Identification and Mechanistic Investigation of Drug-Drug Interactions Associated With Myopathy: A Translational Approach

Myopathy is a group of muscle diseases that can be induced or exacerbated by drug-drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% confidence interval [CI] = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00), and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine-simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the US Food and Drug Administration Adverse Event Reporting System

Associative memory in chronic schizophrenia: a computational model

We developed a computer model to simulate associative memory recall of patients with chronic schizophrenia. Model inputs consisted of words derived from normative data that differed in terms of connectivity and network size, with the former quantitatively represented by parametric weights and the latter by the specific number of word associates that formed a particular network. Previous behavioral studies of normal subjects indicated better recall for words of high connectivity-small network (HCSN), followed by low connectivity-small network (LCSN), high connectivity-large network (HCLN), and low connectivity-large network (LCLN). This pattern of recall differed from that observed in behavioral studies of schizophrenic patients, which showed better recall for high connectivity words, regardless of network size. Holding constant network size while manipulating connection weights effectively simulated this schizophrenic pattern of recall. That is, manipulation of parametric weights coupled with a slight increase in noise significantly and reliably elicited the response pattern of abnormal connectivity demonstrated in the prior behavioral study of patients with chronic schizophrenia. An increase in noise was a necessary, but insufficient step in modeling the response pattern of abnormal connectivity. These findings provide support for the use of computational models to investigate dynamics of associative word recall in patients with chronic schizophrenia

Functional connectivity among brain regions affected in Alzheimer's disease is associated with CSF TNF-alpha in APOE4 carriers

It is now recognized that understanding how neuroinflammation affects brain function may provide new insights into Alzheimer's pathophysiology. Tumor necrosis factor (TNF)-α, an inflammatory cytokine marker, has been implicated in Alzheimer's disease (AD), as it can impair neuronal function through suppression of long-term potentiation. Our study investigated the relationship between cerebrospinal fluid TNF-α and functional connectivity (FC) in a cohort of 64 older adults (μ age = 69.76 years; 30 cognitively normal, 34 mild AD). Higher cerebrospinal fluid TNF-α levels were associated with lower FC among brain regions important for high-level decision-making, inhibitory control, and memory. This effect was moderated by apolipoprotein E-ε4 (APOE4) status. Graph theory metrics revealed there were significant differences between APOE4 carriers at the node level, and by diagnosis at the network level suggesting global brain network dysfunction in participants with AD. These findings suggest proinflammatory mechanisms may contribute to reduced FC in regions important for high-level cognition. Future studies are needed to understand the role of inflammation on brain function and clinical progression, especially in APOE4 carriers

Gluonic and leptonic decays of heavy quarkonia and the determination of αs(mc)\alpha_s(m_c) and αs(mb)\alpha_s(m_b)

QCD running coupling constant $\alpha_s(m_c)$ and $\alpha_s(m_b)$ are determined from heavy quarkonia $c\overline{c}$ and $b\overline{b}$ decays. The decay rates of $V\rightarrow 3g$ and $V\rightarrow e^+ e^-$ for $V=J/\psi$ and $\Upsilon$ are estimated by taking into account both relativistic and QCD radiative corrections. The decay amplitudes are derived in the Bethe-Salpeter formalism, and the decay rates are estimated by using the meson wavefunctions which are obtained with a QCD-inspired inter-quark potential. For the $V\rightarrow 3g$ decay we find the relativistic correction to be very large and to severely suppress the decay rate. Using the experimental values of ratio R_g\equiv \frac {\Gamma (V\longrightarrow 3g)}% {\Gamma (V\longrightarrow e^{+}e^{-})}\approx 10,~32 for $V=J/\psi, ~\Upsilon$ respectively, and the calculated widths , we find $\alpha_{s}(m_c)=0.29\pm 0.02$ and $\alpha_s(m_b)=0.20\pm 0.02$. These values for the QCD running coupling constant are substantially enhanced, as compared with the ones obtained without relativistic corrections, and are consistent with the QCD scale parameter $\Lambda_{\overline {MS}}^{(4)}$. We also find that these results are mainly due to kinematic corrections and not sensitive to the dynamical models.Comment: 15 pages in Late

