties. The mechanisms involved in the pathogenesis of microsatellite repeat expansion disorders remain a hotly debated topic. They are shared between toxic loss/gain of functions due to intranuclear RNA foci that sequesters RNA-binding proteins and RAN translation of repeat proteins in the cytoplasm. We recently elucidated the molecular mechanism driving the nuclear export of C9ORF72 repeat transcripts and showed for the first time that this pathway can be manipulated to confer neuroprotection. Strikingly, we discovered that intron-retaining C9ORF72 repeat transcripts hijack the physiological NXF1-dependent export pathway by selective RNA-repeat sequestration of SRSF1. Antagonizing SRSF1 and the nuclear export of C9ORF72 repeat transcripts promoted in turn the survival of patient-derived motor neurons and suppressed neurodegeneration-associated motor deficits in Drosophila (Hautbergue et al. Nature Communications 2017; 8:16063). In this invited Research Highlight review, we aim to place this work in the context of our previous studies on the nuclear export of mRNAs, provide a summary of the published research and highlight the significance of these findings as a novel therapeutic strategy for neuroprotection in C9ORF72-ALS/FTD. In addition, we emphasize that protein sequestration, often thought as of inducing loss-of-function mechanisms, can also trigger unwanted protein interactions and toxic gain-of-functions

Decoherence of electron spin qubits in Si-based quantum computers

Direct phonon spin-lattice relaxation of an electron qubit bound by a donor impurity or quantum dot in SiGe heterostructures is investigated. The aim is to evaluate the importance of decoherence from this mechanism in several important solid-state quantum computer designs operating at low temperatures. We calculate the relaxation rate $1/T_1$ as a function of [100] uniaxial strain, temperature, magnetic field, and silicon/germanium content for Si:P bound electrons. The quantum dot potential is much smoother, leading to smaller splittings of the valley degeneracies. We have estimated these splittings in order to obtain upper bounds for the relaxation rate. In general, we find that the relaxation rate is strongly decreased by uniaxial compressive strain in a SiGe-Si-SiGe quantum well, making this strain an important positive design feature. Ge in high concentrations (particularly over 85%) increases the rate, making Si-rich materials preferable. We conclude that SiGe bound electron qubits must meet certain conditions to minimize decoherence but that spin-phonon relaxation does not rule out the solid-state implementation of error-tolerant quantum computing.Comment: 8 figures. To appear in PRB-July 2002. Revisions include: some references added/corrected, several typos fixed, a few things clarified. Nothing dramati

Association of change in daily step count over five years with insulin sensitivity and adiposity: population based cohort study

Objectives: To investigate the association between change in daily step count and both adiposity and insulin sensitivity and the extent to which the association between change in daily step count and insulin sensitivity may be mediated by adiposity. Design: Population based cohort study. Setting: Tasmania, Australia. Participants: 592 adults (men (n=267), mean age 51.4 (SD 12.2) years; women (n=325), mean age 50.3 (12.3) years) who participated in the Tasmanian component of the national AusDiab Study in 2000 and 2005. Main outcome measures: Body mass index, waist to hip ratio, and HOMA insulin sensitivity at follow-up in 2005. Results: Over the five year period, the daily step count decreased for 65% (n=382) of participants. Having a higher daily step count in 2005 than in 2000 was independently associated with lower body mass index (0.08 (95% confidence interval 0.04 to 0.12) lower per 1000 steps), lower waist to hip ratio (0.15 (0.07 to 0.23) lower), and greater insulin sensitivity (1.38 (0.14 to 2.63) HOMA units higher) in 2005. The mean increase in HOMA units fell to 0.34 (-0.79 to 1.47) after adjustment for body mass index in 2005. Conclusions: Among community dwelling, middle aged adults, a higher daily step count at five year follow-up than at baseline was associated with better insulin sensitivity. This effect seems to be largely mediated through lower adiposity

Effective Lagrangian Approach to the Theory of Eta Photoproduction in the N∗(1535)N^{*}(1535) Region

We investigate eta photoproduction in the $N^{*}(1535)$ resonance region within the effective Lagrangian approach (ELA), wherein leading contributions to the amplitude at the tree level are taken into account. These include the nucleon Born terms and the leading $t$-channel vector meson exchanges as the non-resonant pieces. In addition, we consider five resonance contributions in the $s$- and $u$- channel; besides the dominant $N^{*}(1535)$, these are: $N^{*}(1440),N^{*}(1520),N^{*}(1650)$ and $N^{*}(1710)$. The amplitudes for the $\pi^\circ$ and the $\eta$ photoproduction near threshold have significant differences, even as they share common contributions, such as those of the nucleon Born terms. Among these differences, the contribution to the $\eta$ photoproduction of the $s$-channel excitation of the $N^{*}(1535)$ is the most significant. We find the off-shell properties of the spin-3/2 resonances to be important in determining the background contributions. Fitting our effective amplitude to the available data base allows us to extract the quantity $\sqrt{\chi \Gamma_\eta} A_{1/2}/\Gamma_T$, characteristic of the photoexcitation of the $N^{*}(1535)$ resonance and its decay into the $\eta$-nucleon channel, of interest to precise tests of hadron models. At the photon point, we determine it to be $(2.2\pm 0.2)\times 10^{-1} GeV^{-1}$ from the old data base, and $(2.2\pm 0.1) \times 10^{-1} GeV^{-1}$ from a combination of old data base and new Bates data. We obtain the helicity amplitude for $N^{*}(1535)\rightarrow \gamma p$ to be $A_{1/2}=(97\pm 7)\times 10^{-3} GeV^{-1/2}$ from the old data base, and $A_{1/2}=(97\pm 6)\times 10^{-3} GeV^{-1/2}$ from the combination of the old data base and new Bates data, compared with the results of the analysis of pion photoproduction yielding $74\pm 11$, in the same units.Comment: 43 pages, RevTeX, 9 figures available upon request, to appear in Phys. Rev.