Anti-calmodulins and Tricyclic Adjuvants in Pain Therapy Block the TRPV1 Channel

Ca2+-loaded calmodulin normally inhibits multiple Ca2+-channels upon dangerous elevation of intracellular Ca2+ and protects cells from Ca2+-cytotoxicity, so blocking of calmodulin should theoretically lead to uncontrolled elevation of intracellular Ca2+. Paradoxically, classical anti-psychotic, anti-calmodulin drugs were noted here to inhibit Ca2+-uptake via the vanilloid inducible Ca2+-channel/inflamatory pain receptor 1 (TRPV1), which suggests that calmodulin inhibitors may block pore formation and Ca2+ entry. Functional assays on TRPV1 expressing cells support direct, dose-dependent inhibition of vanilloid-induced 45Ca2+-uptake at µM concentrations: calmidazolium (broad range)≥trifluoperazine (narrow range)>chlorpromazine/amitriptyline>fluphenazine>>W-7 and W-13 (only partially). Most likely a short acidic domain at the pore loop of the channel orifice functions as binding site either for Ca2+ or anti-calmodulin drugs. Camstatin, a selective peptide blocker of calmodulin, inhibits vanilloid-induced Ca2+-uptake in intact TRPV1+ cells, and suggests an extracellular site of inhibition. TRPV1+, inflammatory pain-conferring nociceptive neurons from sensory ganglia, were blocked by various anti-psychotic and anti-calmodulin drugs. Among them, calmidazolium, the most effective calmodulin agonist, blocked Ca2+-entry by a non-competitive kinetics, affecting the TRPV1 at a different site than the vanilloid binding pocket. Data suggest that various calmodulin antagonists dock to an extracellular site, not found in other Ca2+-channels. Calmodulin antagonist-evoked inhibition of TRPV1 and NMDA receptors/Ca2+-channels was validated by microiontophoresis of calmidazolium to laminectomised rat monitored with extracellular single unit recordings in vivo. These unexpected findings may explain empirically noted efficacy of clinical pain adjuvant therapy that justify efforts to develop hits into painkillers, selective to sensory Ca2+-channels but not affecting motoneurons

Suspected clinical toxoplasmosis in a 12-week-old puppy in Singapore

Abstract Background Toxoplasma gondii is traditionally known as a parasite of felids, with possible infection in intermediate hosts such as dogs and humans, and thus a disease of public health significance. Published data on the prevalence of toxoplasmosis in dogs and cats in Singapore is scanty, and this paper documents a suspect clinical case of toxoplasmosis in a free-roaming puppy trapped from an offshore island of Singapore. Case presentation A 12-week-old puppy presented with hindlimb weakness and sarcopenia, with rapidly progressing ascending paralysis and respiratory distress, one week after trapping. Toxoplasmosis was suspected after indirect fluorescence antibody testing (IFAT) revealed anti-T. gondii antibodies. The puppy responded quickly to clindamycin treatment and was discharged from hospital after 10 days. Conclusion While rare and undocumented, veterinary clinicians in Singapore are advised to also include toxoplasmosis infection as a differential diagnosis in dogs presenting with similar clinical signs. This is especially so for dogs which have access to the outdoors

Neodymium isotopic composition in foraminifera and authigenic phases of South China Sea sediments: implications for the hydrology of the North Pacific Ocean over the past 25 kyr

International audienceεNd and normalized Rare Earth Elements (REE) patterns of benthic and planktonic foraminifera and Fe-Mn coatings precipitated on sediments have been investigated for the South China Sea (SCS) to (1) assess the reliability of the extraction of past seawater εNd in the SCS and to (2) reconstruct past hydrological changes during the last 25 kyr. Reductively cleaned mono-specific planktonic foraminifera (Globigerinoides ruber) and mixed benthic foraminifera in core-top sediments from 1500 to 2400 m display similar εNd values to those of the modern Pacific Deep Water (PDW) (εNd of −3.9 to −4.4). Furthermore, the εNd of the reductive cleaning solutions shows similar εNd values to ones obtained on cleaned foraminifera. Combined with PAAS-normalized REE patterns, these results confirm that the oxidative and reductive cleaning procedure applied to foraminifera does not totally remove all of the Fe-Mn coatings and that εNd values yielded by cleaned planktonic foraminifera retain the εNd imprint of the bottom and/or pore water. εNd values obtained from a leaching procedure carried out on the bulk non-decarbonated sediments are comparable to the εNd values of the modern PDW, whereas a similar leaching procedure applied to decarbonated sediments reveals a bias due to contamination with Nd deriving from lithogenic particles. In core MD05-2904, seawater εNd, reconstructed from planktonic foraminifera, indicates that the last glacial period is characterized by lower εNd (−5.2 ± 0.2 to −6.4 ± 0.3) than the late Holocene (−4.1 ± 0.2). Assuming that Nd input from river does not change strongly the εNd of the PDW of the northern SCS, these εNd variations suggest a higher relative proportions of southern-sourced water in the deep water of the western subtropical Pacific Ocean during the last glacial period

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