PARP inhibitor rucaparib induces changes in NAD levels in cells and liver tissues as assessed by MRS

Poly(adenosine diphosphate ribose) polymerases (PARPs) are multifunctional proteins which play a role in many cellular processes. Namely, PARP1 and PARP2 have been shown to be involved in DNA repair, and therefore are valid targets in cancer treatment with PARP inhibitors, such as rucaparib, currently in clinical trials. Proton magnetic resonance spectroscopy (¹H‐MRS) was used to study the impact of rucaparib in vitro and ex vivo in liver tissue from mice, via quantitative analysis of nicotinamide adenosine diphosphate (NAD⁺) spectra, to assess the potential of MRS as a biomarker of the PARP inhibitor response. SW620 (colorectal) and A2780 (ovarian) cancer cell lines, and PARP1 wild‐type (WT) and PARP1 knock‐out (KO) mice, were treated with rucaparib, temozolomide (methylating agent) or a combination of both drugs. ¹H‐MRS spectra were obtained from perchloric acid extracts of tumour cells and mouse liver. Both cell lines showed an increase in NAD⁺ levels following PARP inhibitor treatment in comparison with temozolomide treatment. Liver extracts from PARP1 WT mice showed a significant increase in NAD⁺ levels after rucaparib treatment compared with untreated mouse liver, and a significant decrease in NAD⁺ levels in the temozolomide‐treated group. The combination of rucaparib and temozolomide did not prevent the NAD⁺ depletion caused by temozolomide treatment. The ¹H‐MRS results show that NAD⁺ levels can be used as a biomarker of PARP inhibitor and methylating agent treatments, and suggest that in vivo measurement of NAD⁺ would be valuable.     

Keeping the body in mind: Insula functional organization and functional connectivity integrate interoceptive,exteroceptive, and emotional awareness

Relatively discrete experimental literatures have grown to support the insula's role in the domains of interoception, focal exteroceptive attention and cognitive control, and the experience of anxiety, even as theoretical accounts have asserted that the insula is a critical zone for integrating across these domains. Here we provide the first experimental demonstration that there exists a functional topography across the insula, with distinct regions in the same participants responding in a highly selective fashion for interoceptive, exteroceptive, and affective processing. Although each insular region is associated with areas of differential resting state functional connectivity relative to the other regions, overall their functional connectivity profiles are quite similar, thereby providing a map of how interoceptive, exteroceptive, and emotional awareness are integrated within the insular cortex. Hum Brain Mapp 34:2944–2958, 2013. © 2012 Wiley Periodicals, Inc.     

A low‐cost,mechanically simple apparatus for measuring eddy current‐induced magnetic fields in MRI

The fidelity of gradient waveforms in MRI pulse sequences is essential to the acquisition of images and spectra with minimal distortion artefacts. Gradient waveforms can become nonideal when eddy currents are created in nearby conducting structures; however, the resultant magnetic fields can be characterised and compensated for by measuring the spatial and temporal field response following a gradient impulse. This can be accomplished using a grid of radiofrequency (RF) coils. The RF coils must adhere to strict performance requirements: they must achieve a high sensitivity and signal‐to‐noise ratio (SNR), have minimal susceptibility field gradients between the sample and surrounding material interfaces and be highly decoupled from each other. In this study, an apparatus is presented that accomplishes these tasks with a low‐cost, mechanically simple solution. The coil system consists of six transmit/receive RF coils immersed in a high‐molarity saline solution. The sensitivity and SNR following an excitation pulse are sufficiently high to allow accurate phase measurements during free‐induction decays; the intrinsic susceptibility matching of the materials, because of the unique design of the coil system, results in sufficiently narrow spectral line widths (mean of 19 Hz), and adjacent RF coils are highly decoupled (mean S₁₂ of ?47 dB). The temporal and spatial distributions of eddy currents following a gradient pulse are measured to validate the efficacy of the design, and the resultant amplitudes and time constants required for zeroth‐ and first‐order compensation are provided. Copyright © 2013 John Wiley & Sons, Ltd.     

Impact of Community-Associated Methicillin Resistant Staphylococcus aureus on HIV-Infected Patients

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as an increasingly important pathogen, causing infections in persons who have no significant healthcare exposures. Persons with human immunodeficiency virus (HIV) infection have been disproportionately affected by CA-MRSA, with increased colonization and infection documented. Several factors are likely involved in the increased CA-MRSA burden observed among HIV-infected patients, including immune factors as well as healthcare and community exposures. Proposed community exposures that have been associated with increased CA-MRSA risk include substance abuse, incarceration, geographic area of residence, and social networks. This article explores these associations and reviews the current knowledge of the epidemiology, pathogenesis, clinical manifestations, and treatment of CA-MRSA in HIV-infected persons.     

Thrombotic thrombocytopenic purpura in a postoperative patient taking cephalexin responding to plasmapheresis: A case report and review of cephalosporin‐induced TTP

The clinical presentation of thrombotic thrombocytopenic purpura (TTP) is often atypical delaying diagnosis and treatment. A number of drugs have been implicated in the development of TTP, including cyclosporine, tacrolimus, clopidogrel, and quinine. To our knowledge, only three cases of cephalosporin‐induced TTP have been described, with two of these cases occurring with these use of cephalexin. We herein describe a case of TTP occurring in a postoperative patient taking cephalexin, requiring plasmapheresis. Following plasmapheresis, the patient's mental status and platelet count significantly improved. J. Clin. Apheresis 31:473–475, 2016. © 2015 Wiley Periodicals, Inc.     

Wound ballistic evaluation of the TASER® XREP ammunition

The Taser® eXtended Range Electronic Projectile (XREP®) is a wireless conducted electrical weapon (CEW) designed to incapacitate a person from a larger distance. The aim of this study was to analyze the ballistic injury potential of the XREP. Twenty rounds were fired from the Taser®X12 TM shotgun into ballistic soap covered with artificial skin and clothing at different shooting distances (1–25 m). One shot was fired at pig skin at a shooting distance of 10 m. The average projectile velocity was 67.0 m/s. The kinetic energy levels on impact varied from 28–52 J. Depending on the intermediate target, the projectiles penetrated up to 4.2 cm into the ballistic soap. On impact the nose assembly did not separate from the chassis, and no electrical activation was registered. Upon impact, a skin penetration of the XREP cannot be excluded. However, it is very unlikely at shooting distances of 10 m or more. Clothing and a high elasticity limit of the target body area can significantly reduce the penetration risk on impact.     

Performance of Older Depressed Patients on Two Cognitive Malingering Tests: False Positive Rates for the Rey 15-item Memorization and Dot Counting Tests

To our knowledge, no investigations have been undertaken to determine whether depression impacts performance on two commonly used tests to detect malingering of cognitive symptoms, the Rey 15-item Memorization Test and the Rey Dot Counting Test. This is a critical issue because of the high rate of depressive symptoms in patients with neurological conditions. It was hypothesized that depressed individuals, especially those with more severe depression, might be at risk for failing the tests, because these patients exhibit mild deficits in mental speed, visual perceptual/spatial skills, and visual memory, abilities required for successful completion of the malingering tests. However, examination of test performance in 64 older participants with major depression generally revealed very low false positive rates for most test scores, and severity of depression was unrelated to test scores. These results add to accumulating data supporting the validity of these cognitive malingering tests by documenting few false positive identifications.