Cumulative sum (CUSUM) plots and methods have wide‐ranging applications in healthcare. We review and discuss some issues related to the analysis of surgical learning curve (LC) data with a focus on ...three types of CUSUM statistical approaches. The underlying assumptions, benefits, and weaknesses of each approach are given. Our primary conclusion is that two types of CUSUM methods are useful in providing visual aids, but are subject to overinterpretation due to the lack of well‐defined decision rules and performance metrics. The third type is based on plotting the CUSUM of the differences between observations and their average value. We show that this commonly applied retrospective method is frequently interpreted incorrectly and is thus unhelpful in the LC application. Curve‐fitting methods are more suitable for meeting many of the goals associated with the study of surgical LCs.
American efforts continue to help resolve intractable Israel-Palestine conflict. I. William Zartman, Amira Schiff, Galia Golan, Walid Salem, and Barry Steiner, seek here to enhance the American ...contribution to a two-state Israel-Palestine solution.
In a positron-emission tomography (PET) study with the β-amyloid (Aβ) tracer (18)F-florbetaben, we previously showed that Aβ deposition in transgenic mice expressing Swedish mutant APP (APP-Swe) mice ...can be tracked in vivo. γ-Secretase modulators (GSMs) are promising therapeutic agents by reducing generation of the aggregation prone Aβ42 species without blocking general γ-secretase activity. We now aimed to investigate the effects of a novel GSM 8-(4-Fluoro-phenyl)-1,2,4triazolo1,5-apyridin-2-yl-1-(3-methyl-1,2,4thiadiazol-5-yl)-piperidin-4-yl-amine (RO5506284) displaying high potency in vitro and in vivo on amyloid plaque burden and used longitudinal Aβ-microPET to trace individual animals. Female transgenic (TG) APP-Swe mice aged 12 months (m) were assigned to vehicle (TG-VEH, n=12) and treatment groups (TG-GSM, n=12), which received daily RO5506284 (30 mg kg(-1)) treatment for 6 months. A total of 131 Aβ-PET recordings were acquired at baseline (12 months), follow-up 1 (16 months) and follow-up 2 (18 months, termination scan), whereupon histological and biochemical analyses of Aβ were performed. We analyzed the PET data as VOI-based cortical standard-uptake-value ratios (SUVR), using cerebellum as reference region. Individual plaque load assessed by PET remained nearly constant in the TG-GSM group during 6 months of RO5506284 treatment, whereas it increased progressively in the TG-VEH group. Baseline SUVR in TG-GSM mice correlated with Δ%-SUVR, indicating individual response prediction. Insoluble Aβ42 was reduced by 56% in the TG-GSM versus the TG-VEH group relative to the individual baseline plaque load estimates. Furthermore, plaque size histograms showed differing distribution between groups of TG mice, with fewer small plaques in TG-GSM animals. Taken together, in the first Aβ-PET study monitoring prolonged treatment with a potent GSM in an AD mouse model, we found clear attenuation of de novo amyloidogenesis. Moreover, longitudinal PET allows non-invasive assessment of individual plaque-load kinetics, thereby accommodating inter-animal variations.
This work utilises advances in multi-tissue imaging, and incorporates new metrics which define in situ joint changes and individual tissue changes in osteoarthritis (OA). The aims are to (1) ...demonstrate a protocol for processing intact animal joints for microCT to visualise relevant joint, bone and cartilage structures for understanding OA in a preclinical rabbit model, and (2) introduce a comprehensive three-dimensional (3D) quantitative morphometric analysis (QMA), including an assessment of reproducibility. Sixteen rabbit joints with and without transection of the anterior cruciate ligament were scanned with microCT and contrast agents, and processed for histology. Semi-quantitative evaluation was performed on matching two-dimensional (2D) histology and microCT images. Subsequently, 3D QMA was performed; including measures of cartilage, subchondral cortical and epiphyseal bone, and novel tibio-femoral joint metrics. Reproducibility of the QMA was tested on seven additional joints. A significant correlation was observed in cartilage thickness from matching histology-microCT pairs. The lateral compartment of operated joints had larger joint space width, thicker femoral cartilage and reduced bone volume, while osteophytes could be detected quantitatively. Measures between the in situ tibia and femur indicated an altered loading scenario. High measurement reproducibility was observed for all new parameters; with ICC ranging from 0.754 to 0.998. In conclusion, this study provides a novel 3D QMA to quantify macro and micro tissue measures in the joint of a rabbit OA model. New metrics were established consisting of: an angle to quantitatively measure osteophytes (σ), an angle to indicate erosion between the lateral and medial femoral condyles (ρ), a vector defining altered angulation (λ, α, β, γ) and a twist angle (τ) measuring instability and tissue degeneration between the femur and tibia, a length measure of joint space width (JSW), and a slope and intercept (m, Χ) of joint contact to demonstrate altered loading with disease progression, as well as traditional bone and cartilage and histo-morphometry measures. We demonstrate correlation of microCT and histology, sensitive discrimination of OA change and robust reproducibility.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Projection neurons in the striatum give rise to two output systems, the "direct" and "indirect" pathways, which antagonistically regulate basal ganglia output. While all striatal projection neurons ...utilize GABA as their principal neurotransmitter, they express different opioid peptide co-transmitters and also different dopamine receptor subtypes. Neurons of the direct pathway express the peptide dynorphin and the D1 dopamine receptor, whereas indirect pathway neurons express the peptide enkephalin and the D2 receptor. In the present review, we summarize our findings on the function of dynorphin and enkephalin in these striatal output pathways. In these studies, we used D1- or D2-receptor-mediated induction of immediate-early genes as a cellular response in direct or indirect projection neurons, respectively, to investigate the role of these opioid peptides. Our results suggest that the specific function of dynorphin and enkephalin is to dampen excessive activation of these neurons by dopamine and other neurotransmitters. Levels of these opioid peptides are elevated by repeated, excessive activation of these pathways, which appears to be an adaptive or compensatory response. Behavioral consequences of increased opioid peptide function in striatal output pathways may include behavioral sensitization (dynorphin) and recovery of motor function (enkephalin).
