Methoxetamine toxicity reported to the National Poisons Information Service: clinical characteristics and patterns of enquiries (including the period of the introduction of the UK's first Temporary Class Drug Order).

Objective: To report the demographic and clinical characteristics of cases of methoxetamine toxicity reported to The National Poisons Information Service (NPIS) by healthcare professionals. To assess the pattern of enquiries from health professionals to the UK NPIS related to methoxetamine, including the period of the making of the UK first Temporary Class Drug Order (TCDO).

Methods: All telephone enquiries to and user sessions for TOXBASE, the NPIS on-line information resource, related to methoxetamine (and synonyms 'MXE', 'mket' and '2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone') were reviewed from 1 April 2010 to 1 August 2012.

Evaluation of protective and restoring effects of a mixture of silanols on photoaging. Use of a device allowing the quantification of contractile strengths of human fibroblasts after UVA irradiation.

Chronic sun exposure and especially UVA wavelengths are responsible for long-term clinical skin changes such as photoageing and photocancers. The objectives of the present study were to analyse the contractile activity of fibroblasts irradiated with several doses of UVA and to evaluate the preventive, protective and restoring effects of a mixture of monomethylsilanetriol mannuronate and dimethylsilanediol salicylate. The forces generated by fibroblasts in tense collagen lattices were quantified using Glasbox device before and after UVA irradiation and the addition of a mixture of monomethylsilanetriol mannuronate and dimethylsilanediol salicylate.

ET-1 stimulates ERK signaling pathway through sequential activation of PKC and Src in rat myometrial cells.

In this study, we analyzed in rat myometrial cells the signaling pathways involved in the endothelin (ET)-1-induced extracellular signal-regulated kinase (ERK) activation required for the induction of DNA synthesis. We found that inhibition of protein kinase C (PKC) by Ro-31-8220 abolished ERK activation. Inhibition of phospholipase C (PLC) by U-73122 or of phosphoinositide (PI) 3-kinase by wortmannin partially reduced ERK activation.

Differential involvement of Src family kinases in pervanadate-mediated responses in rat myometrial cells.

We previously described that pervanadate, a potent tyrosine phosphatase inhibitor, induced contraction of rat myometrium via phospholipase (PL) C-gamma1 activation [Biol Reprod 54 (1996) 1383]. In this study, we found that pervanadate induced tyrosine phosphorylation of the platelet-derived growth factor (PDGF)-beta receptor, interaction of the phosphorylated PDGF receptor with the phosphorylated PLC-gamma1, production of inositol phosphates (InsPs), extracellular signal-regulated kinase (ERK) activation and DNA synthesis. All these responses were insensitive to PDGF receptor kinase inhibition or PDGF receptor down-regulation.

Platelet-derived growth factor stimulates phospholipase C-gamma 1, extracellular signal-regulated kinase, and arachidonic acid release in rat myometrial cells: contribution to cyclic 3',5'-adenosine monophosphate production and effect on cell proliferation.

In the present study, we examined downstream signaling events that followed exposure of cultured rat myometrial cells to platelet-derived growth factor (PDGF) and their effect on cell proliferation. PDGF-BB induced tyrosine phosphorylation of PDGF-beta receptors and increased inositol trisphosphate production via the tyrosine phosphorylation of phospholipase (PL)C-gamma 1. PDGF-BB also increased cAMP synthesis.

Phospholipase D in rat myometrium: occurrence of a membrane-bound ARF6 (ADP-ribosylation factor 6)-regulated activity controlled by betagamma subunits of heterotrimeric G-proteins.

Both protein kinase C and protein tyrosine kinases have been shown to be involved in phospholipase D (PLD) activation in intact rat myometrium [Le Stunff, Dokhac and Harbon (2000) J. Pharmacol. Exp.

Differential expression of inositol 1,4,5-trisphosphate receptor types 1, 2, and 3 in rat myometrium and endometrium during gestation.

The regulation of the phospholipase C (PLC) and the expression of inositol 1,4,5-trisphosphate receptors (IP(3)Rs) in terms of mRNA, proteins, and binding capacity were examined in the rat myometrium and endometrium at midgestation (Day 12) and at term (Day 21) comparatively to the estrogen-treated tissues (Day 0). In both uterine tissues, the production of inositol phosphates mediated by carbachol as well as by AlF(4)(-) was enhanced with advancing gestation. (3)[H]IP(3) binding sites in membranes also increased during pregnancy (Day 21 > Day 12 > Day 0).

The roles of protein kinase C and tyrosine kinases in mediating endothelin-1-stimulated phospholipase D activity in rat myometrium: differential inhibition by ceramides and cyclic AMP.

The aim of the present study was to investigate the mechanisms that regulate the activation of phospholipase D (PLD) by endothelin (ET)-1 in rat myometrium. We previously reported that ET-1 exerted part ( approximately 50%) of its effect via protein kinase C (PKC) activation. We now show that in addition to ET-1 and 4beta-phorbol-12,13-dibutyrate (PDBu), pervanadate also stimulated PLD activity.

