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Biomedical subjects

J H Gill

Publications and source records attributed to J H Gill.

At least 19 recordsLinked to original sources
PubMed2005

Treatment of bilateral corneal ulceration in a Peregrine Falcon (Falco peregrinus) using 360 degree conjunctival flaps.

A wild Peregrine Falcon (Falco peregrinus) was presented with extensive bilateral fluorescein positive corneal damage. Local therapy and bilateral tarsorrhaphies resulted in slow improvement over 5 weeks. When bilateral 360 degree conjunctival flaps were used subsequently, healing proceeded more rapidly over the next 8 weeks. Although bulbar conjunctival flaps have been reported as difficult in birds due to their small size and relatively immobile bulbar conjunctiva, 360 degree conjunctival flaps made from palpebral rather than bulbar conjunctiva were found to be technically feasible in a larger bird species such as the Peregrine Falcon.

Animals↗
PubMed2001

The isolation and synthesis of novel nematocidal dithiocyanates from an Australian marine sponge, Oceanapia sp.

Bioassay-directed fractionation of the EtOH extract of an Oceanapia sp. collected off the northern Rottnest Shelf, Australia, has yielded three novel dithiocyanates, thiocyanatins A (1), B (2a), and C (2b). The structures were determined by detailed spectroscopic analysis and confirmed by total synthesis. In addition to featuring an unprecedented dithiocyanate functionality, thiocyanatins possess an unusual 1,16-difunctionalized n-hexadecane carbon skeleton and are revealed as a hitherto unknown class of nematocidal agent.

Alkenes↗
PubMed2001

Negative regulation of G(1)/S transition by the candidate bladder tumour suppressor gene DBCCR1.

Deletion of all or part of chromosome 9q is the most common genetic alteration in all stages and grades of bladder cancer. DBCCR1 (deleted in bladder cancer chromosome region candidate 1) maps to the chromosome region 9q32-33, a candidate tumour suppressor locus for bladder cancer. Although no mutations of DBCCR1 have been detected in bladder tumours, expression of DBCCR1 is silenced by promoter hypermethylation in 50% of bladder cancer cell lines analysed. Here we sought to provide functional evidence to authenticate DBCCR1 as a tumour suppressor using gene-transfer methods. Exogenous expression of DBCCR1 protein or an HA epitope-tagged fusion protein, HA-DBCCR1 in NIH3T3 cells and human bladder tumour cell lines resulted in suppression of proliferation. Cell cycle analyses in NIH3T3 cells revealed that DBCCR1-mediated growth inhibition was due to an increase in the number of cells in the G(1) phase of the cell cycle. The levels of apoptosis were not altered. These results demonstrate a role for DBCCR1 in cell cycle control, thereby supporting the hypothesis that this is the tumour suppressor gene targeted by 9q32-33 deletion in bladder cancer.

3T3 Cells↗
PubMed2001

Avian skin diseases.

Avian dermatology is an important part of avian practice. Feather plucking, or self-mutilation, is one of the most common and challenging syndromes seen in avian practices, yet our understanding of it has developed piecemeal. Psittacine circovirus, which causes psittacine beak and feather disease, can devastate breeding programs and cause masked distress to new bird owners and their young birds. Cutaneous neoplasms are increasing in incidence as veterinarians are seeing more older bird patients.

Animals↗
PubMed2001

Onnamide F: a new nematocide from a southern Australian marine sponge, Trachycladus laevispirulifer.

A southern Australian marine sponge, Trachycladus laevispirulifer, has yielded a potent new nematocide with antifungal activity which has been identified as onnamide F (1). The structure for 1 was assigned by detailed spectroscopic analysis and chemical conversion to the methyl ester 2. Onnamide F contains a common structural motif previously described in a number of natural products exhibiting interesting pharmacological activities, including the insect chemical defense agent pederin (3), and the sponge metabolites the onnamides, mycalamides, and theopederins.

Animals↗
PubMed2000

Inheritance of avermectin resistance in Haemonchus contortus.