Corticostriatal circuits participate in limbic, attentional, motor and other networks, and are implicated in psychostimulant addiction. The psychostimulant methylphenidate is used in the treatment of ...attention-deficit hyperactivity disorder and for recreational purposes. Recent studies indicate that methylphenidate alters gene expression in striatal neurons. We investigated whether methylphenidate affects gene regulation in specific corticostriatal circuits, by comparing drug-induced molecular changes in different functional domains of the striatum with changes in their cortical input regions. In order to assess the potential functional significance of methylphenidate-induced molecular changes, we examined members of two different classes of plasticity-related molecules, the transcription factor
zif 268 and the synaptic plasticity factor Homer 1a. Acute methylphenidate administration in adult rats increased the expression of Homer 1a and
zif 268 in both cortex and striatum in a dose-dependent and regionally selective manner. These changes in gene expression occurred after doses of 2 mg/kg (i.p.) and higher, and were highly correlated between cortical regions and their striatal targets. In the cortex, increases were maximal in the medial agranular (premotor) and cingulate cortex, followed by motor and somatosensory cortex, and were minimal in the insular cortex. Correspondingly, in the striatum, increases were most robust in sensorimotor sectors that receive medial agranular input, and were weaker or absent in ventral sectors. The methylphenidate-induced increases in cortical Homer 1a and
zif 268 expression were also correlated with increases in striatal substance P and dynorphin expression (direct pathway). Overall, the regional distribution of methylphenidate-induced molecular changes in the striatum was similar to that of changes induced by psychostimulants such as cocaine. These findings demonstrate that methylphenidate affects transcription and synaptic plasticity regulatory proteins in specific corticostriatal circuits, including those implicated in attentional functions and psychostimulant addiction. Such methylphenidate-induced gene regulation may contribute to the therapeutic effects and/or abuse liability of this psychostimulant.
Abstract Evidence indicates that dopamine receptors regulate processes of procedural learning in the sensorimotor striatum. Our previous studies revealed that the indirect dopamine receptor agonist ...cocaine alters motor-skill learning-associated gene regulation in the sensorimotor striatum. Cocaine-induced gene regulation in the striatum is principally mediated by D1 dopamine receptors. We investigated the effects of cocaine and striatal D1 receptor antagonism on motor-skill learning. Rats were trained on a running wheel (40–60 min, 2–5 days) to learn a new motor skill, that is, the ability to control the movement of the wheel. Immediately before each training session, the animals received an injection of vehicle or cocaine (25 mg/kg, i.p.), and/or the D1 receptor antagonist SCH-23390 (0, 3, 10 μg/kg, i.p., or 0, 0.3, 1 μg, intrastriatal via chronically implanted cannula). The animal's ability to control/balance the moving wheel (wheel skill) was tested before and repeatedly after the training. Normal wheel-skill memory lasted for at least 4 weeks. Cocaine administered before the training tended to attenuate skill learning. Systemic administration of SCH-23390 alone also impaired skill learning. However, cocaine given in conjunction with the lower SCH-23390 dose (3 μg/kg) reversed the inhibition of skill learning produced by the D1 receptor antagonist, enabling intact skill performance during the whole post-training period. In contrast, when cocaine was administered with the higher SCH-23390 dose (10 μg/kg), skill performance was normalized 1–6 days after the training, but these rats lost their improved wheel skill by day 18 after the training. Similar effects were produced by SCH-23390 (0.3–1 μg) infused into the striatum. Our results indicate that cocaine interferes with normal motor-skill learning, which seems to be dependent on optimal D1 receptor signaling. Furthermore, our findings demonstrate that D1 receptors in the striatum are critical for consolidation of long-term skill memory.
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