Validation of a Rodent Model of Chemotherapy-Induced Peripheral Neuropathy Using Oxaliplatin

poster abstractOxaliplatin (OXPL) is one of the most widely used and effective chemotherapeutic agents for colorectal cancer. However, the drug therapy is accompanied by severe dose-limiting off-target effects including tingling, burning pain and mechanical allodynia in the extremities of patients; together these symptomology is better known as chemotherapy-induced peripheral neuropathy (CIPN). The underlying pathophysiological mechanisms of CIPN are poorly understood and current therapeutic options only serve to alleviate the symptoms rather than prevent CIPN. To better understand mechanisms of OXPL-induced CIPN (OXPLN), we exposed adult female Sprague-Dawley rats to four intraperitoneal injections of vehicle or OXPL on alternative days. Behavioral results showed that thermal sensitivity failed to be affected by the OXPL. In contrast, the magnitude of mechanical allodynia increased such that the baseline withdrawal threshold for drug-treated animals was significantly lower than that for unprimed animals. Application of OXPL to afferent sensory neurons produced an increased amplitude and duration of compound action potentials that could be reversed with the voltage-gated sodium channel blocker, carbamazepine (CBZ). Astroglial and microglial markers glial fibrillary acidic protein (GFAP) and Iba-1 were imaged to examine glial reactivity in OXPLN at day 14. Microglia were not activated following OXPL whereas astrocytes exhibited increased GFAP fluorescence which paralleled OXPLN. Activation of astrocytes was prevented by co-administration of CBZ. These observations suggest that CBZ may serve to diminish OXPLN in the patient population. Oxaliplatin (OXPL) is one of the most widely used and effective chemotherapeutic agents for colorectal cancer. However, the drug therapy is accompanied by severe dose-limiting off-target effects including tingling, burning pain and mechanical allodynia in the extremities of patients; together these symptomology is better known as chemotherapy-induced peripheral neuropathy (CIPN). The underlying pathophysiological mechanisms of CIPN are poorly understood and current therapeutic options only serve to alleviate the symptoms rather than prevent CIPN. To better understand mechanisms of OXPL-induced CIPN (OXPLN), we exposed adult female Sprague-Dawley rats to four intraperitoneal injections of vehicle or OXPL on alternative days. Behavioral results showed that thermal sensitivity failed to be affected by the OXPL. In contrast, the magnitude of mechanical allodynia increased such that the baseline withdrawal threshold for drug-treated animals was significantly lower than that for unprimed animals. Application of OXPL to afferent sensory neurons produced an increased amplitude and duration of compound action potentials that could be reversed with the voltage-gated sodium channel blocker, carbamazepine (CBZ). Astroglial and microglial markers glial fibrillary acidic protein (GFAP) and Iba-1 were imaged to examine glial reactivity in OXPLN at day 14. Microglia were not activated following OXPL whereas astrocytes exhibited increased GFAP fluorescence which paralleled OXPLN. Activation of astrocytes was prevented by co-administration of CBZ. These observations suggest that CBZ may serve to diminish OXPLN in the patient population

Serum antioxidants as predictors of the adult respiratory distress syndrome in septic patients

Adult respiratory distress syndrome (ARDS) can develop as a complication of various disorders, including sepsis, but it has not been possible to identify which of the patients at risk will develop this serious disorder. We have investigated the ability of six markers, measured sequentially in blood, to predict development of ARDS in 26 patients with sepsis. At the initial diagnosis of sepsis (6-24 h before the development of ARDS), serum manganese superoxide dismutase concentration and catalase activity were higher in the 6 patients who subsequently developed ARDS than in 20 patients who did not develop ARDS. These changes in antioxidant enzymes predicted the development of ARDS in septic patients with the same sensitivity, specificity, and efficiency as simultaneous assessments of serum lactate dehydrogenase activity and factor VIII concentration. By contrast, serum glutathione peroxidase activity and α1Pi-elastase complex concentration did not differ at the initial diagnosis of sepsis between patients who did and did not subsequently develop ARDS, and were not as effective in predicting the development of ARDS. Measurement of manganese superoxide dismutase and catalase, in addition to the other markers, should facilitate identification of patients at highest risk of ARDS and allow prospective treatment

Control of Autophagosome Axonal Retrograde Flux by Presynaptic Activity Unveiled Using Botulinum Neurotoxin Type A

