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Biomedical subjects

M A Lovell

Publications and source records attributed to M A Lovell.

At least 19 recordsLinked to original sources
PubMed2003

Rapid protection of gnotobiotic pigs against experimental salmonellosis following induction of polymorphonuclear leukocytes by avirulent Salmonella enterica.

Oral inoculation of 5-day-old gnotobiotic pigs with Salmonella enterica serovar Typhimurium strain F98 resulted in severe enteritis and invasive disease. Preinoculation 24 h earlier with an avirulent mutant of Salmonella enterica serovar Infantis (1326/28) completely prevented disease for up to 14 days (when the experiment was terminated). S. enterica serovar Infantis colonized the alimentary tract well, with high bacterial counts in the intestinal lumen but with almost no invasion into the tissues. Unprotected pigs had high S. enterica serovar Typhimurium counts in the intestines, blood, and major nonintestinal organs. Recovery of this strain from the blood and major organs in S. enterica serovar Infantis-protected pigs was substantially reduced despite the fact that intestinal counts were also very high. Protection against disease thus did not involve a colonization exclusion phenomenon. Significant (P < 0.05) infiltration of monocytes/macrophages was observed in the submucosal regions of the intestines of both S. enterica serovar Infantis-protected S. enterica serovar Typhimurium-challenged pigs and unprotected S. enterica serovar Typhimurium-challenged pigs. However, only polymorphonuclear neutrophils (PMNs) were observed throughout the villus, where significant (P < 0.05) numbers infiltrated the lamina propria and the subnuclear and supranuclear regions of the epithelia, indicating that PMN induction and positioning following S. enterica serovar Infantis inoculation was consistent with rapid protection against the challenge strain. Similarly, in vitro experiments using a human fetal intestinal epithelial cell line (INT 407) demonstrated that, although significantly (P < 0.05) fewer S. enterica serovar Infantis than S. enterica serovar Typhimurium organisms invaded the monolayers, S. enterica serovar Infantis induced an NF-kappaB response and significantly (P < 0.05) raised interleukin 8 levels and transmigration of porcine PMN. The results of this study suggest that attenuated Salmonella strains can protect the immature intestine against clinical salmonellosis by PMN induction. They also demonstrate that PMN induction is not necessarily associated with clinical symptoms and/or intestinal pathology.

Animals↗
PubMed2003

Contribution of proton-translocating proteins to the virulence of Salmonella enterica serovars Typhimurium, Gallinarum, and Dublin in chickens and mice.

We investigated the attenuating effects of a range of respiratory chain mutations in three Salmonella serovars which might be used in the development of live vaccines. We tested mutations in nuoG, cydA, cyoA, atpB, and atpH in three serovars of Salmonella enterica: Typhimurium, Dublin, and Gallinarum. All three serovars were assessed for attenuation in their relevant virulence assays of typhoid-like infections. Serovar Typhimurium was assessed in 1-day-old chickens and the mouse. Serovar Gallinarum 9 was assessed in 3-week-old chickens, and serovar Dublin was assessed in 6-week-old mice. Our data show variation in attenuation for the nuoG, cydA, and cyoA mutations within the different serovar-host combinations. However, mutations in atpB and atpH were highly attenuating for all three serovars in the various virulence assays. Further investigation of the mutations in the atp operon showed that the bacteria were less invasive in vivo, showing reduced in vitro survival within phagocytic cells and reduced acid tolerance. We present data showing that this reduced acid tolerance is due to an inability to adapt to conditions rather than a general sensitivity to reduced pH. The data support the targeting of respiratory components for the production of live vaccines and suggest that mutations in the atp operon provide suitable candidates for broad-spectrum attenuation of a range of Salmonella serovars.

Animals↗
PubMed2001

Expression of glutathione-S-transferase isozyme in the SY5Y neuroblastoma cell line increases resistance to oxidative stress.

