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"Clift, Sarah"
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The Approximate Subcutaneous LD50 and Associated Lesions Induced by Ivalin, Extracted and Purified from Geigeria aspera Harv., in Sprague–Dawley Rats
“Vomiting disease” in ruminants is one of the most economically significant phytotoxicities in South Africa and is caused by chronic ingestion of sesquiterpene lactone compounds present in plants of the Geigeria genus. Affected livestock demonstrate mortality due to actin and myosin damage in the striated musculature; however, a validated parental-exposure laboratory animal model would be useful for further study of the toxicodynamics. We exposed Sprague–Dawley rats to ivalin in a sequential dosing procedure and evaluated clinical signs, mortality, histopathology and muscle ultrastructure. Three of the five exposed rats died acutely, and a maximum likelihood estimate method was used to calculate a Median Lethality (LD50) of 135.4 mg/kg Body Weight (BW). Striated muscle in exposed rats showed only minimal and inconsistent histopathological and ultrastructural changes. Subcutaneous ivalin exposure causes acute mortality with minimal muscle pathology, contrasting with the more protracted muscular disease seen in ruminants after plant ingestion. This suggests toxicity by parenteral exposure is due to another mechanism, most likely mitochondrial energy pathway disturbances. Whilst subcutaneously exposed rats do not appear to provide a suitable model for oral sesquiterpene lactone exposure in ruminants, this study provides a starting dose for further investigation of plant extracts in both species.
Journal Article
Characterising non-structural protein NS4 of African horse sickness virus
African horse sickness is a serious equid disease caused by the orbivirus African horse sickness virus (AHSV). The virus has ten double-stranded RNA genome segments encoding seven structural and three non-structural proteins. Recently, an additional protein was predicted to be encoded by genome segment 9 (Seg-9), which also encodes VP6, of most orbiviruses. This has since been confirmed in bluetongue virus and Great Island virus, and the non-structural protein was named NS4. In this study, in silico analysis of AHSV Seg-9 sequences revealed the existence of two main types of AHSV NS4, designated NS4-I and NS4-II, with different lengths and amino acid sequences. The AHSV NS4 coding sequences were in the +1 reading frame relative to that of VP6. Both types of AHSV NS4 were expressed in cultured mammalian cells, with sizes close to the predicted 17–20 kDa. Fluorescence microscopy of these cells revealed a dual cytoplasmic and nuclear, but not nucleolar, distribution that was very similar for NS4-I and NS4-II. Immunohistochemistry on heart, spleen, and lung tissues from AHSV-infected horses showed that NS4 occurs in microvascular endothelial cells and mononuclear phagocytes in all of these tissues, localising to the both the cytoplasm and the nucleus. Interestingly, NS4 was also detected in stellate-shaped dendritic macrophage-like cells with long cytoplasmic processes in the red pulp of the spleen. Finally, nucleic acid protection assays using bacterially expressed recombinant AHSV NS4 showed that both types of AHSV NS4 bind dsDNA, but not dsRNA. Further studies will be required to determine the exact function of AHSV NS4 during viral replication
Journal Article
Is Time out of Joint?
Is, as Hamlet once complained, time out joint? Have the ways we understand the past and the future-and their relationship to the present-been reordered? The past, it seems, has returned with a vengeance: as aggressive nostalgia, as traumatic memory, or as atavistic origin narratives rooted in nation, race, or tribe. The future, meanwhile, has lost its utopian glamor, with the belief in progress and hope for a better future eroded by fears of ecological collapse.
In this provocative book, Aleida Assmann argues that the apparently solid moorings of our temporal orientation have collapsed within the span of a generation. To understand this profound cultural crisis, she reconstructs the rise and fall of what she calls \"time regime of modernity\" that underpins notions of modernization and progress, a shared understanding that is now under threat. IsTime Out of Joint? assesses the deep change in the temporality of modern Western culture as it relates to our historical experience, historical theory, and our life-world of shared experience, explaining what we have both gained and lost during this profound transformation.