A tyrosine kinase signaling pathway, regulated by calcium entry and dissociated from tyrosine phosphorylation of phospholipase Cgamma-1, is involved in inositol phosphate production by activated G protein-coupled receptors in myometrium.

Our experiments were conducted to evaluate, in rat myometrium, the potential contribution of a protein tyrosine kinase (PTK) pathway in the hydrolysis of phosphatidylinositol-4,5-bisphosphate mediated by bombesin, endothelin-1 (ET-1), and carbachol. The production of inositol phosphates (InsP) by agonists and AlF4- was partly inhibited (35-40%) by genistein and tyrphostins, two PTK inhibitors. Genistein attenuated uterine contractions elicited by the stimulation of muscarinic and bombesin receptors, whereas pervanadate, a protein tyrosine phosphatase inhibitor, potentiated receptor-mediated contraction.

Carbachol-induced desensitization of PLC-beta pathway in rat myometrium: downregulation of Gqalpha/G11alpha.

In the estrogen-treated rat myometrium, carbachol increased the generation of inositol phosphates by stimulating the muscarinic receptor-Gq/G11-phospholipase C-beta3 (PLC-beta3) cascade. Exposure to carbachol resulted in a rapid and specific (homologous) attenuation of the subsequent muscarinic responses in terms of inositol phosphate production, PLC-beta3 translocation to membrane, and contraction. Refractoriness was accompanied by a reduction of membrane muscarinic binding sites and an uncoupled state of residual receptors.

Activation of phospholipase D by endothelin-1 in rat myometrium. Role of calcium and protein kinase C.

In rat myometrium labeled with [3H]myristic acid, endothelin (ET)-1 via ET(A) receptors stimulated, in the presence of 0.3% butanol, the formation of [3H]phosphatidylbutanol ([3H]PBut) as a result of phospholipase D activity. Fluoroaluminates increased [3H]PBut generation, which indicated that a heterotrimeric G protein was involved.

Modulation of phospholipase C pathway and level of Gq alpha/G11 alpha in rat myometrium during gestation.

The regulation of the receptor-G protein-phospholipase C (PLC) cascade was investigated in rat myometrium at midgestation (day 12) and at term (day 21) comparatively to the estrogen-treated tissue (day 0). Carbachol-mediated generation of [3H]inositol phosphates was insensitive to pertussis toxin and was enhanced at days 12 and 21 two- and threefold, respectively, with no alteration of muscarinic sites (M3 subtype). A similar increase could be detected in the production of inositol 1,4,5-trisphosphate, indicating the stimulation of a PLC degrading phosphatidylinositol 4,5-bisphosphate.

Pervanadate mediated an increased generation of inositol phosphates and tension in rat myometrium. Activation and phosphorylation of phospholipase C-gamma 1.

Stimulation of [3H]inositol-labeled rat myometrial strips with pervanadate, formed by mixing orthovanadate and H2O2, induced a dose-dependent accumulation of [3H]inositol phosphates. Orthovanadate or H2O2 added alone had no effect. Pretreatment of myometrium with two tyrosine kinase inhibitors, namely genistein and tyrphostin 47 (at 100 microM), reduced pervanadate-stimulated inositol phosphate formation by 50%.

Beta adrenergic receptor activation attenuates the generation of inositol phosphates in the pregnant rat myometrium. Correlation with inhibition of Ca++ influx, a cAMP-independent mechanism.

In the pregnant rat myometrium, an averaged 30% of inositol phosphate accumulation induced by carbachol and oxytocin was inhibited by oxodipine indicating that a part of receptor-mediated generation of inositol phosphates depended on Ca++ influx through voltage-gated Ca++ channels. In fura-2-loaded cells, carbachol and oxytocin caused a two-phase [Ca++]i response, made up of a transient [Ca++]i peak of about 700 nM followed by a sustained phase of about 120 nM. Oxodipine reduced the [Ca++]i peak by 40% and the plateau phase by 50%, pointing to a contribution of Ca++ influx in both the [Ca++]i peak and sustained phase.

ETA receptors mediate activation of phospholipases C and D in rat myometrium.

In estrogen-treated rat myometrium, endothelin-1 (ET-1) activated both the phospholipase C (PLC) which degrades PtdInsP2, resulting in an increased accumulation of inositol phosphates, and the phospholipase D pathway (PLD) as evidenced in the presence of butanol by an increased production of phosphatidylbutanol (PBut). Both ET-1 effects displayed similar concentration dependencies (EC50 50 nM) and were mediated by ET(A) receptors in that they were antagonized by BQ123 and were elicited by ET-3 with a rank order of potency ET-1 >> ET-3. Bombesin, another activator of the PLC/PtdInsP2 pathway, also increased PBut accumulation.

Endothelin receptor type A signals both the accumulation of inositol phosphates and the inhibition of cyclic AMP generation in rat myometrium: stimulation and desensitization.

