Oxidant stress as a regulator of renal function in disease

There is evidence to suggest that oxidant injury plays a part in the pathogenesis of renal impairment in a number of conditions. Rhabdomyolysis and liver disease were studied because oxidant stress has been previously implicated in the renal impairment of these conditions. In this thesis oxidative stress was assessed by quantification of the plasma, urine and tissue F2-isoprostanes, which are prostaglandin-like compounds formed by peroxidation of arachidonic acid and have been shown to be excellent markers of lipid peroxidation in vivo. These compounds also possess biological activity and can cause renal vasoconstriction, raising the possibility that they may themselves be modulators of renal dysfunction. Studies in the acute bile duct ligated animal, a model of renal dysfunction in liver disease, there was marked lipid peroxidation but treatment with effective anti-oxidants confers some, but incomplete protection against renal impairment. Moreover, N-acetylcysteine conferred good protection against development of renal failure, but was relatively ineffective at inhibiting lipid peroxidation, suggesting that a mechanism other than lipid peroxidation is involved. A pilot study demonstrated that N-acetylcysteine improved renal function in patients with the hepatorenal syndrome. By contrast the studies in patients with rhabdomyolysis as well as in an animal model of this syndrome demonstrate that oxidant injury and lipid peroxidation is important in the pathogenesis of this form of renal failure. However, in contrast to previous studies that implicate free iron as the initiator of oxidant injury, the work in this thesis implicates myoglobin itself, involving redox cycling of the haem iron, which remains co-ordinated within the protein. Alkalinization of the urine decreases oxidant injury to the kidney by stabilising one of the higher oxidation states of myoglobin. This has led to preliminary experimental work suggesting that antioxidants may be useful in preventing rhabdomyolysis-induced acute renal failure

Is the Compact Source at the Center of Cas A Pulsed?

A 50 ksec observation of the Supernova Remnant Cas A was taken using the Chandra X-Ray Observatory High Resolution Camera (HRC) to search for periodic signals from the compact source located near the center. Using the HRC-S in imaging mode, problems with correctly assigning times to events were overcome, allowing the period search to be extended to higher frequencies than possible with previous observations. In an extensive analysis of the HRC data, several possible candidate signals are found using various algorithms, including advanced techniques developed by Ransom to search for low significance periodic signals. Of the candidate periods, none is at a high enough confidence level to be particularly favored over the rest. When combined with other information, however (e.g., spectra, total energetics, and the historical age of the remnant), a 12 ms candidate period seems to be more physically plausible than the others, and we use it for illustrative purposes in discussing the possible properties of a putative neutron star in the remnant. We emphasize that this is not necessarily the true period, and that a follow-up observation, scheduled for the fall of 2001, is required. A 50 ksec Advanced CCD Imaging Spectrometer (ACIS) observation was taken, and analysis of these data for the central object shows that the spectrum is consistent with several forms, and that the emitted X-ray luminosity in the 0.1 -10 keV band is 10^{33}-10^{35}erg cm^{-2}sec^{-1} depending on the spectral model and the interstellar absorption along the line of sight to the source.Comment: 14 pages, 3 figures Submitted to ApJ 2001 June 2

Muscimol inactivation of the dorsal hippocampus impairs contextual retrieval of fear memory

Some models of hippocampal function have suggested a role of the hippocampus in contextual memory retrieval. We have examined this hypothesis by assessing the impact of reversible inactivation of the dorsal hippocampus (DH) on the context-specific expression of latent inhibition, a decrement in conditional responding produced by preexposure to a to-be-conditional stimulus. In Experiment 1, rats received tone preexposure either in the context that would later be used for extinction testing (context A) or in a different context (context C); a third group of rats did not receive tone preexposure. All rats then received fear conditioning, which consisted of tone-footshock pairings, in a third distinct context (context B). The following day conditional fear to the tone was assessed in one of the preexposure contexts (context A) by measuring freezing during a tone extinction test. Rats preexposed and tested in the same context exhibited less freezing to the tone than either rats preexposed and tested in different contexts or non-preexposed rats. These results indicate that the expression of latent inhibition is context specific. In Experiment 2, DH inactivation eliminated the context-specific expression of latent inhibition. Compared with saline-infused rats, rats infused with muscimol into the DH exhibited low levels of tone freezing independent of whether they had received tone preexposure in the test context or in a different context. Experiment 3 revealed normal contextual discrimination in rats after DH inactivation. These results suggest the DH is required for contextual memory retrieval in a latent inhibition paradigm.http://deepblue.lib.umich.edu/bitstream/2027.42/56237/1/holtJN99.pd