eBook
Committing the Future to Memory: History, Experience, Trauma
Whereas historical determinacy conceives the past as a complex and unstable network of causalities, this book asks how history can be related to a more radical future. To pose that question, it does not reject determinacy outright but rather seeks to explore how it works. In examining what it means to be \"determined\" by history, it also asks what kind of openings there might be in our encounters with history for interruptions, re-readings, and re-writings. Engaging texts spanning multiple genres and several centuries from John Locke to Maurice Blanchot, from Hegel to Benjamin Clift looks at experiences of time that exceed the historical narration of experiences said to have occurred in time. She focuses on the co-existence of multiple temporalities and opens up the quintessentially modern notion of historical succession to other possibilities. The alternatives she draws out include the mediations of language and narration, temporal leaps, oscillations and blockages, and the role played by contingency in representation. She argues that such alternatives compel us to reassess the ways we understand history and identity in a traumatic, or indeed in a post-traumatic, age.
eBook
Lack of Marburg Virus Transmission From Experimentally Infected to Susceptible In-Contact Egyptian Fruit Bats
Egyptian fruit bats (Rousettus aegyptiacus) were inoculated subcutaneously (n = 22) with Marburg virus (MARV). No deaths, overt signs of morbidity, or gross lesions was identified, but microscopic pathological changes were seen in the liver of infected bats. The virus was detected in 15 different tissues and plasma but only sporadically in mucosal swab samples, urine, and fecal samples. Neither seroconversion nor viremia could be demonstrated in any of the in-contact susceptible bats (n = 14) up to 42 days after exposure to infected bats. In bats rechallenged (n = 4) on day 48 after infection, there was no viremia, and the virus could not be isolated from any of the tissues tested. This study confirmed that infection profiles are consistent with MARV replication in a reservoir host but failed to demonstrate MARV transmission through direct physical contact or indirectly via air. Bats develop strong protective immunity after infection with MARV.
Journal Article
Virological and serological findings in Rousettus aegyptiacus experimentally inoculated with vero cells-adapted hogan strain of Marburg virus
The Egyptian fruit bat, Rousettus aegyptiacus, is currently regarded as a potential reservoir host for Marburg virus (MARV). However, the modes of transmission, the level of viral replication, tissue tropism and viral shedding pattern remains to be described. Captive-bred R. aegyptiacus, including adult males, females and pups were exposed to MARV by different inoculation routes. Blood, tissues, feces and urine from 9 bats inoculated by combination of nasal and oral routes were all negative for the virus and ELISA IgG antibody could not be demonstrated for up to 21 days post inoculation (p.i.). In 21 bats inoculated by a combination of intraperitoneal/subcutaneous route, viremia and the presence of MARV in different tissues was detected on days 2–9 p.i., and IgG antibody on days 9–21 p.i. In 3 bats inoculated subcutaneously, viremia was detected on days 5 and 8 (termination of experiment), with virus isolation from different organs. MARV could not be detected in urine, feces or oral swabs in any of the 3 experimental groups. However, it was detected in tissues which might contribute to horizontal or vertical transmission, e.g. lung, intestines, kidney, bladder, salivary glands, and female reproductive tract. Viremia lasting at least 5 days could also facilitate MARV mechanical transmission by blood sucking arthropods and infections of susceptible vertebrate hosts by direct contact with infected blood. All bats were clinically normal and no gross pathology was identified on post mortem examination. This work confirms the susceptibility of R. aegyptiacus to infection with MARV irrespective of sex and age and contributes to establishing a bat-filovirus experimental model. Further studies are required to uncover the mode of MARV transmission, and to investigate the putative role of R. aegyptiacus as a reservoir host.