Glutathione-S-transferases (GSTs) are a superfamily of enzymes that function to catalyze the nucleophilic attack of glutathione on electrophilic groups of a second substrate. GSTs are present in many organs and have been implicated in the detoxification of endogenous alpha, beta unsaturated aldehydes, including 4-hydroxynonenal (HNE). Exogenous GST protects hippocampal neurons against HNE in culture. To test the hypothesis that overexpression of GST in cells would increase resistance to exogenous or endogenous HNE induced by oxidative stress, stable transfectants of SY5Y neuroblastoma cells with GST were established. Stable GST transfectants demonstrated enzyme activities 13.7 times (Clone 1) and 30 times (Clone 2) higher than cells transfected with vector alone. GST transfectants (both Clones 1 and 2) demonstrated significantly (p <.05) increased resistance to ferrous sulfate/hydrogen peroxide (20.9% for Clone 1; 46.5% for Clone 2), amyloid beta-peptide (12.2% for Clone 1; 27.5.% for Clone 2), and peroxynitrite (24.3% for Clone 1; 43.9% for Clone 2), but not to exogenous application of HNE in culture medium. GST transfectants treated with 1,1,4-tris (acetyloxy)nonane, a nontoxic derivative of HNE that is degraded to HNE intracellularly, demonstrated a statistically significant (p <.05) increase in viability in a dose-dependent manner compared with SY5Y cells transfected with vector alone. These results suggest that overexpression of GST increases resistance to endogenous HNE induced by oxidative stress or released in the degradation of 1,1,4-tris (acetyloxy)nonane, but not to exogenous application of HNE.

Aldehydes↗
PubMed2001

The virulence for gnotobiotic pigs of live attenuated vaccine strains of Salmonella enterica serovars Typhimurium and Enteritidis.

Gnotobiotic pigs were inoculated orally with wild-type or defined aroA or cya crp vaccine strains of Salmonella enterica serovars Typhimurium and S. Enteritidis. The parental strains were virulent, inducing severe diarrhoea, dehydration and systemic disease. The cya crp mutant was also highly virulent whereas the aroA strains were attenuated.

Adenylyl Cyclases↗
PubMed2001

Ratio of 8-hydroxyguanine in intact DNA to free 8-hydroxyguanine is increased in Alzheimer disease ventricular cerebrospinal fluid.

BACKGROUND: Markers of oxidative stress are increased in cerebrospinal fluid (CSF) of patients with Alzheimer disease (AD), although none of those reported are appropriate diagnostic markers because of the overlap between patients with AD and control subjects. OBJECTIVE: To determine the ratio of 8-hydroxyguanine (8-OHG) levels in intact DNA to free 8-OHG in the ventricular CSF of patients with AD and age-matched control subjects. The most prominent marker of DNA oxidation is 8-OHG. METHODS: Free 8-hydroxy-2'-deoxyguanosine (8-OHdG) was isolated from ventricular CSF taken at autopsy from 18 subjects with AD and 7 control subjects using solid-phase extraction columns. Levels were measured as the hydrolysis product, 8-OHG, using gas chromatography/mass spectrometry with selective ion monitoring. Intact DNA was isolated from the same CSF and the levels of 8-OHG were determined in the intact structures. Stable-labeled 8-OHG was used for quantification. RESULTS: A statistically significant (P<.05) 108-fold increase in the ratio of 8-OHG in intact DNA to free 8-OHG was observed in patients with AD. Analysis of the data distribution indicated that the lowest AD ratio was 3.5 times higher than the highest control ratio; there was no overlap of the 2 populations. CONCLUSION: Although the data for each individual measurement demonstrates overlap between patients with AD and control subjects, the ratio of 8-OHG intact in DNA to free 8-OHG demonstrates a delineation between patients with AD and control 8-OHG subjects and may be useful as a marker of disease progression or the efficacy of therapeutic antioxidant intervention.

Aged↗
PubMed2001

Prenatal diagnosis of multiple acyl-CoA dehydrogenase deficiency: association with elevated alpha-fetoprotein and cystic renal changes.

We report the occurrence of multiple acyl-CoA dehydrogenase deficiency (MADD) in two consecutive pregnancies in a young, Caucasian, non-consanguineous couple. In the first pregnancy, the maternal serum alpha-fetoprotein was elevated. A sonogram showed growth delay, cystic renal disease, and oligohydramnios; the parents decided to terminate the pregnancy. Postmortem examination confirmed the cystic renal disease and showed hepatic steatosis, raising the suspicion of a metabolic disorder. The diagnosis of MADD was made by immunoblot studies on cultured fibroblasts. In the subsequent pregnancy, a sonogram at 15 weeks' gestation showed an early growth delay but normal kidneys. The maternal serum and amniotic fluid concentrations of alpha-fetoprotein were elevated, and the amniotic fluid acylcarnitine profile was consistent with MADD. In vitro metabolic studies on cultured amniocytes confirmed the diagnosis. A follow-up sonogram showed cystic renal changes. These cases provide additional information regarding the evolution of renal changes in affected fetuses and show a relationship with elevated alpha-fetoprotein, which may be useful in counseling the couple at risk. MADD should be considered in the differential diagnosis of elevated alpha-fetoprotein and cystic renal disease. Early growth delay may be an additional feature.

