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

The Tensor to Scalar Ratio of Phantom Dark Energy Models

We investigate the anisotropies in the cosmic microwave background in a class of models which possess a positive cosmic energy density but negative pressure, with a constant equation of state w = p/rho < -1. We calculate the temperature and polarization anisotropy spectra for both scalar and tensor perturbations by modifying the publicly available code CMBfast. For a constant initial curvature perturbation or tensor normalization, we have calculated the final anisotropy spectra as a function of the dark energy density and equation of state w and of the scalar and tensor spectral indices. This allows us to calculate the dependence of the tensor-to-scalar ratio on w in a model with phantom dark energy, which may be important for interpreting any future detection of long-wavelength gravitational waves.Comment: 5 pages, 4 figure

Diabetogenic drugs in the vervet monkey

Alloxan and streptozotocin were used to cause beta cell lysis in vervet monkeys used as recipient models for pancreatic allografts. Tests were performed on these animals to evaluate the effect of the drugs on carbohydrate metabolism. Streptozotocin is preferred as the drug of choice in creating a non-pancreatectomised hyperglycaemic recipient for pancreatic allografting.S. Afr. Med. J., 48, 273 (1974)

On the degree of scale invariance of inflationary perturbations

Many, if not most, inflationary models predict the power-law index of the spectrum of density perturbations is close to one, though not precisely equal to one, |n-1| \sim O(0.1), implying that the spectrum of density perturbations is nearly, but not exactly, scale invariant. Some models allow n to be significantly less than one (n \sim 0.7); a spectral index significantly greater than one is more difficult to achieve. We show that n \approx 1 is a consequence of the slow-roll conditions for inflation and ``naturalness,'' and thus is a generic prediction of inflation. We discuss what is required to deviate significantly from scale invariance, and then show, by explicit construction, the existence of smooth potentials that satisfy all the conditions for successful inflation and give $n$ as large as 2.Comment: 7 pages, 2 figures, submitted to Phys. Rev.

The seismic response to Faroe basalts from integrated borehole and wide-angle seismic data

We study the seismic response of layered basalts in the Faroe Islands using borehole data and\ud vertical seismic profiles from the Vestmanna borehole, combined with reflection and wideangle\ud seismic data recorded into arrays of both borehole and land multicomponent receivers.\ud Imaging through the basalt cover in the Faroe-Shetland Basin is a challenge for conventional\ud seismic surveys: scattering caused by the high reflectivity of the basalt as well as intra-basalt\ud multiples and high attenuation from the layered sequence make it difficult to image within\ud and beneath the basalts. This project allows us to correlate ultrasonic-scale velocity and\ud density measurements from the borehole together with ground-truthing from borehole logs\ud and core samples with the seismic-scale velocities and reflection images derived from VSP\ud and surface data. We find a good match of observed travel-times of borehole and wide-angle\ud P-wave data with those predicted from the borehole measurements, suggesting lateral\ud homogeneity over horizontal distances on the kilometre scale, and restricted transverse\ud anisotropy of the layered basalts. A pronounced intra-basalt reflector identified on the\ud multichannel surface seismic can be correlated with lithostratigraphic interpretation of the\ud borehole logs as caused by thick flows near the top of the Lower Basalt formation

Magnetic and pair correlations of the Hubbard model with next-nearest-neighbor hopping

A combination of analytical approaches and quantum Monte Carlo simulations is used to study both magnetic and pairing correlations for a version of the Hubbard model that includes second-neighbor hopping $t^{\prime }=-0.35t$ as a model for high-temperature superconductors. Magnetic properties are analyzed using the Two-Particle Self-Consistent approach. The maximum in magnetic susceptibility as a function of doping appears both at finite $$ and at $t^{\prime }=0$ but for two totally different physical reasons. When $t^{\prime }=0$, it is induced by antiferromagnetic correlations while at $t^{\prime }=-0.35t$ it is a band structure effect amplified by interactions. Finally, pairing fluctuations are compared with $$-matrix results to disentangle the effects of van Hove singularity and of nesting on superconducting correlations. The addition of antiferromagnetic fluctuations increases slightly the $d$-wave superconducting correlations despite the presence of a van Hove singularity which tends to decrease them in the repulsive model. Some aspects of the phase diagram and some subtleties of finite-size scaling in Monte Carlo simulations, such as inverted finite-size dependence, are also discussed.Comment: Revtex, 8 pages + 15 uuencoded postcript figure

Limits on the gravity wave contribution to microwave anisotropies

We present limits on the fraction of large angle microwave anisotropies which could come from tensor perturbations. We use the COBE results as well as smaller scale CMB observations, measurements of galaxy correlations, abundances of galaxy clusters, and Lyman alpha absorption cloud statistics. Our aim is to provide conservative limits on the tensor-to-scalar ratio for standard inflationary models. For power-law inflation, for example, we find T/S<0.52 at 95% confidence, with a similar constraint for phi^p potentials. However, for models with tensor amplitude unrelated to the scalar spectral index it is still currently possible to have T/S>1.Comment: 23 pages, 7 figures, accepted for publication in Phys. Rev. D. Calculations extended to blue spectral index, Fig. 6 added, discussion of results expande