The authors compared the efficacy of olanzapine and lithium in the prevention of mood episode relapse/recurrence.
Patients with a diagnosis of bipolar disorder (manic/mixed), a history of two or more ...manic or mixed episodes within 6 years, and a Young Mania Rating Scale total score > or =20 entered the study and received open-label co-treatment with olanzapine and lithium for 6-12 weeks. Those meeting symptomatic remission criteria (Young Mania Rating Scale score < or =12; 21-item Hamilton depression scale score < or =8) were randomly assigned to 52 weeks of double-blind monotherapy with olanzapine, 5-20 mg/day (N=217), or lithium (target blood level: 0.6-1.2 meq/liter) (N=214).
Symptomatic relapse/recurrence (score > or =15 on either the Young Mania Rating Scale or Hamilton depression scale) occurred in 30.0% of olanzapine-treated and 38.8% of lithium-treated patients. The noninferiority of olanzapine relative to lithium (primary objective) in preventing relapse/recurrence was met, since the lower limit of the 95% confidence interval on the 8.8% risk difference (-0.1% to 17.8%) exceeded the predefined noninferiority margin (-7.3%). Secondary results showed that compared with lithium, olanzapine had significantly lower risks of manic episode and mixed episode relapse/recurrence. Depression relapse/recurrence occurred in 15.7% of olanzapine-treated and 10.7% of lithium-treated patients. Mean weight gain during open-label co-treatment was 2.7 kg; during double-blind monotherapy, weight gain was significantly greater with olanzapine (1.8 kg) than with lithium (-1.4 kg).
These results suggest that olanzapine was significantly more effective than lithium in preventing manic and mixed episode relapse/recurrence in patients acutely stabilized with olanzapine and lithium co-treatment. Both agents were comparable in preventing depression relapse/recurrence.
The long baseline between Earth and the Sun makes solar neutrinos an excellent test beam for exploring possible neutrino decay. The signature of such decay would be an energy-dependent distortion of ...the traditional survival probability which can be fit for using well-developed and high-precision analysis methods. Here a model including neutrino decay is fit to all three phases of B8 solar neutrino data taken by the Sudbury Neutrino Observatory (SNO). This fit constrains the lifetime of neutrino mass state ν2 to be >8.08×10−5 s/eV at 90% confidence. An analysis combining this SNO result with those from other solar neutrino experiments results in a combined limit for the lifetime of mass state ν2 of >1.92×10−3 s/eV at 90% confidence.
In small volumes, the kinetics of filamentous protein self-assembly is expected to show significant variability, arising from intrinsic molecular noise. This is not accounted for in existing ...deterministic models. We introduce a simple stochastic model including nucleation and autocatalytic growth via elongation and fragmentation, which allows us to predict the effects of molecular noise on the kinetics of autocatalytic self-assembly. We derive an analytic expression for the lag-time distribution, which agrees well with experimental results for the fibrillation of bovine insulin. Our expression decomposes the lag-time variability into contributions from primary nucleation and autocatalytic growth and reveals how each of these scales with the key kinetic parameters. Our analysis shows that significant lag-time variability can arise from both primary nucleation and from autocatalytic growth and should provide a way to extract mechanistic information on early-stage aggregation from small-volume experiments.
Phase variation, or stochastic switching between alternative states of gene expression, is common among microbes, and may be important in coping with changing environments. We use a theoretical model ...to assess whether such switching is a good strategy for growth in environments with occasional catastrophic events. We find that switching can be advantageous, but only when the environment is responsive to the microbial population. In our model, microbes switch randomly between two phenotypic states, with different growth rates. The environment undergoes sudden catastrophes, the probability of which depends on the composition of the population. We derive a simple analytical result for the population growth rate. For a responsive environment, two alternative strategies emerge. In the no-switching strategy, the population maximizes its instantaneous growth rate, regardless of catastrophes. In the switching strategy, the microbial switching rate is tuned to minimize the environmental response. Which of these strategies is most favorable depends on the parameters of the model. Previous studies have shown that microbial switching can be favorable when the environment changes in an unresponsive fashion between several states. Here, we demonstrate an alternative role for phase variation in allowing microbes to maximize their growth in catastrophic responsive environments.
Abstract Osteoporosis is a prevalent bone condition, characterised by low bone mass and increased fracture risk. Currently, the gold standard for identifying osteoporosis and increased fracture risk ...is through quantification of bone mineral density (BMD) using dual energy X-ray absorption (DEXA). However, the risk of osteoporotic fracture is determined collectively by bone mass, architecture and physicochemistry of the mineral composite building blocks. Thus DEXA scans alone inevitably fail to fully discriminate individuals who will suffer a fragility fracture. This study examines trabecular bone at both ultrastructure and microarchitectural levels to provide a detailed material view of bone, and therefore provides a more comprehensive explanation of osteoporotic fracture risk. Physicochemical characterisation obtained through X-ray diffraction and infrared analysis indicated significant differences in apatite crystal chemistry and nanostructure between fracture and non-fracture groups. Further, this study, through considering the potential correlations between the chemical biomarkers and microarchitectural properties of trabecular bone, has investigated the relationship between bone mechanical properties (e.g. fragility) and physicochemical material features.
Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this ...decline whilst aiming to improve regeneration, we focused on phosphoinositide 3‐kinase (PI3K) and its product phosphatidylinositol (3,4,5)‐trisphosphate (PIP3). We demonstrate that adult PNS neurons utilise two catalytic subunits of PI3K for axon regeneration: p110α and p110δ. However, in the CNS, axonal PIP3 decreases with development at the time when axon transport declines and regenerative competence is lost. Overexpressing p110α in CNS neurons had no effect; however, expression of p110δ restored axonal PIP3 and increased regenerative axon transport. p110δ expression enhanced CNS regeneration in both rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110α. Furthermore, viral delivery of p110δ promoted robust regeneration after optic nerve injury. These findings establish a deficit of axonal PIP3 as a key reason for intrinsic regeneration failure and demonstrate that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion.
Synopsis
CNS axons lose the ability to regenerate with maturity, whilst PNS axons do not. This study shows that PIP3 levels decline in CNS neurons at the time when regenerative ability is lost. CNS overexpression of one isoform of PI3K, p110δ, enhances axonal PIP3, axon transport, and regenerative ability.
p110α and p110δ were found to be required for axon regeneration in adult PNS neurons, however PI3K and PIP3 declined in CNS neurons as they developed to maturity.
p110α or p110δ were overexpressed in mature CNS neurons, but only p110δ restored PIP3 and regeneration, whilst the activating H1047R mutation was required in p110α to promote regeneration similarly.
p110δ mediated regeneration through multiple downstream pathways, including mTOR, pS6, CRMP2, ARF6, and increased axonal transport of integrins and Rab11‐positive endosomes.
Transgenic expression of p110δ or hyperactive p110αH1047R stimulated axon regeneration after optic nerve injury and increased RGC survival, whilst viral delivery of p110δ led to further enhanced axon regeneration.
CNS axons lose the ability to regenerate with maturity, whilst PNS axons do not. This study shows that PIP3 levels decline in CNS neurons at the time when regenerative ability is lost. CNS overexpression of one isoform of PI3K, p110δ, enhances axonal PIP3, axon transport, and regenerative ability.
BACKGROUNDDespite the wide-ranging benefits of pulmonary rehabilitation, conflicting results remain regarding whether people with COPD can improve their peak oxygen uptake (V˙O2peak) with aerobic ...training. RESEARCH QUESTIONThe goal of this study was to investigate the effect of aerobic training and exercise prescription on V˙O2peak in COPD. STUDY DESIGN AND METHODSA systematic review was performed by using MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, and Cochrane databases for all studies measuring V˙O2peak prior to and following supervised lower-limb aerobic training in COPD. A random effects meta-analysis limited to randomized controlled trials comparing aerobic training vs usual care was conducted. Other study designs were included in a secondary meta-analysis and meta-regression to investigate the influence of program and patient factors on outcome. RESULTSA total of 112 studies were included (participants, N = 3,484): 21 controlled trials (n = 489), of which 13 were randomized (n = 288) and 91 were uncontrolled (n = 2,995) studies. Meta-analysis found a moderate positive change in V˙O2peak (standardized mean difference, 0.52; 95% CI, 0.34-0.69) with the intervention. The change in V˙O2peak was positively associated with target duration of exercise session (P = .01) and, when studies > 1 year duration were excluded, greater total volume of exercise training (P = .01). Similarly, the change in V˙O2peak was greater for programs > 12 weeks compared with those 6 to 12 weeks when adjusted for age and sex. However, reported prescribed exercise intensity (P = .77), training modality (P > .35), and mode (P = .29) did not affect V˙O2peak. Cohorts with more severe airflow obstruction exhibited smaller improvements in V˙O2peak (P < .001). INTERPRETATIONOverall, people with COPD achieved moderate improvements in V˙O2peak through supervised aerobic training. There is sufficient evidence to show that programs with greater total exercise volume, including duration of exercise session and program duration, are more effective. Reduced effects in severe disease suggest alternative aerobic training methods may be needed in this population. CLINICAL TRIAL REGISTRATIONPROSPERO; No.: CRD42018099300; URL: https://www.crd.york.ac.uk/prospero/.
We address the question: for which collections of finite simple groups does there exist an algorithm that determines the images of an arbitrary finitely presented group that lie in the collection? We ...prove both positive and negative results. For a collection of finite simple groups that contains infinitely many alternating groups, or contains classical groups of unbounded dimensions, we prove that there is no such algorithm. On the other hand, for families of simple groups of Lie type of bounded rank, we obtain positive results. For example, for any fixed untwisted Lie type
X
there is an algorithm that determines whether or not any given finitely presented group has simple images of the form
X
(
q
) for infinitely many
q
, and if there are finitely many, the algorithm determines them.
Kinetic roughening in active interfaces Cagnetta, Francesco; Evans, Martin R.; Marenduzzo, Davide
EPJ Web of Conferences,
2020, Letnik:
230
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
The essential features of many interfaces driven out of equilibrium are described by the same equation—the Kardar-Parisi-Zhang (KPZ) equation. How do living interfaces, such as the cell membrane, fit ...into this picture? In an endeavour to answer such a question, we proposed in F. Cagnetta, M. R. Evans, D. Marenduzzo, PRL 120, 258001 (2018) an idealised model for the membrane of a moving cell. Here we discuss how the addition of simple ingredients inspired by the dynamics of the membrane of moving cells affects common kinetic roughening theories such as the KPZ and Edwards-Wilkinson equations.
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