A larval development assay was used to compare the responses of the Chiswick Avermectin Resistant (CAVRS) isolate of Haemonchus contortus, an avermectin-susceptible isolate (VRSG) and their crosses to avermectins. The F(1) and F(2) generations of reciprocal crosses between CAVRS and VRSG were denoted as CAVRS malesxVRSG females=CXV, and VRSG malesxCAVRS females=VXC. The levels of avermectin resistance in the developing larvae of the F(1) of both CXV and VXC were indistinguishable from that in the avermectin-resistant parent, indicating that the resistance trait is completely dominant. Avermectin dose-response curves for the CXV F(1) did not show a 50% mortality rate at low concentrations, indicating that avermectin resistance is not sex-linked. This conclusion was confirmed when adult male worms of the F(1) of the CXV mating were found to have survived treatment of the host with 200microgkg(-1) ivermectin. This dose rate (200microgkg(-1) ivermectin) caused a 50% reduction in the number of adult males in the F(1) from both CXV and VXC crosses, but only a non-significant reduction in the number of adult females in the F(1). Dose-response curves obtained for the F(2) generations in the larval development assay indicated the presence of 25% of avermectin-susceptible individuals, suggesting that a single major gene largely controls the avermectin-resistance trait. This genetic analysis of avermectin resistance in an Australian H. contortus isolate indicates that the expression of the gene for avermectin resistance is an autosomal, complete dominant in the larvae; however, in adults its expression is sex-influenced, with males having a lower resistance to avermectin than females.

Animals↗
PubMed1998

Peroxisome proliferator-activated receptor (PPAR) alpha-regulated growth responses and their importance to hepatocarcinogenesis.

Peroxisome proliferators (PPs) are a class of non-genotoxic rodent hepatocarcinogens that act by perturbing liver growth regulation. We have demonstrated previously that PPs suppress both spontaneous rat hepatocyte apoptosis and that induced by exogenous stimuli such as transforming growth factor-beta1 (TGF beta1). More recently, we have demonstrated that PPs can suppress apoptosis induced by more diverse stimuli such as DNA damage or ligation of Fas, a receptor related to the tumour necrosis factor alpha (TNF alpha) family of cell surface receptors. PPs transcriptionally activate the peroxisome proliferator activated receptor-alpha, PPAR alpha, a member of the nuclear hormone receptor superfamily. We investigated whether activation of PPAR alpha mediates the suppression of rat hepatocyte apoptosis induced by PPs. We isolated a naturally occurring variant form of PPAR alpha (hPPAR alpha-6/29) from human liver by PCR cloning. hPPAR alpha-6/29 shared the ability of mPPAR alpha to bind to DNA but, unlike mPPAR alpha, could not be activated by PPs. Furthermore, hPPAR alpha-6/29 could act as a dominant negative regulator of PPAR-mediated gene transcription. When introduced into primary rat liver cell cultures by transient transfection, hPPAR alpha-6/29 prevented the suppression of hepatocyte apoptosis by the PP nafenopin, but not that seen in response to phenobarbitone (PB), a non-genotoxic carcinogen whose action does not involve PPAR alpha. The suppression of hepatocyte apoptosis was abrogated completely even though only 30% of hepatocytes were transfected, suggesting the involvement of a soluble factor. Recent data have suggested that TNF alpha, perhaps released by liver Kupffer cells in response to PPs, may play a key role in mediating the effects of PPs on hepatocyte growth regulation.

Animals↗
PubMed1998

Evidence of multiple mechanisms of avermectin resistance in haemonchus contortus--comparison of selection protocols.

Three isolates of Haemonchus contortus selected for avermectin resistance in sheep were compared in three in vitro pharmacological tests previously shown to discriminate between field isolates of H. contortus resistant and susceptible to the avermectins. Two isolates, F7-A and IVC, were selected for avermectin resistance in the laboratory from a reference susceptible isolate using suboptimal doses of ivermectin (LD95) for 7 and 16 generations, respectively. In these isolates avermectin resistance was not associated with a decreased sensitivity to avermectin inhibition of larval development or L3 motility but was associated with an increased sensitivity to paraherquamide. The third isolate, Warren, was derived from an overwhelmingly avermectin-susceptible, mixed species field isolate in a single generation by propagating the small number of survivors of a 0.2 mg/kg ivermectin treatment (i.e. 10 x LD95). This isolate, like previously characterised avermectin-resistant H. contortus isolates derived from the field in South Africa and Australia, showed a markedly reduced sensitivity to avermectin inhibition of larval development and L3 motility, as well as an increased sensitivity to paraherquamide. These results suggest that avermectin resistance can manifest itself in different ways and that the two selection protocols used to generate the F7-A, IVC and Warren isolates have resulted in the selection of different resistance phenotypes.

