Detecting acute neurotoxicity during platinum chemotherapy by neurophysiological assessment of motor nerve hyperexcitability

<p>Abstract</p> <p>Background</p> <p>Platinum-based drugs, such as cisplatin and oxaliplatin, are well-known for inducing chronic sensory neuropathies but their acute and motor neurotoxicities are less well characterised. Use was made of nerve conduction studies and needle electromyography (EMG) to assess motor nerve excitability in cancer patients during their first treatment cycle with platinum-based chemotherapy in this study.</p> <p>Methods</p> <p>Twenty-nine adult cancer patients had a neurophysiological assessment either before oxaliplatin plus capecitabine, on days 2 to 4 or 14 to 20 after oxaliplatin plus capecitabine, or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin, undertaken by a neurophysiologist who was blinded to patient and treatment details. Patients completed a symptom questionnaire at the end of the treatment cycle.</p> <p>Results</p> <p>Abnormal spontaneous high frequency motor fibre action potentials were detected in 100% of patients (n = 6) and 72% of muscles (n = 22) on days 2 to 4 post-oxaliplatin, and in 25% of patients (n = 8) and 13% of muscles (n = 32) on days 14 to 20 post-oxaliplatin, but in none of the patients (n = 14) or muscles (n = 56) tested prior to oxaliplatin or on days 2 to 4 after carboplatin plus paclitaxel or cisplatin. Repetitive compound motor action potentials were less sensitive and less specific than spontaneous high frequency motor fibre action potentials for detection of acute oxaliplatin-induced motor nerve hyperexcitability but were present in 71% of patients (n = 7) and 32% of muscles (n = 32) on days 2 to 4 after oxaliplatin treatment. Acute neurotoxicity symptoms, most commonly cold-induced paraesthesiae and jaw or throat tightness, were reported by all patients treated with oxaliplatin (n = 22) and none of those treated with carboplatin plus paclitaxel or cisplatin (n = 6).</p> <p>Conclusions</p> <p>Abnormal spontaneous high frequency motor fibre activity is a sensitive and specific endpoint of acute oxaliplatin-induced motor nerve hyperexcitability, detectable on EMG on days 2 to 4 post-treatment. Objective EMG assessment of motor nerve excitability could compliment patient-reported symptomatic endpoints of acute oxaliplatin-induced neurotoxicity in future studies.</p

Inhibition of cerebrovascular raf activation attenuates cerebral blood flow and prevents upregulation of contractile receptors after subarachnoid hemorrhage

<p>Abstract</p> <p>Background</p> <p>Late cerebral ischemia carries high morbidity and mortality after subarachnoid hemorrhage (SAH) due to reduced cerebral blood flow (CBF) and the subsequent cerebral ischemia which is associated with upregulation of contractile receptors in the vascular smooth muscle cells (SMC) via activation of mitogen-activated protein kinase (MAPK) of the extracellular signal-regulated kinase (ERK)1/2 signal pathway. We hypothesize that SAH initiates cerebrovascular ERK1/2 activation, resulting in receptor upregulation. The raf inhibitor will inhibit the molecular events upstream ERK1/2 and may provide a therapeutic window for treatment of cerebral ischemia after SAH.</p> <p>Results</p> <p>Here we demonstrate that SAH increases the phosphorylation level of ERK1/2 in cerebral vessels and reduces the neurology score in rats in additional with the CBF measured by an autoradiographic method. The intracisternal administration of SB-386023-b, a specific inhibitor of raf, given 6 h after SAH, aborts the receptor changes and protects the brain from the development of late cerebral ischemia at 48 h. This is accompanied by reduced phosphorylation of ERK1/2 in cerebrovascular SMC. SAH per se enhances contractile responses to endothelin-1 (ET-1), 5-carboxamidotryptamine (5-CT) and angiotensin II (Ang II), upregulates ET_B, 5-HT_1Band AT₁receptor mRNA and protein levels. Treatment with SB-386023-b given as late as at 6 h but not at 12 h after the SAH significantly decreased the receptor upregulation, the reduction in CBF and the neurology score.</p> <p>Conclusion</p> <p>These results provide evidence for a role of the ERK1/2 pathway in regulation of expression of cerebrovascular SMC receptors. It is suggested that raf inhibition may reduce late cerebral ischemia after SAH and provides a realistic time window for therapy.</p

Identification of polyhydroxyalkanoates in Halococcus and other haloarchaeal species

