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The discriminative‐stimulus (SD) effects of CB1 ligands can be reproduced in mice by non‐selective inhibition of the anandamide‐(AEA‐) and 2‐arachidinoyl glycerol‐(2‐AG‐) inactivating ...enzymes, respectively, fatty‐acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MGL). Additionally, we have shown that nonselective FAAH/MGL inhibitors produce a CB1‐like SD effect in squirrel monkeys. The present studies with selective and nonselective ligands FAAH (URB597; AM2018), MGL (AM2036); and FAAH/MGL‐mixed (AM2129) were conducted to further evaluate the effects of FAAH and MGL inhibition in squirrel monkeys trained to discriminate the CB1 agonist AM4054 from vehicle (n=4). Results indicate that: 1) co‐administration of selective FAAH‐ and MGL‐inhibitors, but not FAAH‐ or MGL‐selective inhibitors alone, produces CB1‐related SD effects;2) AEA, but not 2‐AG, produces CB1‐like SD effects after either FAAH or mixed FAAH/MGL inhibition; and 3) CB1 receptor antagonism effectively and blocks the CB1‐like effects of combined FAAH/MGL inhibition; this effect was insurmountable. The present data strengthen the idea that complementary, but not individual, actions of the endocannabinoids AEA and 2‐AG produce CB1‐related SD, and perhaps subjective, effects in primate species.
Human endocannabinoid signaling is primarily mediated by the cannabinoid receptors, CB1 and CB2, which are G protein-coupled receptors (GPCRs). These receptors have been linked to a variety of ...physiological processes and are being pursued as prospective drug targets due to their potential in treating pain and inflammation. However, because of their homology and shared signaling mechanisms, investigating the individual physiological roles of these receptors and designing subtype-selective ligands has been challenging. Using active-state CB1 and CB2 structures as guides, homologous residues within the orthosteric pocket of each receptor were mutated to alanine to test whether they equally impair CB1 and CB2 activity in response to two high-affinity, nonselective agonists (CP55,940 and AM12033). Interestingly, mutating the Y5.39 position impairs CB1 but not CB2 function. Conversely, mutating residue C6.47 improves CB1 but impairs CB2 signaling. The F7.35A mutation leads to a decrease in CP55,940 potency at CB1 and impairs internalization; however, AM12033 gains potency and promotes CB1 internalization. In CB2, mutation of F7.35A decreases the potency of CP55,940 and neither agonist induces internalization. These observations provide some insight into functional sensitivity of CB1 and CB2 to different agonists when conserved residues are mutated in the orthosteric pocket.
Evidence-based guidelines are not currently available for the treatment of positional plagiocephaly and, in particular, for the use of physical therapy for treatment.
To answer the question: "does ...physical therapy provide effective treatment for positional plagiocephaly?" Treatment recommendations are created based on the available evidence.
The PubMed and the Cochrane Library were queried using MeSH headings and key words relevant to the objective of this systematic review. Abstracts were reviewed, after which studies meeting the inclusion criteria were selected and graded according to their quality of evidence (Classes I-III). Evidentiary tables were constructed that summarized pertinent study results, and recommendations were made based on the quality of the literature (Levels I-III).
Three studies met criteria for inclusion. Two randomized, controlled trials (Class I and Class II) and 1 prospective study assessing plagiocephaly as a secondary outcome measure (Class III) were included.
Within the limits of this systematic review, physical therapy is significantly more effective than repositioning education as a treatment for positional plagiocephaly. There is no significant difference between physical therapy and a positioning pillow as a treatment for positional plagiocephaly. However, given the American Academy of Pediatrics' recommendation against soft pillows in cribs to ensure a safe sleeping environment for infants, physical therapy must be recommended over the use of a positioning pillow. The full guidelines document can be located at https://www.cns.org/guidelines/guidelines-management-patients-positional-plagiocephaly/Chapter_4.
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Spontaneous cannabinoid (CB) withdrawal following exposure to Δ
9
‐tetrahydrocannabinol (THC) has been described man but has been inadequately characterized in mice. To address this ...issue, radiotelemetry was used to measure body temperature and locomotor activity in different groups of CD1 or C57 mice treated for 5–60 days with saline, 10–20 mg/kg/day of the CB partial agonist THC or 0.03–0.1 mg/kg/day of the CB high‐efficacy agonist AM2389. The effects of treatment were assessed throughout the regimen and for up to 10 days after the last injection to capture withdrawal‐related perturbations in thermoregulation or motor activity. Results show that acute exposure to AM2389 or THC decreased both temperature and activity. Rapid tolerance occurred to the hypothermic effects of the cannabinoids, whereas locomotor activity continued to be suppressed following each drug injection. In contrast, increases in locomotor activity were evident 12–72 hrs after discontinuing daily injections of AM2389, but not THC. Measurable effects following discontinuation of AM2389 injections were mild but reproducible across different groups of mice. These results indicate that the discontinuation of daily treatment with a CB high‐efficacy agonist will yield evidence of spontaneous withdrawal that may reflect prior dependence, but that the degree of cannabinoid dependence may vary in relation to the dose or efficacy of the agonist injected daily.