Animals↗
PubMed1998

Avermectin/milbemycin resistance in trichostrongyloid nematodes.

Resistance to levamisole and the benzimidazoles appears to be achieved by one or, at most, two mechanisms in the common trichostrongyloid parasites of sheep. For the avermectin/milbemycin anthelmintic class the picture is more complex. In-vitro assays employing the free-living stages of trichostrongyloid nematodes were used to investigate structure-activity relationships for the avermectins/milbemycins. While avermectin/milbemycin-susceptible isolates of Haemonchus contortus, Trichostrongylus colubriformis and Ostertagia circumcincta were found to differ in their intrinsic sensitivities to avermectin/milbemycin inhibition of larval development and L3 motility, structure-activity profiles against all three species were similar. In-vivo avermectin/milbemycin resistance was associated with a reduced sensitivity to avermectin/milbemycin inhibition of larval motility and/or development in some, but not all, isolates. Where a reduced sensitivity to avermectin/milbemycin inhibition of larval development was observed, different groups of resistant isolates displayed different structure-activity profiles. Many avermectin/milbemycin-resistant isolates showed an increased sensitivity to paraherquamide. These in-vitro data have allowed the classification of avermectin/milbemycin-resistant isolates into a number of distinct types. Study of the inheritance of avermectin/milbemycin resistance in two resistance types suggests that the in-vitro differences between resistant isolates reflect important differences in the mechanism of resistance present. The kinetics of expulsion of H. contortus, T. colubriformis and O. circumcincta from sheep following treatment with ivermectin indicate that, in vivo, the critical action of avermectins/milbemycin against O. circumcincta may be different to that which results in H. contortus and T. colubriformis elimination. This observation provides some explanation for the differences between resistant isolates. If, for different species, the critical event(s) leading to expulsion are different, then it follows that the mechanisms of resistance observed may also differ.

Animals↗
PubMed1998

The rodent non-genotoxic hepatocarcinogen nafenopin suppresses apoptosis preferentially in non-cycling hepatocytes but also elevates CDK4, a cell cycle progression factor.

Rodent non-genotoxic hepatocarcinogens such as nafenopin suppress spontaneous and transforming growth factor beta1 (TGFbeta1)-induced rat hepatocyte apoptosis as well as inducing DNA synthesis. We wished to determine if these two processes are associated. In primary rat hepatocytes, nafenopin suppressed apoptosis from 1.9 to 0.63% but more apoptotic bodies were bromodeoxyuridine (BrdU)-labelled (0.35%) than predicted statistically from a random distribution of apoptosis within the cycling and non-cycling populations (0.10%). In contrast, TGFbeta1 induced hepatocyte apoptosis (7.8%) but fewer hepatocytes were BrdU-labelled (0.29%) than predicted (0.82%). Western blot analyses showed that nafenopin and TGFbeta1 had opposing effects on cyclin-dependent kinase 4 (CDK4) protein: nafenopin elevated CDK4 compared with controls, whereas TGFbeta1 caused a reduction. These data suggest that non-genotoxic hepatocarcinogens suppress apoptosis in the non-cycling population of hepatocytes and elevate CDK4 levels, possibly allowing potentially tumourigenic cells to enter the cell cycle.

Animals↗
PubMed1998

The non-genotoxic hepatocarcinogen nafenopin suppresses rodent hepatocyte apoptosis induced by TGFbeta1, DNA damage and Fas.

