Deletion of annexin 2 light chain p11 in nociceptors causes deficits in somatosensory coding and pain behavior

The S100 family protein p11 (S100A10, annexin 2 light chain) is involved in the trafficking of the voltage-gated sodium channel Na(V)1.8, TWIK-related acid-sensitive K+ channel (TASK-1), the ligand-gated ion channels acid-sensing ion channel 1a (ASIC1a) and transient receptor potential vanilloid 5/6 (TRPV5/V6), as well as 5-hydroxytryptamine receptor 1B (5-HT1B), a G-protein-coupled receptor. To evaluate the role of p11 in peripheral pain pathways, we generated a loxP-flanked (floxed) p11 mouse and used the Cre-loxP recombinase system to delete p11 exclusively from nociceptive primary sensory neurons in mice. p11-null neurons showed deficits in the expression of NaV1.8, but not of annexin 2. Damage-sensing primary neurons from these animals show a reduced tetrodotoxin-resistant sodium current density, consistent with a loss of membrane-associated NaV1.8. Noxious coding in wide-dynamic-range neurons in the dorsal horn was markedly compromised. Acute pain behavior was attenuated in certain models, but no deficits in inflammatory pain were observed. A significant deficit in neuropathic pain behavior was also apparent in the conditional-null mice. These results confirm an important role for p11 in nociceptor function

Revisiting the analytical solution approach to mixing-limited equilibrium multicomponent reactive transport using mixing ratios: identification of basis, fixing an error, and dealing with multiple minerals

Multicomponent reactive transport involves the solution of a system of nonlinear coupled partial differential equations. A number of methods have been developed to simplify the problem. In the case where all reactions are in instantaneous equilibrium and the mineral assemblage is constant in both space and time, de Simoni et al. (2007) provide an analytical solution that separates transport of aqueous components and minerals using scalar dissipation ofPeer ReviewedPostprint (published version

Analgesic Effects of GpTx-1, PF-04856264 and CNV1014802 in a Mouse Model of NaV1.7-Mediated Pain

Loss-of-function mutations of NaV1.7 lead to congenital insensitivity to pain, a rare condition resulting in individuals who are otherwise normal except for the inability to sense pain, making pharmacological inhibition of NaV1.7 a promising therapeutic strategy for the treatment of pain. We characterized a novel mouse model of NaV1.7-mediated pain based on intraplantar injection of the scorpion toxin OD1, which is suitable for rapid in vivo profiling of NaV1.7 inhibitors. Intraplantar injection of OD1 caused spontaneous pain behaviors, which were reversed by co-injection with NaV1.7 inhibitors and significantly reduced in NaV1.7−/− mice. To validate the use of the model for profiling NaV1.7 inhibitors, we determined the NaV selectivity and tested the efficacy of the reported NaV1.7 inhibitors GpTx-1, PF-04856264 and CNV1014802 (raxatrigine). GpTx-1 selectively inhibited NaV1.7 and was effective when co-administered with OD1, but lacked efficacy when delivered systemically. PF-04856264 state-dependently and selectively inhibited NaV1.7 and significantly reduced OD1-induced spontaneous pain when delivered locally and systemically. CNV1014802 state-dependently, but non-selectively, inhibited NaV channels and was only effective in the OD1 model when delivered systemically. Our novel model of NaV1.7-mediated pain based on intraplantar injection of OD1 is thus suitable for the rapid in vivo characterization of the analgesic efficacy of NaV1.7 inhibitors

A one-dimensional spot welding model

A one-dimensional model is proposed for the simulations of resistance spot welding, which is a common industrial method used to join metallic plates by electrical heating. The model consists of the Stefan problem, in enthalpy form, coupled with the equation of charge conservation for the electrical potential. The temperature dependence of the density, thermal conductivity, specific heat, and electrical conductivity are taken into account, since the process generally involves a large temperature range, on the order of 1000 K. The model is general enough to allow for the welding of plates of different thicknesses or dissimilar materials and to account for variations in the Joule heating through the material thickness due to the dependence of electrical resistivity on the temperature. A novel feature in the model is the inclusion of the effects of interface resistance between the plates which is also assumed to be temperature dependent. In addition to constructing the model, a finite difference scheme for its numerical approximations is described, and representative computer simulations are depicted. These describe welding processes involving different interface resistances, different thicknesses, different materials, and different voltage forms. The differences in the process due to AC or DC currents are depicted as well

