Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors

BACKGROUND: Cannabinoid receptor agonists inhibit inflammatory hyperalgesia in animal models. Nonselective cannabinoid receptor agonists also produce central nervous system (CNS) side effects. Agonists selective for CB2 cannabinoid receptors, which are not found in the CNS, do not produce the CNS effects typical of nonselective cannabinoid receptor agonists but do inhibit acute nociception. The authors used the CB2 receptor-selective agonist AM1241 to test the hypothesis that selective activation of peripheral CB2 receptors inhibits inflammatory hyperalgesia. METHODS: Rats were injected in the hind paw with carrageenan or capsaicin. Paw withdrawal latencies were measured using a focused thermal stimulus. The effects of peripheral CB2 receptor activation were determined by using local injection of AM1241. CB2 receptor mediation of the actions of AM1241 was shown by using the CB2 receptor-selective antagonist AM630 and the CB1 receptor-selective antagonist AM251. RESULTS: AM1241 fully reversed carrageenan-induced inflammatory thermal hyperalgesia when injected into the inflamed paw. In contrast, AM1241 injected into the contralateral paw had no effect, showing that its effects were local. AM1241 also reversed the local edema produced by hind paw carrageenan injection. The effects of AM1241 were reversed by the CB2 receptor-selective antagonist AM630, but not by the CB1 receptor-selective antagonist AM251. AM1241 also inhibited flinching and thermal hyperalgesia produced by hind paw capsaicin injection. CONCLUSIONS: Local, peripheral CB2 receptor activation inhibits inflammation and inflammatory hyperalgesia. These results suggest that peripheral CB2 receptors may be an appropriate target for eliciting relief of inflammatory pain without the CNS effects of nonselective cannabinoid receptor agonists.     

Primitive neuroectodermal tumor of the vagina

OBJECTIVES: Primitive neuroectodermal tumor is grouped together with Ewing sarcoma of the bone, but its presentation includes a wider age range and more central locations than its osseous counterpart. Presentation in vagina is exceedingly rare. CASE: A 34-year-old woman with personal history of kidney transplant presented with a painless vaginal mass. After surgical excision, pathology results demonstrated a primitive neuroectodermal tumor. Chemotherapy was given, followed by external beam and vaginal intracavitary brachytherapy. After 20 months postexcision, there is no clinical nor radiographic evidence of recurrence. CONCLUSIONS: This is the second case of primitive neuroectodermal tumor located in the vagina reported in the literature.     

Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS

We designed AM1241, a selective CB2 cannabinoid receptor agonist, and used it to test the hypothesis that CB2 receptor activation would reverse the sensory hypersensitivity observed in neuropathic pain states. AM1241 exhibits high affinity and selectivity for CB2 receptors. It also exhibits high potency in vivo. AM1241 dose-dependently reversed tactile and thermal hypersensitivity produced by ligation of the L5 and L6 spinal nerves in rats. These effects were selectively antagonized by a CB2 but not by a CB1 receptor antagonist, suggesting that they were produced by actions of AM1241 at CB2 receptors. AM1241 was also active in blocking spinal nerve ligation-induced tactile and thermal hypersensitivity in mice lacking CB1 receptors (CB1-/- mice), confirming that AM1241 reverses sensory hypersensitivity independent of actions at CB1 receptors. These findings demonstrate a mechanism leading to the inhibition of pain, one that targets receptors localized exclusively outside the CNS. Further, they suggest the potential use of CB2 receptor-selective agonists for treatment of human neuropathic pain, a condition currently without consistently effective therapies. CB2 receptor-selective agonist medications are predicted to be without the CNS side effects that limit the effectiveness of currently available medications.     

A case of spontaneous innominate artery perforation with pericardial tamponade

We describe a case of a spontaneously occurring innominate artery perforation which, rather than resulting in immediate death, developed a subacute course with findings suggestive of an expanding mediastinal mass. The cause of the spontaneous perforation appears to have been a combination of atherosclerosis, infection, and infiltration of the underlying structures with malignancy. This is a unique case of subacute spontaneous perforation of a great vessel. © 1996 Wiley-Liss, Inc.     