The suppression of apoptosis may contribute to the carcinogenicity of the peroxisome proliferators (PPs), a class of non-genotoxic rodent hepatocarcinogens. Our previous work demonstrated that the PP nafenopin suppressed both spontaneous and transforming growth factor beta1 (TGFbeta1)-induced hepatocyte apoptosis both in vivo and in vitro. Here, we extend these observations by demonstrating the ability of nafenopin to suppress apoptosis induced by other major candidates for the signalling of cell death in the liver. Treatment of rat or mouse hepatocyte monolayers with TGFbeta1 or the DNA damaging drugs etoposide or hydroxyurea induced high levels of apoptosis. Western blot analysis did not support a role for either p53 or p21waf1 in etoposide-induced apoptosis in rat hepatocytes. Treatment of mouse hepatocytes with an agonistic anti-Fas antibody also resulted in an induction of high levels of apoptosis. Pre-addition and continued exposure to nafenopin suppressed apoptosis induced by all three stimuli. Overall, our studies demonstrate that the ability of nafenopin to protect hepatocytes from apoptosis is not restricted to species or apoptotic stimulus. It is possible, therefore, that the PPs may suppress apoptosis by acting on diverse signalling pathways. However, it seems more likely that nafenopin suppresses hepatocyte apoptosis elicited by each death stimulus by impinging on a core apoptotic mechanism.

Animals↗
PubMed1995

Dosing-induced stress causes hepatocyte apoptosis in rats primed by the rodent nongenotoxic hepatocarcinogen cyproterone acetate.

It has been proposed that several nongenotoxic compounds act as hepatocarcinogens by suppressing the apoptosis that would normally act to remove damaged or potentially initiated cells from the liver. During our investigations of this hypothesis using a widely applied protocol, we have found that the stress induced by the process of gavage dosing can induce massive apoptosis in livers uniquely primed by withdrawal of the hepatomitogen cyproterone acetate from the hyperplastic rat liver. This effect of gavage dosing was not seen in livers of naive animals. Apoptosis was measured by both in situ end labeling (ISEL) of the DNA damage associated with programmed cell death and conventional hematoxylin and eosin (H&E) staining of apoptotic morphology. Apoptotic rates measured by H&E increased significantly from 0.005 +/- 0.010% on Day 11 to 0.657 +/- 0.315% of hepatocytes on Day 15, 4 days after cessation of 10 days dosing with CPA (120 mg/kg). The readministration of CPA suppressed > 89% of this Day 15 apoptosis. However, the readministration of vehicle alone (corn oil) caused a 390% increase in apoptosis to 2.56 +/- 1.31% of hepatocytes. Similar results were obtained using ISEL. Measurements of liver to body weight ratios and total DNA per liver reflected these changes in cell loss by apoptosis. In a second experiment, CPA was administered for 10 days as before then animals were subjected to readministration of CPA in corn oil, CPA in saline, corn oil, saline, or sham dosed. Again, apoptosis was dramatically suppressed by the readministration of CPA in either vehicle but was dramatically increased to around 2% of hepatocytes in all other groups, including the sham dosed group. Data on food consumption provided no evidence for a reduction in food intake as a causative agent but rather pointed to a less efficient usage of food in the stressed animals. The ability of stress to induce liver apoptosis should be borne in mind in the design and interpretation of future toxicological studies aimed at understanding the putative suppression of apoptosis by liver nongenotoxic carcinogens and other toxicants.

Animals↗
PubMed1995

Bafilolides, potent inhibitors of the motility and development of the free-living stages of parasitic nematodes.

Three Streptomyces isolates were identified as producing macrolide antibiotics of the bafilomycin or leucanicidin types during an evaluation of Australian actinomyces for the production of inhibitors of larval development in the parasitic nematode, Haemonchus contortus. Bafilomycins A1, B1, C1, and D were obtained from culture A239 and the 2-O-methyl-L-rhamnosyl derivative of bafilomycin A1, leucanicidin, from cultures A223 and A240. All these 'bafilolides' gave similar patterns of inhibition typified by an initial paralysis of newly hatched L1 larvae and a lethal toxicity within 24 h. LD50 values for inhibition of larval development of McMaster H. contortus ranged from 0.23 micrograms ml-1 for leucanicidin to 2.5 micrograms ml-1 for bafilomycin D. The bafilolides had broad spectrum nematocidal activity, being equi-potent as inhibitors of H. contortus, Trichostrongylus colubriformis and Ostertagia circumcincta larval development. Further, all bafilolides caused some inhibition of H. contortus L3 motility, with the semi-synthetic analogue, bafilomycin B2, the most potent inhibitor (LP50 against McMaster H. contortus 1.9 microgram ml-1). Nematode strains resistant to the known benzimidazole, levamisole and avermectin anthelmintics showed no cross resistance to the bafilolides, supporting the hypothesis that the bafilolides act by an independent mechanism.