Support or Funding Information
Acknowledgements: Funded by NIH/NIDA: DA035411, DA031020
Pinopodes represent the morphological and integrins, the biomollecular markers of endometrial receptivity. We studied using scanning electron microscopy, the expression of pinopodes on tubal samples ...and their corresponding endometria, from 21 women of reproductive age (7 from proliferative phase, 7 from day LH +5 and 7 from day LH +7). In addition, we examined the immunohistochemical staining of integrins αvβ3, αvβ5 and their ligands, fibronectin (FN) and osteopontin (OPN) in the same tubal epithelium samples. Pinopodes were detected on the tubal epithelium exclusively during day LH +7, coincident with their formation in the endometrium and synchronous to αvβ3 sharp increase in the oviduct epithelium, suggesting a regulation similar to the endometrium. In contrast, αvβ5, FN and OPN remained unchanged during the cycle. These results show for the first time the formation of pinopodes in the tubal epithelium at the time of endometrial receptivity and correlate it with the upregulation of the intact dimmer αvβ3 in the tubes.
Duchenne muscular dystrophy (DMD) is an X‐linked muscle disorder characterized by progressive and irreversible loss of muscular function. As muscular disease progresses, the repair mechanisms cannot ...compensate for cellular damage, leading inevitably to necrosis and progressive replacement by fibrous and fatty tissue. Cardiomyopathy and respiratory failure are the main causes of death in DMD. In addition to the well‐described muscle and heart disease, cognitive dysfunction affects around 30% of DMD boys. Myocardial fibrosis, assessed by late gadolinium enhancement (LGE), using cardiovascular magnetic resonance imaging (CMR), is an early marker of heart involvement in both DMD patients and female carriers. In parallel, brain MRI identifies smaller total brain volume, smaller grey matter volume, lower white matter fractional anisotropy and higher white matter radial diffusivity in DMD patients. The in vivo brain evaluation of mdx mice, a surrogate animal model of DMD, showed an increased inorganic phosphate (P(i))/phosphocreatine (PCr) and pH. In this paper, we propose a holistic approach using techniques of magnetic resonance imaging, spectroscopy and diffusion tensor imaging as a tool to create a “heart and brain imaging map” in DMD patients that could potentially facilitate the patients’ risk stratification and also future research studies in the field.
Optical coherence tomography (OCT) is an increasingly used intravascular imaging modality to assess coronary stent implantation and vessel healing. A recently developed catheter (C7 Dragonfly; ...LightLab Imaging Inc.,Westford, MA, USA) allows visualisation of peripheral arteries up to 10 mm of diameter with high speed pullback. Safety, feasibility and the technique of OCT following carotid artery stenting (CAS) were evaluated in the present study.
OCT was performed in seven consecutive patients following successful CAS using proximal cerebral protection devices, occluding the common and external carotid artery and gentle manual injection of a total of 8-14 ml of 50% diluted contrast media with normal saline in order to displace the blood from the artery. Once the blood was displaced, pullback was started through the stented segment continuing the gentle contrast injection. After completion of the pullback all injected contrast was aspirated and discarded. In the first three patients, OCT was also performed without internal carotid artery flow blockage. Due to the high blood flow in the ICA it was not possible to replace all residual blood and obtain adequate OCT images. No procedural, in-hospital, or 30-day follow-up complications occurred. One patient experienced transient intolerance to vessel occlusion without any neurological sequels. OCT images were of good quality providing important information regarding stent geometry, presence and lack of strut apposition, plaque fracture, and plaque prolapse.
Intravascular OCT under occlusive proximal protection appears feasible and safe to assess stent implantation in carotid arteries.
ABSTRACT
Introduction: The dystrophinopathies include a spectrum of muscle diseases caused by mutations in the dystrophin (DMD) gene. The clinical phenotype ranges from severe Duchenne muscular ...dystrophy to a mild phenotype with elevated creatine kinase (CK). Methods: Clinical and molecular assessment of 7 patients carrying a single amino acid loss in the dystrophin protein (p.His1690del) caused by a c.5068_5070delCAC tri‐nucleotide deletion in exon 36 of the DMD gene. Results: All patients were asymptomatic or oligosymptomatic and had elevated CK levels. Febrile illness, but not exercise, induced muscle symptoms in some patients. None had evidence of cardiomyopathy. Analysis of the short tandem repeat (STR)45 locus and sequencing of exon 36 of the DMD gene indicates that c.5068_5070delCAC is a founder mutation. Conclusions: The c.5068_5070delCAC locus in the DMD gene is associated with a very mild phenotype. Further study is needed to evaluate disease progression in these patients. Muscle Nerve 55: 46–50, 2017
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