Botulinum neurotoxin type A (BoNT/A) is a highly potent neurotoxin that elicits flaccid paralysis by enzymatic cleavage of the exocytic machinery component SNAP25 in motor nerve terminals. However, recent evidence suggests that the neurotoxic activity of BoNT/A is not restricted to the periphery, but also reaches the CNS after retrograde axonal transport. Because BoNT/A is internalized in recycling synaptic vesicles, it is unclear which compartment facilitates this transport. Using live-cell confocal and single-molecule imaging of rat hippocampal neurons cultured in microfluidic devices, we show that the activity-dependent uptake of the binding domain of the BoNT/A heavy chain (BoNT/A-Hc) is followed by a delayed increase in retrograde axonal transport of BoNT/A-Hc carriers. Consistent with a role of presynaptic activity in initiating transport of the active toxin, activity-dependent uptake of BoNT/A in the terminal led to a significant increase in SNAP25 cleavage detected in the soma chamber compared with nonstimulated neurons. Surprisingly, most endocytosed BoNT/A-Hc was incorporated into LC3-positive autophagosomes generated in the nerve terminals, which then underwent retrograde transport to the cell soma, where they fused with lysosomes both in vitro and in vivo. Blocking autophagosome formation or acidification with wortmannin or bafilomycin A1, respectively, inhibited the activity-dependent retrograde trafficking of BoNT/A-Hc. Our data demonstrate that both the presynaptic formation of autophagosomes and the initiation of their retrograde trafficking are tightly regulated by presynaptic activity

Spin-1/2 frustrated antiferromagnet on a spatially anisotopic square lattice: contribution of exact diagonalizations

The phase diagram of a spin-1/2 $J-J'-J_2$ model is investigated by means of exact diagonalizations on finite samples. This model is a generalization of the $J_1-J_2$ model on the square lattice with two different nearest-neighbor couplings $J,J'$ and may be also viewed as an array of coupled Heisenberg chains. The results suggest that the resonnating valence bond state predicted by Nersesyan and Tsvelik [Phys. Rev. B {\bf 67}, 024422 (2003)] for $J_2=0.5J' \ll J$ is realized and extends beyond the limit of small interchain coupling along a curve nearly coincident with the line where the energy per spin is maximum. This line is likely bordered on both side by a columnar dimer long range order. This columnar order could extends for $J'\to J$ which correspond to the $J_1-J_2$ model.Comment: 14 pages, 21 figures, final versio

Generating mixtures of spatial qubits

In a recent letter [Phys. Rev. Lett. 94, 100501 (2005)], we presented a scheme for generating pure entangled states of spatial qudits ($D$-dimensional quantum systems) by using the momentum transverse correlation of the parametric down-converted photons. In this work we discuss a generalization of this process to enable the creation of mixed states. With the technique proposed we experimentally generated a mixture of two spatial qubits.Comment: To appear in Optics Communication

The fate of spinons in spontaneously dimerised spin-1/2 ladders

We study a weakly coupled, frustrated two-leg spin-1/2 Heisenberg ladder. For vanishing coupling between the chains, elementary excitations are deconfined, gapless spin-1/2 objects called spinons. We investigate the fate of spinons for the case of a weak interchain interaction. We show that despite a drastic change in ground state, which becomes spontaneously dimerised, spinons survive as elementary excitations but acquire a spectral gap. We furthermore determine the exact dynamical structure factor for several values of momentum transfer.Comment: 8 pages of revtex, 7 figures; discussion of physical picture for ground state and excitations in the "twistless" ladder expanded, version to appear in Phys Rev

Edge Detection, Cosmic Strings and the South Pole Telescope

We develop a method of constraining the cosmic string tension $G\mu$ which uses the Canny edge detection algorithm as a means of searching CMB temperature maps for the signature of the Kaiser-Stebbins effect. We test the potential of this method using high resolution, simulated CMB temperature maps. By modeling the future output from the South Pole Telescope project (including anticipated instrumental noise), we find that cosmic strings with $G\mu > 5.5\times10^{-8}$ could be detected.Comment: 27 pages, 5 figures, reference and minor notes added, discussion of noise expanded, explanation of equation (4) expande

Relations between Financing and Output in the Not-for-Profit Hospital

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68639/2/10.1177_107755878804500204.pd