Highlights • Myshkin mice exhibit a mania-related phenotype. • Melatonin and exercise are therapies that may be effective in treating mania. • Melatonin reduced mania behavior and increased REM sleep ...duration in Myshkin mice. • Wheel running reduced mania behavior in Myshkin mice. • Hippocampal BDNF was elevated in Myshkin mice and not affected by wheel running.
The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 ...systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% confidence interval (CI), 8.0-29.2%) among child contacts, 4.8% (95% CI, 3.0-7.7%) among adult contacts, 5.0% (95% CI, 1.6-14.5%) among migrants and 4.8% (95% CI, 1.5-14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal-external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82-0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide.
Members of the Eph family of receptor tyrosine kinases control many aspects of cellular interactions during development, including axon guidance. Here, we demonstrate that EphB2 also regulates ...postnatal synaptic function in the mammalian CNS. Mice lacking the EphB2 intracellular kinase domain showed wild-type levels of LTP, whereas mice lacking the entire EphB2 receptor had reduced LTP at hippocampal CA1 and dentate gyrus synapses. Synaptic NMDA-mediated current was reduced in dentate granule neurons in
EphB2 null mice, as was synaptically localized NR1 as revealed by immunogold localization. Finally, we show that EphB2 is upregulated in hippocampal pyramidal neurons in vitro and in vivo by stimuli known to induce changes in synaptic structure. Together, these data demonstrate that EphB2 plays an important role in regulating synaptic function.
Background Subcutaneous allergen immunotherapy (SCIT) and sublingual allergen immunotherapy (SLIT) are safe and effective treatments of allergic rhinitis, but high levels of compliance and ...persistence are crucial to achieving the desired clinical effects. Objective Our objective was to assess levels and predictors of compliance and persistence among grass pollen, tree pollen, and house dust mite immunotherapy users in real life and to estimate the costs of premature discontinuation. Methods We performed a retrospective analysis of a community pharmacy database from The Netherlands containing data from 6486 patients starting immunotherapy for 1 or more of the allergens of interest between 1994 and 2009. Two thousand seven hundred ninety-six patients received SCIT, and 3690 received SLIT. Time to treatment discontinuation was analyzed and included Cox proportional hazard models with time-dependent covariates, where appropriate. Results Overall, only 18% of users reached the minimally required duration of treatment of 3 years (SCIT, 23%; SLIT, 7%). Median durations for SCIT and SLIT users were 1.7 and 0.6 years, respectively ( P < .001). Other independent predictors of premature discontinuation were prescriber, with patients of general practitioners demonstrating longer persistence than those of allergologists and other medical specialists; single-allergen immunotherapy, lower socioeconomic status; and younger age. Of the persistent patients, 56% were never late in picking up their medication from the pharmacy. Direct medication costs per nonpersistent patient discontinuing in the third year of treatment were €3800, an amount that was largely misspent. Conclusion Real-life persistence is better in SCIT users than in SLIT users, although it is low overall. There is an urgent need for further identification of potential barriers and measures that will enhance persistence and compliance.
1 Department of Neuroscience, Howard Hughes
Medical Institute, Brown University, Providence, Rhode Island 02912;
and 2 Program in Developmental and Fetal Health,
Samuel Lunenfeld Research ...Institute, Toronto, Ontario M5G 1X5, Canada
Huber, Kimberly M.,
John
C. Roder, and
Mark F. Bear.
Chemical Induction of mGluR5- and Protein Synthesis-Dependent
Long-Term Depression in Hippocampal Area CA1. J. Neurophysiol. 86: 321-325, 2001. Recent work has
demonstrated that specific patterns of synaptic stimulation can induce
long-term depression (LTD) in area CA1 that depends on activation of
metabotropic glutamate receptors (mGluRs) and rapid protein synthesis.