Polyhydroxyalkanoates (PHAs) are accumulated in many prokaryotes. Several members of the Halobacteriaceae produce poly-3-hydroxybutyrate (PHB), but it is not known if this is a general property of the family. We evaluated identification methods for PHAs with 20 haloarchaeal species, three of them isolates from Permian salt. Staining with Sudan Black B, Nile Blue A, or Nile Red was applied to screen for the presence of PHAs. Transmission electron microscopy and 1H-nuclear magnetic resonance spectroscopy were used for visualization of PHB granules and chemical confirmation of PHAs in cell extracts, respectively. We report for the first time the production of PHAs by Halococcus sp. (Halococcus morrhuae DSM 1307T, Halococcus saccharolyticus DSM 5350T, Halococcus salifodinae DSM 8989T, Halococcus dombrowskii DSM 14522T, Halococcus hamelinensis JCM 12892T, Halococcus qingdaonensis JCM 13587T), Halorubrum sp. (Hrr. coriense DSM 10284T, Halorubrum chaoviator DSM 19316T, Hrr. chaoviator strains NaxosII and AUS-1), haloalkaliphiles (Natronobacterium gregoryi NCMB 2189T, Natronococcus occultus DSM 3396T) and Halobacterium noricense DSM 9758T. No PHB was detected in Halobacterium salinarum NRC-1 ATCC 700922, Hbt. salinarum R1 and Haloferax volcanii DSM 3757T. Most species synthesized PHAs when growing in synthetic as well as in complex medium. The polyesters were generally composed of PHB and poly-ß-hydroxybutyrate-co-3-hydroxyvalerate (PHBV). Available genomic data suggest the absence of PHA synthesis in some haloarchaea and in all other Euryarchaeota and Crenarchaeota. Homologies between haloarchaeal and bacterial PHA synthesizing enzymes had indicated to some authors probable horizontal gene transfer, which, considering the data obtained in this study, may have occurred already before Permian times

Effects of Elevated Temperature and Carbon Dioxide on the Growth and Survival of Larvae and Juveniles of Three Species of Northwest Atlantic Bivalves

Rising CO2 concentrations and water temperatures this century are likely to have transformative effects on many coastal marine organisms. Here, we compared the responses of two life history stages (larval, juvenile) of three species of calcifying bivalves (Mercenaria mercenaria, Crassostrea virginica, and Argopecten irradians) to temperatures (24 and 28°C) and CO2 concentrations (∼250, 390, and 750 ppm) representative of past, present, and future summer conditions in temperate estuaries. Results demonstrated that increases in temperature and CO2 each significantly depressed survival, development, growth, and lipid synthesis of M. mercenaria and A. irradians larvae and that the effects were additive. Juvenile M. mercenaria and A. irradians were negatively impacted by higher temperatures while C. virginica juveniles were not. C. virginica and A. irradians juveniles were negatively affected by higher CO2 concentrations, while M. mercenaria was not. Larvae were substantially more vulnerable to elevated CO2 than juvenile stages. These findings suggest that current and future increases in temperature and CO2 are likely to have negative consequences for coastal bivalve populations

Focal dose escalation using FDG-PET-guided intensity-modulated radiation therapy boost for postoperative local recurrent rectal cancer: a planning study with comparison of DVH and NTCP

<p>Abstract</p> <p>Background</p> <p>To evaluate the safety of focal dose escalation to regions with standardized uptake value (SUV) >2.0 using intensity-modulated radiation therapy (IMRT) by comparison of radiotherapy plans using dose-volume histograms (DVHs) and normal tissue complication probability (NTCP) for postoperative local recurrent rectal cancer</p> <p>Methods</p> <p>First, we performed conventional radiotherapy with 40 Gy/20 fr. (CRT 40 Gy) for 12 patients with postoperative local recurrent rectal cancer, and then we performed FDG-PET/CT radiotherapy planning for those patients. We defined the regions with SUV > 2.0 as biological target volume (BTV) and made three boost plans for each patient: 1) CRT boost plan, 2) IMRT without dose-painting boost plan, and 3) IMRT with dose-painting boost plan. The total boost dose was 20 Gy. In IMRT with dose-painting boost plan, we increased the dose for BTV+5 mm by 30% of the prescribed dose. We added CRT boost plan to CRT 40 Gy (<it>summed plan 1</it>), IMRT without dose-painting boost plan to CRT 40 Gy (<it>summed plan 2</it>) and IMRT with dose-painting boost plan to CRT 40 Gy (<it>summed plan 3</it>), and we compared those plans using DVHs and NTCP.</p> <p>Results</p> <p>D_meanof PTV-PET and that of PTV-CT were 26.5 Gy and 21.3 Gy, respectively. V₅₀of small bowel PRV in <it>summed plan 1 </it>was significantly higher than those in other plans ((<it>summed plan 1 </it>vs. <it>summed plan 2 </it>vs. <it>summed plan 3</it>: 47.11 ± 45.33 cm³vs. 40.63 ± 39.13 cm³vs. 41.25 ± 39.96 cm³(p < 0.01, respectively)). There were no significant differences in V₃₀, V₄₀, V₆₀, D_meanor NTCP of small bowel PRV.</p> <p>Conclusions</p> <p>FDG-PET-guided IMRT can facilitate focal dose-escalation to regions with SUV above 2.0 for postoperative local recurrent rectal cancer.</p

Population Structure of Humpback Whales from Their Breeding Grounds in the South Atlantic and Indian Oceans