Acyl-CoA Dehydrogenase↗
PubMed2001

Intrahospital transport of critically ill patients: complications and difficulties.

An audit of 97 intrahospital transports of critically ill patients was undertaken within Westmead Hospital. The aims of this audit were to assess all factors that may lead to problems during intrahospital transports. At the completion of a transport medical staff were asked to provide information about their patient and their treatment, as well as any difficulties they may have encountered. Overall, 62% of transports reported some difficulty or complication. Of these, 31% were patient-related and 45% were related to equipment or the transport environment. (15% encountered problems in both areas). Many of the difficulties were preventable with adequate pre-transport communication and planning. Other problems were directly related to the increased severity of illness in these patients.

Adolescent↗
PubMed2001

Long-term urological complications in survivors younger than 15 months of advanced stage abdominal neuroblastoma.

PURPOSE: We evaluated the long-term urological complications in survivors of infant advanced stage abdominal neuroblastoma. MATERIALS AND METHODS: The records of patients who presented during an 8-year period with surgical problems related to the kidney and who had survived advanced stage (IV and IV-S) neuroblastoma were reviewed. RESULTS: Of 7 patients identified 3 had complications of obstruction from retroperitoneal fibrosis and 4 had renal cell carcinoma. In the renal cell carcinoma group 3 patients had synchronous, multifocal, bilateral tumors and 1 had a tumor in a solitary kidney. Pathological examination of renal cell carcinoma revealed oncocytoidy with solid and papillary patterns. One patient underwent bilateral nephrectomy but in the remaining 3 renal preservation surgery was performed. All 7 patients have no progression of secondary complications 2 to 8 years after initial presentation. CONCLUSIONS: Survivors of advanced stage abdominal neuroblastoma may be predisposed to long-term urological complications well after initial diagnosis. Because of the risk of renal damage from obstruction secondary to retroperitoneal fibrosis, and the propensity to have renal cell carcinoma, close long-term followup using abdominal imaging is recommended.

Abdominal Neoplasms↗
PubMed2000

Acrolein, a product of lipid peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures.

Oxidative stress has been implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease (AD). Increased lipid peroxidation, decreased levels of polyunsaturated fatty acids, and increased levels of 4-hydroxynonenal (HNE), F(2)-isoprostanes, and F(4)-neuroprostanes are present in the brain in patients with AD. Acrolein, an alpha,beta-unsaturated aldehydic product of lipid peroxidation has been demonstrated to be approximately 100 times more reactive than HNE and is present in neurofibrillary tangles in the brain in AD. We recently demonstrated statistically significant elevated concentrations of extractable acrolein in the hippocampus/parahippocampal gyrus and amygdala in AD compared with age-matched control subjects. Concentrations of acrolein were two to five times those of HNE in the same samples. Treatment of hippocampal cultures with acrolein led to a time- and concentration-dependent decrease in cell survival as well as a concentration-dependent increase in intracellular calcium. In cortical neuron cultures, we now report that acrolein causes a concentration-dependent impairment of glutamate uptake and glucose transport in cortical neuron cultures. Treatment of cortical astrocyte cultures with acrolein led to the same pattern of impairment of glutamate uptake as observed in cortical neuron cultures. Collectively, these data demonstrate neurotoxicity mechanisms of arolein that might be important in the pathogenesis of neuron degeneration in AD.

Acrolein↗
PubMed2000

Survival of hippocampal and cortical neurons in a mixture of MEM+ and B27-supplemented neurobasal medium.