State of the art in farm animal sperm evaluation

Our ability to screen the structural and functional integrity of the spermatozoon in vitro has increased markedly over the past decades, but our capacity to estimate the fertility of a semen sample or of the sire from which it has been collected, especially in selected farm animal breeders, has not. The estimation of fertility is constrained by several factors (e.g. type of cell, analysis strength, sperm deposition strategies, recordings of fertility), including the fact that the ejaculate is composed of a diverse sperm population. Such cell heterogeneity is reflected not only in differences in the intactness of attributes needed for fertilisation, such as motility or morphology, but also in the relative ability of the spermatozoa to remain fertile over time, to sustain selection steps and responses to exogenous stimuli similar to those during sperm transport in the female genital tract, all of which account for innate variations in the fertilising ability among doses, ejaculates and sires. Determination of how large such a sperm population with competence for fertilisation and in-built ability to display these attributes under physiological signalling is would allow for a better estimation o f fertility, provided that th e particular s ire produces this sub-population in a repeatable manner. The value of these analyses is discussed in the present paper.     

Tumor cell metabolism: an integral view

Cancer is a genetic disease that is caused by mutations in oncogenes, tumor suppressor genes and stability genes. The fact that the metabolism of tumor cells is altered has been known for many years. However, the mechanisms and consequences of metabolic reprogramming have just begun to be understood. In this review, an integral view of tumor cell metabolism is presented, showing how metabolic pathways are reprogrammed to satisfy tumor cell proliferation and survival requirements. In tumor cells, glycolysis is strongly enhanced to fulfill the high ATP demands of these cells; glucose carbons are the main building blocks in fatty acid and nucleotide biosynthesis. Glutaminolysis is also increased to satisfy NADPH regeneration, whereas glutamine carbons replenish the Krebs cycle, which produces metabolites that are constantly used for macromolecular biosynthesis. A characteristic feature of the tumor microenvironment is acidosis, which results from the local increase in lactic acid production by tumor cells. This phenomenon is attributed to the carbons from glutamine and glucose, which are also used for lactic acid production. Lactic acidosis also directs the metabolic reprogramming of tumor cells and serves as an additional selective pressure. Finally, we also discuss the role of mitochondria in supporting tumor cell metabolism.     

Resección completa de neurocitoma extraventricular hipervascularizado tras embolización preoperatoria

A 13-year-old female arrived at the Emergency Department with a two-week history of headache, and bilateral papilloedema on examination. The initial study with CT and MRI showed a large multicystic left frontal mass with calcification surrounded by peripheral oedema, subacute intralesional bleeding and association of multiple large vessels. She was initially operated on in another centre where a subacute haematoma was found, evacuating to multiple vessels and arteriolised veins. Despite the earlier neuroimaging findings, arteriovenous malformation (AVM) was suspected, so she was referred to our centre for further treatment. We performed angiography, MR angiography and MRI with advanced sequences, diagnosing a highly vascularised intra-axial tumour which was embolised. The patient was then definitively operated on, with the resulting finding of extraventricular neurocytoma (EVN). EVN are extremely rare lesions, not previously described in the literature as hypervascularised lesions, which in our case required prior angiography and embolisation for proper diagnosis and adequate management.     

Intralesional injections of Citoprot-P (recombinant human epidermal growth factor) in advanced diabetic foot ulcers with risk of amputation

To investigate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) in advanced diabetic foot ulcers (DFU) A double-blind trial was carried out to test two rhEGF dose levels in type 1 or 2 diabetes patients with Wagner's grade 3 or 4 ulcers, with high risk of amputation. Subjects were randomised to receive 75 (group I) or 25 mug (group II) rhEGF through intralesional injections, three times per week for 5-8 weeks together with standardised good wound care. Endpoints were granulation tissue formation, complete healing and need of amputation. Safety was assessed by clinical adverse events (AEs) and laboratory evaluations. Forty-one patients were included. After 5-8 weeks of treatment, 83% patients in the higher dose group and 61% in group II achieved useful granulation tissue covering more than 98% of the wound area. At long-term assessment, 13 (56.5%) patients healed in group I and 9 (50%) in group II. The mean time to complete healing in group I was 20.6 weeks (95% CI: 17.0-24.2) and 19.5 weeks (16.3-22.7) in group II. After 1-year follow-up, only one patient relapsed. Amputation was not necessary in 65% and 66.7% of groups I and II, respectively. The AEs rates were similar. The most frequent were sepsis (33%), burning sensation (29%), tremors, chills and local pain (25% each). rhEGF local injection enhances advanced DFU healing and reduces the risk of major amputation. No dose dependency was observed.