The possibility of detecting planets in the Andromeda Galaxy

The Angstrom Project is using a global network of 2m-class telescopes to conduct a high cadence pixel microlensing survey of the bulge of the Andromeda Galaxy (M31), with the primary aim of constraining its underlying bulge mass distribution and stellar mass function. Here we investigate the feasibility of using such a survey to detect planets in M31. We estimate the efficiency of detecting signals for events induced by planetary systems as a function of planet/star mass ratio and separation, source type and background M31 surface brightness. We find that for planets of a Jupiter-mass or above that are within the lensing zone (~1 -3 AU) detection is possible above 3 $\sigma$, with detection efficiencies ~3% for events associated with giant stars, which are the typical source stars of pixel-lensing surveys. A dramatic improvement in the efficiency of ~40 -- 60% is expected if follow-up observations on an 8m telescope are made possible by a real-time alert system.Comment: total 8 pages, including 8 figures, ApJ, submitte

Susceptibility to Scams in Older Black and White Adults

Previous reports on racial differences in scam susceptibility have yielded mixed findings, and few studies have examined reasons for any observed race differences. Older Black and White participants without dementia (N = 592) from the Minority Aging Research Study and the Rush Memory and Aging Project who completed a susceptibility to scam questionnaire and other measures were matched according to age, education, sex, and global cognition using Mahalanobis distance. In adjusted models, older Black adults were less susceptible to scams than older White adults (Beta = −0.2496, SE = 0.0649, p = 0.0001). Contextual factors did not mediate and affective factors did not moderate this association. Analyses of specific items revealed Black adults had greater knowledge of scam targeting of older adults and were less likely to pick up the phone for unidentified callers. Older Black adults are less susceptible to scams than demographically-matched older White adults, although the reasons remain unknown

The Advancing Understanding of Transportation Options (AUTO) study: design and methods of a multi-center study of decision aid for older drivers

Background: Decision-making about when to stop driving for older adults involves assessment of driving risk, availability of support or resources, and strong emotions about loss of independence. Although the risk of being involved in a fatal crash increases with age, driving cessation can negatively impact an older adult's health and well-being. Decision aids can enhance the decision-making process by increasing knowledge of the risks and benefits of driving cessation and improve decision quality. The impact of decision aids regarding driving cessation for older adults is unknown. Methods: The Advancing Understanding of Transportation Options (AUTO) study is a multi-site, two-armed randomized controlled trial that will test the impact of a decision aid on older adults' decisions about changes in driving behaviors and cessation. AUTO will enroll 300 drivers age ≥ 70 years with a study partner (identified by each driver); the dyads will be randomized into two groups (n = 150/group). The decision aid group will view the web-based decision aid created by Healthwise at baseline and the control group will review information about driving that does not include evidence-based elements on risks and benefits and values clarification about driving decisions. The AUTO trial will compare the effect of the decision aid, versus control, on a) immediate decision quality (measured by the Decisional Conflict Scale; primary outcome); b) longitudinal psychosocial outcomes at 12 and 24 months (secondary outcomes); and c) longitudinal driving behaviors (including reduction or cessation) at 12 and 24 months (secondary outcomes). Planned stratified analyses will examine the effects in subgroups defined by cognitive function, decisional capacity, and readiness to stop driving. Discussion: The AUTO study is the first large-scale randomized trial of a driving decision aid for older adults. Results from this study will directly inform clinical practice about how best to support older adults in decision-making about driving

Renal malformations associated with mutations of developmental genes: messages from the clinic

Renal tract malformations (RTMs) account for about 40% of children with end-stage renal failure. RTMs can be caused by mutations of genes normally active in the developing kidney and lower renal tract. Moreover, some RTMs occur in the context of multi-organ malformation syndromes. For these reasons, and because genetic testing is becoming more widely available, pediatric nephrologists should work closely with clinical geneticists to make genetic diagnoses in children with RTMs, followed by appropriate family counseling. Here we highlight families with renal cysts and diabetes, renal coloboma and Fraser syndromes, and a child with microdeletion of chromosome 19q who had a rare combination of malformations. Such diagnoses provide families with often long-sought answers to the question “why was our child born with kidney disease”. Precise genetic diagnoses will also help to define cohorts of children with RTMs for long-term clinical outcome studies