Impact of the assimilation of ozone from the Tropospheric Emission Spectrometer on surface ozone across North America

We examine the impact of assimilating ozone observations from the Tropospheric Emission Spectrometer (TES) on North American surface ozone abundances in the GEOS-Chem model in August 2006. The assimilation reduces the negative bias in the modeled free tropospheric ozone, which enhances the ozone flux into the boundary layer. Surface ozone abundances increased by as much as 9 ppb in western North America and by less than 2 ppb in the southeast, resulting in a total background source of ozone of 20-40 ppb. The enhanced ozone in the model reduced the model bias with respect to surface ozone observations in the western USA, but exacerbated it in the east. This increase in the bias in the boundary layer in the east, despite the agreement between the assimilation and ozonesonde measurements in the free troposphere, suggests errors in the ozone sources or sinks or in boundary layer mixing in the model. © 2009

Cost and quality issues in establishing hematopoietic cell transplant program in developing countries

The hematopoietic cell transplant (HCT) activity has grown significantly over the past two decades in both developing and developed countries. Many challenges arise in establishing new HCT programs in developing countries, due to scarcity of resources and manpower in expertise in HCT. While cost issues can potentially hinder establishment of new HCT programs in certain regions, the focus on quality and value should be included in the general vision of leadership before establishing an HCT program. The main challenge in most developing countries is the lack of trained/qualified personnel, enormous start-up costs for a tertiary care center, and quality maintenance. Herein, we discuss the main challenges from a cost and quality perspective which occur at initiation of a new HCT program. We give real world examples of two developing countries that have recently started new HCT programs despite significant financial constraints. We also portray recommendations from the Worldwide Network of Blood and Marrow Transplantation for levels of requirements for a new HCT program. We hope that this review will serve as a general guide for new transplant program leadership with respect to the concerns of balancing high quality with concurrently lowering costs

Uterine mullerian adenosarcoma with sarcomatous overgrowth fatal recurrence within two weeks of diagnosis: a case report

Mullerian adenosarcoma with sarcomatous overgrowth (MASO) is a rare variant of uterine sarcomas, associated with postoperative recurrence, metastases and a fatal outcome. The mean age at diagnosis is 54.5 years. A 37-year-old nullipara presented with irregular vaginal bleeding, a normal pelvic examination, and an initially negative ultrasound. Repeat ultrasound one month later revealed an 11-cm heterogeneous pelvic mass. She underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Pathology confirmed uterine MASO. Computed tomography 2 weeks postoperatively showed a huge mass compatible with recurrence. Patient died 2 weeks later. MASO is rarely diagnosed in women in their 4th decade. This case stresses that these aggressive tumors should be considered in the differential of patients with vaginal bleeding and pelvic masses irrespective of their age

Massive stars as thermonuclear reactors and their explosions following core collapse

Nuclear reactions transform atomic nuclei inside stars. This is the process of stellar nucleosynthesis. The basic concepts of determining nuclear reaction rates inside stars are reviewed. How stars manage to burn their fuel so slowly most of the time are also considered. Stellar thermonuclear reactions involving protons in hydrostatic burning are discussed first. Then I discuss triple alpha reactions in the helium burning stage. Carbon and oxygen survive in red giant stars because of the nuclear structure of oxygen and neon. Further nuclear burning of carbon, neon, oxygen and silicon in quiescent conditions are discussed next. In the subsequent core-collapse phase, neutronization due to electron capture from the top of the Fermi sea in a degenerate core takes place. The expected signal of neutrinos from a nearby supernova is calculated. The supernova often explodes inside a dense circumstellar medium, which is established due to the progenitor star losing its outermost envelope in a stellar wind or mass transfer in a binary system. The nature of the circumstellar medium and the ejecta of the supernova and their dynamics are revealed by observations in the optical, IR, radio, and X-ray bands, and I discuss some of these observations and their interpretations.Comment: To be published in " Principles and Perspectives in Cosmochemistry" Lecture Notes on Kodai School on Synthesis of Elements in Stars; ed. by Aruna Goswami & Eswar Reddy, Springer Verlag, 2009. Contains 21 figure