Serum-free B-27 supplemented neurobasal (NB) and a 10% fetal bovine serum-supplemented Eagle's minimum essential medium (MEM+) are used to culture rat embryonic hippocampal neurons for different purposes. Although NB medium leads to enhanced cell survival, it contains biological antioxidants and is not suitable for the study of free radical damage and oxidation in cultured neurons. MEM+ without additional antioxidants has been used widely in the study of free radical damage and oxidation, although it does not support optimum neuronal survival in culture. Serum in MEM+ leads to enhanced cell survival but also promotes glial cell proliferation. In this study, we used a new combination medium (NM-2) that consists of both NB and MEM+ for growing primary hippocampal and cortical neuronal cultures. NM-2 enhanced neuronal survival 78.9% for dissociated neurons at a density of 50 cells/mm(2) and 83.1% for 100 cells/mm(2), while decreasing glial cell proliferation to 2-3% and completely inhibiting oligodendrocytes. The NM-2 minimized the effectiveness of antioxidants in the medium to the neurotoxin 4-hydroxynonenal. It also decreased neuronal clumping and provided a more even distribution of neurons. Neurons survived for 4 weeks in NM-2 without changing the original medium. NM-2 provides a good environment for studies of free radical damage and oxidation of neurons. The combination incorporates the best of both NB and MEM+ that results in high neuron survival rate, low glial cell proliferation, reduced antioxidant level, and provides relatively pure cultures of hippocampal and cortical neurons.

Animals↗
PubMed2000

Decreased base excision repair and increased helicase activity in Alzheimer's disease brain.

Recent studies show an increase in DNA oxidation in brain and cerebrospinal fluid (CSF), and decreased levels of the free repair product in CSF in Alzheimer's disease (AD). This is a study of the activity of the base excision repair enzyme, 8-oxoguanine glycosylase (responsible for the excision of 8-oxoguanine), and DNA helicase activity in nuclear protein samples from four brain regions of 10 AD and eight age-matched control subjects. Statistically significant (p<0.05) decreases in 8-oxoguanine glycosylase activity were observed in the nuclear fraction of AD hippocampal and parahippocampal gyri (HPG), superior and middle temporal gyri (SMTG), and inferior parietal lobule (IPL). DNA helicase activity was elevated in all nuclear samples except the IPL with statistically significant elevations in the HPG and CER. Statistically significant depletion of helicase activity was observed in the nuclear fraction in AD IPL. Our results demonstrate that the repair capabilities for 8-oxoguanine are decreased in AD. The modest increase in DNA helicase activity in some brain regions in AD may interfere with base excision repair mechanisms. Overall, the decreased repair of DNA damage could be involved in the pathogenesis of neurodegeneration in AD.

Aged↗
PubMed2000

Decreased thioredoxin and increased thioredoxin reductase levels in Alzheimer's disease brain.

Increasing evidence supports the role of reactive oxygen species (ROS) in the pathogenesis of Alzheimer's disease (AD). Both in vivo and in vitro studies demonstrate that thioredoxin (Trx) and thioredoxin reductase (TR), the enzyme responsible for reduction of oxidized Trx, have protective roles against cytotoxicity mediated by the generation of ROS. The present study measured levels of Trx protein and activities of TR in the brain in AD compared with control subjects, and evaluated the possible protective role of TR and Trx against amyloid beta-peptide (Abeta) toxicity in neuronal cultures. Analysis of Trx protein levels in 10 AD and 10 control subjects demonstrated a general decrease in all AD brain regions studied, with statistically significant decreases in the amygdala (p <.05), hippocampus/parahippocampal gyrus (p <.05), and marginally significant (p <.10) depletions in the superior and middle temporal gryi. Thioredoxin reductase activity levels were increased in all AD brain regions studied with statistically significant increases occurring in AD amygdala (p =.01) and cerebellum (p =.007). To investigate the protective effects of Trx and TR against Abeta-induced toxicity, primary hippocampal cultures were treated with Trx or TR in combination with toxic doses of Abeta. Treatment of cultures with Trx led to a statistically significant concentration-dependent enhancement in cell survival against Abeta-mediated toxicity as did treatment with TR. Together, these data suggest that, although TR is protective against Abeta-mediated toxicity, the increase observed in AD brain offers no protection due to the significant decrease in Trx levels. This decrease in the antioxidant Trx-TR system may contribute to the increased oxidative stress and subsequent neurodegeneration observed in the brain in AD.

Aged↗
PubMed2000

Glomerular lesions in male rabbits treated with aluminium lactate: with special reference to microaneurysm formation.