Although humpback whales are among the best-studied of the large whales, population boundaries in the Southern Hemisphere (SH) have remained largely untested. We assess population structure of SH humpback whales using 1,527 samples collected from whales at fourteen sampling sites within the Southwestern and Southeastern Atlantic, the Southwestern Indian Ocean, and Northern Indian Ocean (Breeding Stocks A, B, C and X, respectively). Evaluation of mtDNA population structure and migration rates was carried out under different statistical frameworks. Using all genetic evidence, the results suggest significant degrees of population structure between all ocean basins, with the Southwestern and Northern Indian Ocean most differentiated from each other. Effective migration rates were highest between the Southeastern Atlantic and the Southwestern Indian Ocean, followed by rates within the Southeastern Atlantic, and the lowest between the Southwestern and Northern Indian Ocean. At finer scales, very low gene flow was detected between the two neighbouring sub-regions in the Southeastern Atlantic, compared to high gene flow for whales within the Southwestern Indian Ocean. Our genetic results support the current management designations proposed by the International Whaling Commission of Breeding Stocks A, B, C, and X as four strongly structured populations. The population structure patterns found in this study are likely to have been influenced by a combination of long-term maternally directed fidelity of migratory destinations, along with other ecological and oceanographic features in the region

Dilated Thin-Walled Blood and Lymphatic Vessels in Human Endometrium: A Potential Role for VEGF-D in Progestin-Induced Break-Through Bleeding

Progestins provide safe, effective and cheap options for contraception as well as the treatment of a variety of gynaecological disorders. Episodes of irregular endometrial bleeding or breakthrough bleeding (BTB) are a major unwanted side effect of progestin treatment, such that BTB is the leading cause for discontinued use of an otherwise effective and popular medication. The cellular mechanisms leading to BTB are poorly understood. In this study, we make the novel finding that the large, dilated, thin walled vessels characteristic of human progestin-treated endometrium include both blood and lymphatic vessels. Increased blood and lymphatic vessel diameter are features of VEGF-D action in other tissues and we show by immunolocalisation and Western blotting that stromal cell decidualisation results in a significant increase in VEGF-D protein production, particularly of the proteolytically processed 21 kD form. Using a NOD/scid mouse model with xenografted human endometrium we were able to show that progestin treatment causes decidualisation, VEGF-D production and endometrial vessel dilation. Our results lead to a novel hypothesis to explain BTB, with stromal cell decidualisation rather than progestin treatment per se being the proposed causative event, and VEGF-D being the proposed effector agent

Identification of ejaculated proteins in the house mouse (Mus domesticus) via isotopic labeling

<p>Abstract</p> <p>Background</p> <p>Seminal fluid plays an important role in successful fertilization, but knowledge of the full suite of proteins transferred from males to females during copulation is incomplete. The list of ejaculated proteins remains particularly scant in one of the best-studied mammalian systems, the house mouse (<it>Mus domesticus</it>), where artificial ejaculation techniques have proven inadequate. Here we investigate an alternative method for identifying ejaculated proteins, by isotopically labeling females with ¹⁵N and then mating them to unlabeled, vasectomized males. Proteins were then isolated from mated females and identified using mass spectrometry. In addition to gaining insights into possible functions and fates of ejaculated proteins, our study serves as proof of concept that isotopic labeling is a powerful means to study reproductive proteins.</p> <p>Results</p> <p>We identified 69 male-derived proteins from the female reproductive tract following copulation. More than a third of all spectra detected mapped to just seven genes known to be structurally important in the formation of the copulatory plug, a hard coagulum that forms shortly after mating. Seminal fluid is significantly enriched for proteins that function in protection from oxidative stress and endopeptidase inhibition. Females, on the other hand, produce endopeptidases in response to mating. The 69 ejaculated proteins evolve significantly more rapidly than other proteins that we previously identified directly from dissection of the male reproductive tract.</p> <p>Conclusion</p> <p>Our study attempts to comprehensively identify the proteins transferred from males to females during mating, expanding the application of isotopic labeling to mammalian reproductive genomics. This technique opens the way to the targeted monitoring of the fate of ejaculated proteins as they incubate in the female reproductive tract.</p

Changes in managed care activity in outpatient substance abuse treatment organizations, 1995–2000

Using nationally representative data from 1995 and 2000, this study examines trends in managed care penetration and activity among outpatient drug treatment organizations in the United States. Further, it investigates how managed care activity varies across different types of treatment providers and for public and private managed care programs. Overall, managed care activity has increased, with a greater proportion of units having managed care arrangements and a larger percentage of clients covered by managed care. In general, public managed care activity has increased and private managed care activity has decreased. Treatment providers report that they have fewer managed care arrangements, which may reflect consolidation in the managed behavioral care sector. Finally, growth in managed care among outpatient substance abuse treatment units affiliated with hospitals and mental health centers may signal a preference for providers that can effectively link substance abuse treatment with medical and social service provision, or, alternatively, that linkages with such organizations may provide the size necessary to assume the risks associated with managed care contracts.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45778/1/11414_2005_Article_BF02287425.pd