Journal Article
Chemotherapeutic Efficacy of Implantable Antineoplastic-Treatment Protocols in an Optimal Mouse Model for Human Ovarian Carcinoma Cell Targeting
The present study aimed to design and develop a nanocomposite drug delivery system employing an antineoplastic-loaded antibody functionalized nanomicelle encapsulated within a Chitosan–Poly(vinylpyrrolidone)–Poly(N-isopropylacrylamide) (C–P–N) hydrogel to form an in situ forming implant (ISFI), responsive to temperature and pH for cancer cell-targeting following intraperitoneal implantation. The optimum nanomicelle formulation was surface-functionalized with anti-MUC 16 (antibody) for the targeted delivery of methotrexate to human ovarian carcinoma (NIH:OVCAR-5) cells in Athymic nude mice that expressed MUC16, as a preferential form of intraperitoneal ovarian cancer (OC) chemotherapy. The cross-linked interpenetrating C–P–N hydrogel was synthesized for the preparation of an in situ-forming implant (ISFI). Subsequently, the ISFI was fabricated by encapsulating a nanocomposite comprising of anti-MUC16 (antibody) functionalized methotrexate (MTX)-loaded poly(N-isopropylacrylamide)-b-poly(aspartic acid) (PNIPAAm-b-PASP) nanomicelles (AF(MTX)NM’s) within the cross-linked C–P–N hydrogel. This strategy enabled specificity and increased the residence time of the nanomicelles at tumor sites over a period exceeding one month, enhancing uptake of drugs and preventing recurrence and chemo-resistance. Chemotherapeutic efficacy was tested on the optimal ovarian tumor-bearing Athymic nude mouse model and the results demonstrated tumor regression including reduction in mouse weight and tumor size, as well as a significant (p < 0.05) reduction in mucin 16 levels in plasma and ascitic fluid, and improved survival of mice after treatment with the experimental anti-MUC16/CA125 antibody-bound nanotherapeutic implant drug delivery system (ISFI) (p < 0.05). The study also concluded that ISFI could potentially be considered an important immuno-chemotherapeutic agent that could be employed in human clinical trials of advanced, and/or recurring, metastatic epithelial ovarian cancer (EOC). The development of this ISFI may circumvent the treatment flaws experienced with conventional systemic therapies, effectively manage recurrent disease and ultimately prolong disease-free intervals in ovarian cancer patients.
Journal Article
Committing the Future to Memory
Whereas historical determinacy conceives the past as a complex and unstable network of causalities, this book asks how history can be related to a more radical future. To pose that question, it does not reject determinacy outright but rather seeks to explore how it works. In examining what it means to be \"determined\" by history, it also asks what kind of openings there might be in our encounters with history for interruptions, re-readings, and re-writings. Engaging texts spanning multiple genres and several centuries-from John Locke to Maurice Blanchot, from Hegel to Benjamin-Clift looks at experiences of time that exceed the historical narration of experiences said to have occurred in time. She focuses on the co-existence of multiple temporalities and opens up the quintessentially modern notion of historical succession to other possibilities. The alternatives she draws out include the mediations of language and narration, temporal leaps, oscillations and blockages, and the role played by contingency in representation. She argues that such alternatives compel us to reassess the ways we understand history and identity in a traumatic, or indeed in a post-traumatic, age.
eBook
Geigerin-induced cytotoxicity in a murine myoblast cell line (C2C12)
Geigeria poisoning in sheep, locally known as ‘vermeersiekte’, is an economically important plant poisoning in southern Africa. The toxic principles contained by the toxic plants are believed to be several sesquiterpene lactones, such as geigerin, vermeeric acid and vermeerin, which cause striated muscle lesions in small stock. Because of ethical issues surrounding the use of live animals in toxicity studies, there is currently a dire need to establish an in vitro model that can be used to replace traditional animal experimentation. The objective of this study was to determine the cytotoxicity of geigerin in a murine myoblast cell line (C2C12) using methyl-thiazol-tetrazolium (MTT) and lactate dehydrogenase (LDH) assays, annexin V and propidium iodide (PI) flow cytometry and transmission electron microscopy (TEM). Mouse myoblasts were exposed to 2.0 mM, 2.5 mM and 5.0 mM geigerin for 24, 48 and 72 h. A concentration-dependent cytotoxic response was observed. Apoptosis was detected by means of annexin V flow cytometry during the first 24 h and apoptotic bodies were also visible on TEM. According to the LDH and PI flow cytometry results, myoblast cell membranes were not injured. We concluded that the murine myoblast cell line (C2C12) is a suitable model for future studies planned to evaluate the cytotoxicity of other and combinations of sesquiterpene lactones, with and without metabolic activation, implicated in ‘vermeersiekte’ and to elucidate the subcellular effects of these myotoxins on cultured myoblasts.
Journal Article