Novel glomerular lesions were seen in male rabbits after intravenous administration of aluminum lactate. Eight rabbits in the treated group were given 0.1 mmol/kg of aluminum lactate 5 days a week for 4 weeks. The control group of 8 rabbits was given 0.3 mmol/kg of sodium lactate by the same injection protocol. In the treated group, the mesangial cells in the glomerular tufts in 6 of 8 rabbits were distended with grayish blue granular material, which was identified by laser microprobe mass spectrometry and acid solochrome azurine stain as an aluminum compound. Other consistent findings in the glomeruli included microaneurysm in 6 of 8 rabbits and segmental sclerosis in 6 of 8 rabbits. Less frequently observed glomerular changes included crescent formation, necrosis with calcification, fibrosis of the Bowman's capsule, cystic dilation of the Bowman's space, and exudation of erythrocytes into the Bowman's space. The mechanism by which aluminum lactate induces the glomerular changes is not certain. However, the pathogenesis may involve the deposition of aluminum in the mesangial cells, resulting in mesangiolysis which in turn causes microaneurysm. The sclerotic change is interpreted as a sequela of microaneurysm. The findings suggest that aluminum induces glomerular lesions in rabbits. This may serve as a good animal model to study mesangiolysis and microaneurysm formation.

Aluminum↗
PubMed2000

Serum zinc levels and Alzheimer's disease.

Concentrations of zinc in postmortem serum and four brain regions were measured by flame atomic absorption spectrometry and instrumental neutron activation analysis, respectively, in nine Alzheimer's disease (AD) and eight control subjects. A statistically significant elevation of zinc serum was observed in AD subjects (136.4+/-66.8 microg/dL) compared with age-matched control subjects (71.1+/-35.0 microg/dL). No significant differences were observed between AD and control zinc concentrations in the amygdala, hippocampus, cerebellum, and superior and middle temporal gryi.

Aged↗
PubMed1999

Protection against amyloid beta peptide toxicity by zinc.

Zinc (Zn) is an essential element in normal development and biology, although it is toxic at high concentrations. Recent studies show that Zn at high concentrations accelerates aggregation of amyloid beta peptide (Abeta), the major component of senile plaques in Alzheimer's disease (AD). This study reports the effect of varying Zn concentrations on Abeta toxicity and the mechanism by which low concentrations function in a protective role. At Abeta/Zn molar ratios of 1:0.1 and 1:0.01, Zn produces significant protection against Abeta toxicity in cultured primary hippocampal neurons. At higher concentrations (1:1 molar ratio), Zn offers no protection or enhances Abeta toxicity. The protective effect of Zn against Abeta toxicity is due in part to the enhancement of Na+/K+ ATPase activity which prevents the disruption of calcium homeostasis and cell death associated with Abeta toxicity. Analysis of Na+/K+ ATPase activity in cultured rat cortical cells indicated that Zn exposure alone afforded a 20% increase in enzyme activity, although the differences were statistically insignificant. However, in cortical cultures exposed to a toxic dose of Abeta (50 microM), Zn at concentrations of 5 and 0.5 microM led to significant increases in Na+/K+ ATPase activity compared with levels in cells treated with Abeta alone. Zn at a 1:1 molar ratio (50 microM) led to a significant decrease in enzyme activity. Together, these data suggest that Zn functions as a double-edged sword, affording protection against Abeta at low concentrations and enhancing toxicity at high concentrations.

Amyloid beta-Peptides↗
PubMed1999

Salmonella infection in a commercial line of ducks; experimental studies on virulence, intestinal colonization and immune protection.

Experimental infections of different salmonella serotypes were established in a commercial line of ducks to provide baseline information on which control measures might be based. The ducks were very resistant to systemic infection with Salmonella typhimurium, S. enteritidis and S. gallinarum within 36 h of hatching. This was associated with an inherent inability of the strains to multiply in the reticulo-endothelial system. The resistance was not associated with poor invasiveness or serum sensitivity. Individual strains of S. typhimurium, S. enteritidis, S. heidelberg and S. orion colonized the gut well and were excreted in the faeces for at least 6 weeks by ducks when they were infected orally within 2 days of hatching. The main sites of colonization were the caeca and, to a lesser extent, the crop. Viable counts of each inoculated strain in the caeca remained in excess of 10(6) c.f.u. 3 weeks after infection although the organisms had been cleared from the spleen by this time. Much less excretion occurred when the birds were infected at 3 weeks of age. When infected ducks, which had cleared themselves of infection, were challenged orally with the homologous strain expressing a different genetic marker, very low levels of excretion of the challenge strain were detected when compared with a control group. After infection low titres of circulating lipopolysaccharide-specific IgG antibodies were detected by an ELISA. Intestinal colonization of newly hatched ducks with an aroA strain of S. enteritidis resulted in extensive colonization which exerted an exclusion effect on the parent strain inoculated 24 h later.

Animals↗