Current and Future Issues in the Development of Spinal Agents for the Management of Pain.

Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety

Critical interfaces in the random-bond Potts model

We study geometrical properties of interfaces in the random-temperature q-states Potts model as an example of a conformal field theory weakly perturbed by quenched disorder. Using conformal perturbation theory in q-2 we compute the fractal dimension of Fortuin Kasteleyn domain walls. We also compute it numerically both via the Wolff cluster algorithm for q=3 and via transfer-matrix evaluations. We obtain numerical results for the fractal dimension of spin cluster interfaces for q=3. These are found numerically consistent with the duality kappa(spin) * kappa(FK)= 16 as expressed in putative SLE parameters.Comment: 4 page

Interacting crumpled manifolds

In this article we study the effect of a delta-interaction on a polymerized membrane of arbitrary internal dimension D. Depending on the dimensionality of membrane and embedding space, different physical scenarios are observed. We emphasize on the difference of polymers from membranes. For the latter, non-trivial contributions appear at the 2-loop level. We also exploit a ``massive scheme'' inspired by calculations in fixed dimensions for scalar field theories. Despite the fact that these calculations are only amenable numerically, we found that in the limit of D to 2 each diagram can be evaluated analytically. This property extends in fact to any order in perturbation theory, allowing for a summation of all orders. This is a novel and quite surprising result. Finally, an attempt to go beyond D=2 is presented. Applications to the case of self-avoiding membranes are mentioned

Blackbody radiation shift in a 43Ca+ ion optical frequency standard

Motivated by the prospect of an optical frequency standard based on 43Ca+, we calculate the blackbody radiation (BBR) shift of the 4s_1/2-3d_5/2 clock transition, which is a major component of the uncertainty budget. The calculations are based on the relativistic all-order single-double method where all single and double excitations of the Dirac-Fock wave function are included to all orders of perturbation theory. Additional calculations are conducted for the dominant contributions in order to evaluate some omitted high-order corrections and estimate the uncertainties of the final results. The BBR shift obtained for this transition is 0.38(1) Hz. The tensor polarizability of the 3d_5/2 level is also calculated and its uncertainty is evaluated as well. Our results are compared with other calculations.Comment: 4 page

C-Periodicity and the Physical Mass in the 3-State Potts Model

The standard infinite-volume definition of connected correlation function and particle mass in the 3-state Potts model can be implemented in Monte Carlo simulations by using C-periodic spatial boundary conditions. This avoids both the breaking of translation invariance (cold wall b.c.) and the phase-dependent and thus possibly biased evaluation of data (periodic boundary cconditions). The numerical feasibility of the standard definitions is demonstrated by sample computations on a 24*24*48 lattice.Comment: 13 pages + 5 figures Preprint Nos. IC/93/131 and TIFR/TH/93-2

Random RNA under tension

The Laessig-Wiese (LW) field theory for the freezing transition of random RNA secondary structures is generalized to the situation of an external force. We find a second-order phase transition at a critical applied force f = f_c. For f f_c, the extension L as a function of pulling force f scales as (f-f_c)^(1/gamma-1). The exponent gamma is calculated in an epsilon-expansion: At 1-loop order gamma = epsilon/2 = 1/2, equivalent to the disorder-free case. 2-loop results yielding gamma = 0.6 are briefly mentioned. Using a locking argument, we speculate that this result extends to the strong-disorder phase.Comment: 6 pages, 10 figures. v2: corrected typos, discussion on locking argument improve

Super-rough phase of the random-phase sine-Gordon model: Two-loop results

We consider the two-dimensional random-phase sine-Gordon and study the vicinity of its glass transition temperature $T_c$, in an expansion in small $\tau=(T_c-T)/T_c$, where $T$ denotes the temperature. We derive renormalization group equations in cubic order in the anharmonicity, and show that they contain two universal invariants. Using them we obtain that the correlation function in the super-rough phase for temperature $T<T_c$ behaves at large distances as $\bar{} = \mathcal{A}\ln^2(|x|/a) + \mathcal{O}[\ln(|x|/a)]$, where the amplitude $\mathcal{A}$ is a universal function of temperature $\mathcal{A}=2\tau^2-2\tau^3+\mathcal{O}(\tau^4)$. This result differs at two-loop order, i.e., $\mathcal{O}(\tau^3)$, from the prediction based on results from the "nearly conformal" field theory of a related fermion model. We also obtain the correction-to-scaling exponent.Comment: 34 page

TPX2 is required for postmitotic nuclear assembly in cell-free Xenopus laevis egg extracts

Cell division in many metazoa is accompanied by the disassembly of the nuclear envelope and the assembly of the mitotic spindle. These dramatic structural rearrangements are reversed after mitosis, when the mitotic spindle is dismantled and the nuclear envelope reassembles. The targeting protein for XKlp2 (TPX2) plays important roles in mitotic spindle assembly. We report that TPX2 depletion from nuclear assembly extracts prepared from Xenopus laevis eggs results in the formation of nuclei that are only about one fifth the size of control nuclei. TPX2-depleted nuclei assemble nuclear envelopes, nuclear pore complexes, and a lamina, and they perform nuclear-specific functions, including DNA replication. We show that TPX2 interacts with lamina-associated polypeptide 2 (LAP2), a protein known to be required for nuclear assembly in interphase extracts and in vitro. LAP2 localization is disrupted in TPX2-depleted nuclei, suggesting that the interaction between TPX2 and LAP2 is required for postmitotic nuclear reformation