Animals↗
PubMed1995

Avermectin inhibition of larval development in Haemonchus contortus--effects of ivermectin resistance.

Avermectin (AVM) inhibition of the development of the free-living stages of Haemonchus contortus has been quantified in an assay in which nematode eggs are placed on an agar matrix containing serial dilutions of a drug in the wells of a microtitre plate. Development is allowed to proceed for 6 days by which time larvae in control wells (no drug) have reached the infective, third (L3) stage. At high concentrations (> 30 nM) ivermectin (IVM) paralyses L1 larvae soon after hatching, however, much lower concentrations (approximately 1 nM) are sufficient to inhibit development to the L3 stage which suggests that effects of the drug other than those relating to gross motor activity are responsible for the latter effect. The larval stages of IVM-susceptible H. contortus isolates from both Australia and South Africa, including isolates known to be resistant to levamisole or rafoxanide and/or the benzimidazoles, were equally sensitive to inhibition by AVMs. In contrast, 6 isolates of H. contortus resistant to IVM in vivo showed a reduced sensitivity to AVM inhibition of development. The order of potency of a limited range of AVMs as inhibitors of larval development was consistent with in vivo efficacy. Resistance ratios for IVM-resistant isolates were dependent on AVM structure, with AVM B2 the most sensitive probe for IVM resistance in the isolates tested.

Animals↗
PubMed1995

Characterisation of an avermectin resistant strain of Australian Haemonchus contortus.

A strain of Haemonchus contortus (CAVR) isolated in Australia was found to be resistant to ivermectin (IVM) with 0.4 mg kg-1 of the anthelmintic failing to significantly reduce worm burdens. Resistance to IVM was sex-influenced in the CAVR strain with adult males showing a greater sensitivity to IVM. Cross resistance to moxidectin was evident with approximately 15% of the population surviving a dose of 0.1 mg kg-1. The free-living stages of the CAVR isolate had a reduced sensitivity to avermectin (AVM) inhibition of development and motility. Similar structure-activity patterns and resistance factors were obtained for a series of related AVMs as inhibitors of larval development and L3 motility in CAVR and White River II, an IVM-resistant H. contortus isolate from South Africa. Further, both isolates were found to be 3 times more sensitive to paraherquamide than a susceptible H. contortus isolate. This suggest that the same resistance mechanism is operating in both isolates. The CAVR strain is susceptible to the benzimidazoles, levamisole and closantel.

Animals↗
PubMed1995

Cryopreservation of the first-stage larvae of trichostrongylid nematode parasites.

First stage (L1) larvae of Haemonchus contortus, Trichostrongylus colubriformis and Ostertagia circumcincta can be cryopreserved in the presence of DMSO using a two-step freezing protocol involving an initial period at -80 degrees C prior to transfer to liquid nitrogen. Thawed L1 larvae continue development in vitro producing third stage (L3) larvae that are infective to sheep when dosed per os. Establishment rates for L3 larvae grown from thawed L1 larvae were 40 and 80% for H. contortus and T. colubriformis, respectively. There was no difference in survival or infectivity between benzimidazole (BZ)-susceptible and BZ-resistant H. contortus isolates and cryopreservation caused no shift in their BZ-resistance status as indicated in an in vitro larval development assay. Cryopreservation also had no effect on the sensitivity of these isolates to the avermectins or levamisole in vitro. High survival rates (60-70%), good levels of establishment and the stability of anthelmintic resistance status of isolates indicate that little if any selection occurs during the cryopreservation process. L1 larvae of all 3 species have been successfully recovered after 16 months storage in liquid nitrogen, cultured to the L3 stage and established in sheep.

Animals↗