In estradiol-dominated rat myometrium, endothelin (ET)-1 caused contraction and increased the accumulation of [3H]inositol phosphates (EC50 = 70 nM), with the sequential generation of inositol trisphosphate, inositol bisphosphate, and inositol monophosphate. There was a coincident early decrease in phosphatidyl-inositol bisphosphate. The ET-1 stimulatory effect was pertussis toxin insensitive, suggesting an activation of phospholipase C via Gq/G11 proteins.

Activation of alpha-1A adrenoceptors mobilizes calcium from the intracellular stores in myocytes from rat portal vein.

Intracellular free Ca++ concentration ([Ca++]i) was monitored using the fluorescence from the dye fura-2-acetoxymethylester in single myocytes from rat portal vein. In the presence of oxodipine (a L-type Ca++ channel inhibitor), norepinephrine (10 microM) evoked transient increases in [Ca++]i which were related to release of Ca++ from intracellular stores. The alpha-1 adrenoceptors mediating intracellular Ca++ release and inositol phosphate accumulation were identified by using subtype-selective agonists and antagonists.

GRP-preferring bombesin receptors increase generation of inositol phosphates and tension in rat myometrium.

In the estrogen-treated rat myometrium, bombesin (Bn) and related agonists triggered contraction and the increased generation of inositol phosphates. The relative order of potencies was identical for both responses: Bn = gastrin releasing peptide (GRP) = litorin = neuromedin C >> neuromedin B. Two specific GRP-preferring receptor antagonists, namely [D-Phe6]Bn-(6-13) methyl ester and [Leu14,psi 13-14]Bn were inhibitory for both Bn-mediated tension and generation of inositol phosphates.

Diverse prostaglandin receptors activate distinct signal transduction pathways in rat myometrium.

Attempts were made to identify prostaglandin (PG) receptors in rat myometrium, according to the differential rank order of potencies displayed by the natural PGs and their analogues, both at the level of second messenger generation and contraction. In estrogen-treated rat myometrium, PGs [iloprost = PGI2 greater than PGE2 much greater than 16,16-dimethyl (DM)-PGE2; sulprostone = misoprostol = 0] induced adenosine 3',5'-cyclic monophosphate generation, indicating the contribution of a PGI2 receptor. The generation of inositol phosphates was stimulated by PGs (PGF2 alpha greater than PGD2 much greater than PGE2 = DM-PGE2 much greater than iloprost greater than sulprostone = misoprostol = 0), reflecting a PGF2 alpha-receptor-mediated process, which was insensitive to pertussis toxin (PTX).

Activation of beta-adrenergic receptors inhibits Ca2+ entry-mediated generation of inositol phosphates in the guinea pig myometrium, a cyclic AMP-independent event.

In the guinea pig myometrium, carbachol, oxytocin, and fluoroaluminates stimulated the breakdown of phosphatidylinositol 4,5-bisphosphate, which was insensitive to pertussis toxin [Biochem. J. 255:705-713 (1988)].

Characterization of G proteins in rat myometrium. A differential modulation of Gi2 alpha and Gi3 alpha during gestation.

Myometrial membranes, obtained from estrogen-dominated (day 0) rat uteri, were immunoblotted with antiserum (SG1), which recognizes the alpha subunits of both Gi1 and Gi2, with antiserum (LE2) specific for Gi2 alpha, and with I3B antiserum, specific for Gi3 alpha. The data revealed the absence of detectable levels of Gi1 alpha and the simultaneous presence of Gi2 alpha and Gi3 alpha as Gi subunits in rat myometrium. The expression of Gi proteins during gestation (days 0, 12, 21) was studied with the above antibodies.

[Value of a scapular flap in the treatment of axillary hidradenitis. Apropos of a clinical case].

A severe case of axillary hidradenitis suppurativa, treated bilaterally by large excision followed by reconstruction with a pedicled scapular flap is presented. This reliable and thin fasciocutaneous flap provides good cover of large axillary defects with minimal donor site consequences. Its advantage is discussed versus the other surgical procedures used in this pathology for axillary reconstruction.

[Morbidity of iliac bone grafts. A study apropos of 100 consecutive cases].

A study of the real morbidity after iliac bone graft harvesting was conducted on a homogenous series of 100 consecutive cases. Functional and aesthetic consequences were evaluated in relation to the immediate post-operative course and the long-term follow-up and in relation to the indication, the technique used and the amount of bone removed. Considering the small number of sequelae observed, autogenous iliac bone graft remains the best material for craniomaxillofacial reconstruction.

Prostaglandins and muscarinic agonists induce cyclic AMP attenuation by two distinct mechanisms in the pregnant-rat myometrium. Interaction between cyclic AMP and Ca2+ signals.

In pregnant-rat myometrium (day 21 of gestation), isoprenaline-induced cyclic AMP accumulation, resulting from receptor-mediated activation of adenylate cyclase, was negatively regulated by prostaglandins [PGE2, PGF2 alpha; EC50 (concn. giving 50% of maximal response) = 2 nM] and by the muscarinic agonist carbachol (EC50 = 2 microM). PG-induced inhibition was prevented by pertussis-toxin treatment, supporting the idea that it was mediated by the inhibitory G-protein Gi through the inhibitory pathway of the adenylate cyclase.