A tree without leaves

The puzzle presented by the famous stumps of Gilboa, New York, finds a solution in the discovery of two fossil specimens that allow the entire structure of these early trees to be reconstructed

Use of Pharmacokinetic Modeling to Design Studies for Pathway-Specific Exposure Model Evaluation

Validating an exposure pathway model is difficult because the biomarker, which is often used to evaluate the model prediction, is an integrated measure for exposures from all the exposure routes and pathways. The purpose of this article is to demonstrate a method to use pharmacokinetic (PK) modeling and computer simulation to guide the design of field studies to validate pathway models. The children’s dietary intake model is discussed in detail as an example. Three important aspects are identified for a successful design to evaluate the children’s dietary intake model: a) longitudinally designed study with significant changes in the exposure for the route/pathway of interest, b) short biologic half-life of the selected chemical, and c) surface loading of the selected chemical at sufficient levels. Using PK modeling to guide a study design allowed a path-specific exposure model to be evaluated using urinary metabolite biomarkers

Remarks on the method of comparison equations (generalized WKB method) and the generalized Ermakov-Pinney equation

The connection between the method of comparison equations (generalized WKB method) and the Ermakov-Pinney equation is established. A perturbative scheme of solution of the generalized Ermakov-Pinney equation is developed and is applied to the construction of perturbative series for second-order differential equations with and without turning points.Comment: The collective of the authors is enlarged and the calculations in Sec. 3 are correcte

Open-label add-on treatment trial of minocycline in fragile X syndrome

<p>Abstract</p> <p>Background</p> <p>Fragile X syndrome (FXS) is a disorder characterized by a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socio-emotional problems. It is hypothesized that the absence of the fragile X mental retardation protein (FMRP) leads to higher levels of matrix metallo-proteinase-9 activity (MMP-9) in the brain. Minocycline inhibits MMP-9 activity, and alleviates behavioural and synapse abnormalities in <it>fmr1 </it>knockout mice, an established model for FXS. This open-label add-on pilot trial was conducted to evaluate safety and efficacy of minocycline in treating behavioural abnormalities that occur in humans with FXS.</p> <p>Methods</p> <p>Twenty individuals with FXS, ages 13-32, were randomly assigned to receive 100 mg or 200 mg of minocycline daily. Behavioural evaluations were made prior to treatment (baseline) and again 8 weeks after daily minocycline treatment. The primary outcome measure was the Aberrant Behaviour Checklist-Community Edition (ABC-C) Irritability Subscale, and the secondary outcome measures were the other ABC-C subscales, clinical global improvement scale (CGI), and the visual analog scale for behaviour (VAS). Side effects were assessed using an adverse events checklist, a complete blood count (CBC), hepatic and renal function tests, and antinuclear antibody screen (ANA), done at baseline and at 8 weeks.</p> <p>Results</p> <p>The ABC-C Irritability Subscale scores showed significant improvement (p < 0.001), as did the VAS (p = 0.003) and the CGI (p < 0.001). The only significant treatment-related side effects were minor diarrhea (n = 3) and seroconversion to a positive ANA (n = 2).</p> <p>Conclusions</p> <p>Results from this study demonstrate that minocycline provides significant functional benefits to FXS patients and that it is well-tolerated. These findings are consistent with the <it>fmr1 </it>knockout mouse model results, suggesting that minocycline modifies underlying neural defects that account for behavioural abnormalities. A placebo-controlled trial of minocycline in FXS is warranted.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Open-Label Trial NCT00858689.</p

Wideband THz time domain spectroscopy based on optical rectification and electro-optic sampling

We present an analytical model describing the full electromagnetic propagation in a THz time-domain spectroscopy (THz-TDS) system, from the THz pulses via Optical Rectification to the detection via Electro Optic-Sampling. While several investigations deal singularly with the many elements that constitute a THz-TDS, in our work we pay particular attention to the modelling of the time-frequency behaviour of all the stages which compose the experimental set-up. Therefore, our model considers the following main aspects: (i) pump beam focusing into the generation crystal; (ii) phase-matching inside both the generation and detection crystals; (iii) chromatic dispersion and absorption inside the crystals; (iv) Fabry-Perot effect; (v) diffraction outside, i.e. along the propagation, (vi) focalization and overlapping between THz and probe beams, (vii) electro-optic sampling. In order to validate our model, we report on the comparison between the simulations and the experimental data obtained from the same set-up, showing their good agreement

A nonsense mutation in the beta-carotene oxygenase 2 (BCO2) gene is tightly associated with accumulation of carotenoids in adipose tissue in sheep (Ovis aries)