Nanoflow-nanospray mass spectrometry metabolomics reveals disruption of the urinary metabolite profiles of HIV-positive patients on combination antiretroviral therapy

Background: The use of combination antiretroviral therapy (cART) has substantially improved the outlook for patients with HIV infection. However, lifelong exposure to cART is also associated with adverse metabolic changes and an enhanced risk of renal, hepatic and cardiovascular dysfunction. This study investigated disruptions of the urinary metabolome of cART-exposed patients, thereby furthering our understanding of some of the side effects of pharmaceutical intervention. Methods: HIV-positive patients were recruited from an HIV clinic and divided into cART-naive and cART-exposed groups. HIV-negative patients were recruited from a sexual health clinic. All 89 subjects were white males. Targeted biochemistry analyses were performed on plasma samples. Urine samples were collected following an overnight fast and analysed with a highly sensitive untargeted metabolomic method using nanoflow/nanospray liquid chromatography-time of flight mass spectrometry. Datasets were analysed using projection modelling to detect metabolite markers of cART exposure. Results: Metabolites or parent compounds of all cART drugs were detected in urine extracts of all but one of the cART-exposed patients confirming adherence to the pharmaceutical regimen. Analysis of urine samples from patients on cART revealed significant reductions in selected bile acids, lipid, nucleoside and androgen metabolites. However, plasma concentrations of free or conjugated testosterone were unchanged indicating possible disruption of androgen transport or excretion in urine of patients on cART. Conclusions: Discovery-based metabolomics reveals the potential to identify novel markers of cART intervention and metabolite disruption in HIV-positive patients, which may enable the efficacy, compliance and side effects of these pharmaceutical mixtures to be investigated

The X-ray Remnant of SN1987A

We present high resolution Chandra observations of the remnant of SN1987A in the Large Magellanic Cloud. The high angular resolution of the Chandra X-ray Observatory (CXO) permits us to resolve the X-ray remnant. We find that the remnant is shell-like in morphology, with X-ray peaks associated with some of the optical hot spots seen in HST images. The X-ray light curve has departed from the linear flux increase observed by ROSAT, with a 0.5-2.0 keV luminosity of 1.5 x 10^35 erg/s in January 2000. We set an upper limit of 2.3 x 10^34 ergs/s on the luminosity of any embedded central source (0.5 - 2 keV). We also present a high resolution spectrum, showing that the X-ray emission is thermal in origin and is dominated by highly ionized species of O, Ne, Mg, and Si.Comment: 16 pages, 3 figures, Accepted for publication in ApJ Letter

Monitoring the Effects of Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide Switch for Tubulotoxicity in Highly Treatment-Experienced or in Very Sick Individuals Infected with HIV

Tenofovir disoproxil fumarate (TDF) is a common antiretroviral utilised in the treatment of human immunodeficiency virus (HIV) and hepatitis B infections. It is associated with the development of tubulotoxicity and tubulopathies, and is not recommended in the treatment of patients with baseline chronic kidney disease. Until now, guidelines have suggested frequent monitoring of serum biochemistry to detect the development of such complications. In recent trials, a new prodrug formulation of tenofovir alafenamide (TAF) has been shown to exhibit less tubular toxicity than its counterpart due to a lower serum concentration of its metabolites. In this article, we share our experience with two patients who developed tubulotoxicity following the commencement of TDF-based regimens in HIV, and its improvement following its change to TAF, and review the available literature regarding tenofovir-based nephrotoxicity