Here we show that the same form of synaptic modification can be induced
by brief application of the selective mGluR agonist
(RS)-3,5-dihydroxyphenylglycine (DHPG). DHPG-LTD 1 ) is a
saturable form of synaptic plasticity, 2 ) requires mGluR5,
3 ) is mechanistically distinct from
N -methyl- D -aspartate receptor (NMDAR)-dependent
LTD, and 4 ) shares a common expression mechanism with
protein synthesis-dependent LTD evoked using synaptic stimulation.
DHPG-LTD should be useful for biochemical analysis of mGluR5- and
protein synthesis-dependent synaptic modification.
Several newly generated mouse embryonic stem (ES) cell lines were tested for their ability to produce completely ES cell-derived mice at early passage numbers by ES cell$\leftrightarrow$tetraploid ...embryo aggregation. One line, designated R1, produced live offspring which were completely ES cell-derived as judged by isoenzyme analysis and coat color. These cell culture-derived animals were normal, viable, and fertile. However, prolonged in vitro culture negatively affected this initial totipotency of R1, and after passage 14, ES cell-derived newborns died at birth. However, one of the five subclones (R1-S3) derived from single cells at passage 12 retained the original totipotency and gave rise to viable, completely ES cell-derived animals. The total in vitro culture time of the sublines at the time of testing was equivalent to passage 24 of the original line. Fully potent early passage R1 cells and the R1-S3 subclone should be very useful not only for ES cell-based genetic manipulations but also in defining optimal in vitro culture conditions for retaining the initial totipotency of ES cells.
P/Q-type presynaptic calcium currents (IpCa) undergo activity-dependent facilitation during repetitive activation at the calyx of the Held synapse. We investigated whether neuronal calcium sensor 1 ...(NCS-1) may underlie this phenomenon. Direct loading of NCS-1 into the nerve terminal mimicked activity-dependent IpCafacilitation by accelerating the activation time of IpCain a Ca2+-dependent manner. A presynaptically loaded carboxyl-terminal peptide of NCS-1 abolished IpCafacilitation. These results suggest that residual Ca2+activates endogeneous NCS-1, thereby facilitating IpCa. Because both P/Q-type Ca2+channels and NCS-1 are widely expressed in mammalian nerve terminals, NCS-1 may contribute to the activity-dependent synaptic facilitation at many synapses.
Unipolar depression and bipolar depression are prevalent and debilitating diseases in need of effective novel treatments. It is becoming increasingly evident that depressive disorders manifest from a ...combination of inherited susceptibility genes and environmental stress. Genetic mutations resulting in decreased neuronal Na+,K+‐ATPase (sodium‐potassium adenosine triphosphatase) activity may put individuals at risk for depression given that decreased Na+,K+‐ATPase activity is observed in depressive disorders and animal models of depression. Here, we show that Na+,K+‐ATPase α3 heterozygous mice (Atp1a3+/−), with 15% reduced neuronal Na+,K+‐ATPase activity, are vulnerable to develop increased depression‐like endophenotypes in a chronic variable stress (CVS) paradigm compared to wild‐type littermates (Atp1a3+/+). In Atp1a3+/+ mice CVS did not decrease Na+,K+‐ATPase activity, however led to despair‐like behavior in the tail suspension test (TST), anhedonia in a sucrose preference test and a minimal decrease in sociability, whereas in Atp1a3+/− mice CVS decreased neuronal Na+,K+‐ATPase activity to 33% of wild‐type levels, induced despair‐like behavior in the TST, anhedonia in a sucrose preference test, anxiety in the elevated plus maze, a memory deficit in a novel object recognition task and sociability deficits in a social interaction test. We found that a mutation that decreases neuronal Na+,K+‐ATPase activity interacts with stress to exacerbate depression. Furthermore, we observed an interesting correlation between Na+,K+‐ATPase activity and mood that may relate to both unipolar depression and bipolar disorder. Pharmaceuticals that increase Na+,K+‐ATPase activity or block endogenous Na+, K+‐ATPase inhibition may provide effective treatment for depressive disorders and preclude depression in susceptible individuals.
PDF