<p>Abstract</p> <p>Background</p> <p>Sheep carcasses with yellow fat are sporadically observed at Norwegian slaughter houses. This phenomenon is known to be inherited as a recessive trait, and is caused by accumulation of carotenoids in adipose tissue. Two enzymes are known to be important in carotenoid degradation in mammals, and are therefore potential candidate genes for this trait. These are <it>beta-carotene 15,15'-monooxygenase 1 (BCMO1) </it>and the <it>beta-carotene oxygenase 2 (BCO2)</it>.</p> <p>Results</p> <p>In the present study the coding region of the <it>BCMO1 </it>and the <it>BCO2 </it>gene were sequenced in yellow fat individuals and compared to the corresponding sequences from control animals with white fat. In the yellow fat individuals a nonsense mutation was found in <it>BCO2 </it>nucleotide position 196 (<it>c.196C>T</it>), introducing a stop codon in amino acid position 66. The full length protein consists of 575 amino acids. In spite of a very low frequency of this mutation in the Norwegian AI-ram population, 16 out of 18 yellow fat lambs were found to be homozygous for this mutation.</p> <p>Conclusion</p> <p>In the present study a nonsense mutation (<it>c.196C>T</it>) in the <it>beta-carotene oxygenase 2 (BCO2) </it>gene is found to strongly associate with the yellow fat phenotype in sheep. The existence of individuals lacking this mutation, but still demonstrating yellow fat, suggests that additional mutations may cause a similar phenotype in this population. The results demonstrate a quantitatively important role for BCO2 in carotenoid degradation, which might indicate a broad enzyme specificity for carotenoids. Animals homozygous for the mutation are not reported to suffer from any negative health or development traits, pointing towards a minor role of BCO2 in vitamin A formation. Genotyping AI rams for <it>c.196C>T </it>can now be actively used in selection against the yellow fat trait.</p

Insights to advance our management of myocardial ischemia: From obstructive epicardial disease to functional coronary alterations.

STUDY OBJECTIVE: The Coronary Vasomotor Disorders International Study Group (COVADIS) invited leading experts to address strategies to enhance our clinical understanding of INOCA with an emphasis on the management of coronary vasomotor disorders. DESIGN: Under-recognition of coronary vasomotor disorders, distinguishing different presentations of angina due to vasospasm and/or abnormal microvascular vasodilatation, developing invasive/non-invasive testing and treatment protocols, integrating diagnostic protocols into cardiologists' workflow and trials to inform guideline development were identified as key knowledge gaps and will be briefly addressed in this Viewpoint article. SETTING: Virtual international meeting. PARTICIPANTS: Leading international experts in ischemic heart disease with no obstructive coronary artery disease. INTERVENTIONS: None. MAIN OUTCOME MEASURES: None. RESULTS: Topics discussed include: 1. Obstructive epicardial disease, functional vasospasm and microvascular disorders; 2. Under-recognition of coronary vasomotor disorders in clinical practice; 3. Complexity of coronary vasomotor disorders; 4. Understanding different presentations - vasospastic disease and microvascular angina; 5. Invasive/noninvasive testing and treatment protocols for vasospasm and microvascular angina assessment; 6. Treatment challenges; 7. Integrating diagnostic protocols into cardiologists' workflow; 8. The path forward to advance our approach to managing myocardial ischemia. CONCLUSIONS: Obstructive epicardial disease, functional vasospasm and microvascular disorders often co-exist and contribute to myocardial ischemia. Under-recognition, the complexity of coronary vasomotor disorders, understanding different presentations, testing and treatment protocols, treatment challenges, and integrating diagnostic protocols into cardiologists' workflow all contribute to the path forward to advance our management of myocardial ischemia for improved patient outcomes

Developing a utility index for the Aberrant Behavior Checklist (ABC-C) for fragile X syndrome

Purpose This study aimed to develop a utility index (the ABC-UI) from the Aberrant Behavior Checklist-Community (ABC-C), for use in quantifying the benefit of emerging treatments for fragile X syndrome (FXS). Methods The ABC-C is a proxy-completed assessment of behaviour and is a widely used measure in FXS. A subset of ABC-C items across seven dimensions was identified to include in health state descriptions. This item reduction process was based on item performance, factor analysis and Rasch analysis performed on an observational study dataset, and consultation with five clinical experts and a methodological expert. Dimensions were combined into health states using an orthogonal design and valued using time trade-off (TTO), with lead-time TTO methods used where TTO indicated a state valued as worse than dead. Preference weights were estimated using mean, individual level, ordinary least squares and random-effects maximum likelihood estimation [RE (MLE)] regression models. Results A representative sample of the UK general public (n = 349; mean age 35.8 years, 58.2 % female) each valued 12 health states. Mean observed values ranged from 0.92 to 0.16 for best to worst health states. The RE (MLE) model performed best based on number of significant coefficients and mean absolute error of 0.018. Mean utilities predicted by the model covered a similar range to that observed. Conclusions The ABC-UI estimates a wide range of utilities from patient-level FXS ABC-C data, allowing estimation of FXS health-related quality of life impact for economic evaluation from an established FXS clinical trial instrument

Decorrelation and efficient coding by retinal ganglion cells

An influential theory of visual processing asserts that retinal center-surround receptive fields remove spatial correlations in the visual world, producing ganglion cell spike trains that are less redundant than the corresponding image pixels. For bright, high-contrast images, this decorrelation would enhance coding efficiency in optic nerve fibers of limited capacity. We tested the central prediction of the theory and found that the spike trains of retinal ganglion cells were indeed decorrelated compared with the visual input. However, most of the decorrelation was accomplished not by the receptive fields, but by nonlinear processing in the retina. We found that a steep response threshold enhanced efficient coding by noisy spike trains and that the effect of this nonlinearity was near optimal in both salamander and macaque retina. These results offer an explanation for the sparseness of retinal spike trains and highlight the importance of treating the full nonlinear character of neural codes