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Biomedical subjects

L Fitzpatrick

Publications and source records attributed to L Fitzpatrick.

At least 19 recordsLinked to original sources
PubMed2005

Polychlorinated naphthalenes in air and snow in the Norwegian Arctic: a local source or an Eastern Arctic phenomenon?

PCNs were measured in air and snow during separate field campaigns at Ny-Alesund (April 2001) and Tromsø (February/March 2003) in the Norwegian Arctic. Air concentrations ranged from 27 to 48 and 9 to 47 pg sigmaPCN m(-3) for Ny-Alesund (n=6) and Tromsø (n=10), respectively. These concentrations (including the tri-chlorinated naphthalenes) greatly exceeded concentrations previously measured in the Canadian Arctic, but did fall within the upper range of concentrations observed over the eastern Arctic Ocean and regional seas. Local sources appear to be affecting concentrations observed at both sites, with the presence of several hexa-chlorinated naphthalenes at Tromsø probably attributed to local/regional sources. Use of air mass back trajectories at Tromsø revealed that background air concentrations in the Norwegian Arctic are likely to range between <9 and 20 pg sigmaPCN m(-3) and that contemporary concentrations derived close to potential sources (i.e. arctic towns) may equal or exceed those of PCBs. The mean concentration in surface snow was 350 and 240 pg sigmaPCN L(-1) (meltwater) (or 0.014 and 0.01 pg g(-1) (snow)) at Ny-Alesund and Tromsø, respectively. The wide variation in concentrations observed between fresh snowfalls could be explained by different snow densities (as a surrogate of snow surface area), rather than attributed to varying air concentrations. A statistically significant inverse relationship was found between snow density and concentrations of tri- to penta-chlorinated homologues and compliments similar findings for the polychlorinated biphenyls (PCBs). This suggests that the vapour-sorbed quantity changes rapidly with snow ageing/compaction; with implications for the fate of these chemicals in the Arctic.

Journal Article↗
PubMed2004

Investigation of Laboratory cross-contamination of Mycobacterium tuberculosis cultures.

Many clinicians and laboratory personnel are unaware that a culture positive for Mycobacterium tuberculosis may represent contamination. Laboratory cross-contamination with the M. tuberculosis laboratory control strain (H37Ra) occurs infrequently and therefore demands heightened awareness and recognition. We report 3 occurrences of laboratory cross-contamination from the same laboratory. These occurrences illustrate the importance of interpreting laboratory results in conjunction with the patient's clinical presentation. Failure to recognize laboratory cross-contamination with M. tuberculosis leads to both erroneous administration of unnecessary medications and expenditure of resources required to conduct contact investigations.

Adult↗
PubMed2004

Use and validation of novel snow samplers for hydrophobic, semi-volatile organic compounds (SVOCs).

Two novel gas-tight snow samplers (snow-can and snow-tube) are presented and the performance of the snow-can in a field trial was assessed. The methodology for the sampling, extraction and analysis of persistent organic pollutants (POPs) are detailed. These samplers allow the various components of a snow sample to be analysed separately; these included the meltwater (MW), particulate matter (GFF) and vapour in the headspace (HS). Snow samples collected on the Punta Indren glacier in the Italian Alps revealed the occurrence of polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs) and organochlorine pesticides (OC). Replicate samples of the same snow type were undertaken as a test of sampling precision. Relative standard deviations (RSDs) for SigmaPCBs and SigmaPAHs were approximately 30% and approximately 35% respectively. The lowest precision was found for the particle-laden snow, notably for the heavier PCB homologues. For the chlorinated compounds, the pesticides lindane and endosulfan-I had the highest levels in snow, with mean concentrations of 402 and 103 pgl(-1) (snow meltwater) respectively. The vapour present in the headspace (HS) comprised a minor component of a collected sample for all compounds, but HS concentrations for three lighter PAHs gave good agreement with those calculated based on their dimensionless Henry's law constants. This suggests that volatilisation during melting of aged snow-can be reasonably predicted with knowledge of the temperature-dependent Henry's law constant.

Altitude↗
PubMed2001

OPC-compounds prevent oxidant-induced carbonylation and depolymerization of the F-actin cytoskeleton and intestinal barrier hyperpermeability.

Rebamipide (OPC-12759), a quinolone derivative, and OPC-6535, a thiazol-carboxylic acid derivative, are compounds with ability to protect gastrointestinal (GI) mucosal integrity against reactive oxygen metabolites (ROM). The underlying mechanism of OPC-mediated protection remains poorly understood. It is now established that ROM can injure the mucosa by disruption of the cytoskeletal network, a key component of mucosal barrier integrity. We, therefore, investigated whether OPC compounds prevent the oxidation, disassembly, and instability of the cytoskeletal protein actin and, in turn, protect intestinal barrier function against ROM. Human intestinal (Caco-2) cell monolayers were pretreated with OPC (-12759 or -6535) prior to incubation with ROM (H2O2) or HOCl). Effects on cell integrity (ethidium homodimer-1), epithelial barrier function (fluorescein sulfonic acid clearance), and actin cytoskeletal integrity (high-resolution laser confocal) were then determined. Cells were also processed for quantitative immunoblotting of G- and F-actin to measure oxidation (carbonylation) and disassembly of actin. In monolayers exposed to ROM, preincubation with OPC compounds prevented actin oxidation, decreased depolymerized G-actin, and enhanced the stable F-actin. Concomitantly, OPC agents abolished both actin cytoskeletal disruption and monolayer barrier dysfunction. Data suggest for the first time that OPC drugs prevent oxidation of actin and lead to the protection of actin cytoskeleton and intestinal barrier integrity against oxidant insult. Accordingly, these compounds may be used as novel therapeutic agents for the treatment of a variety of oxidative inflammatory intestinal disorders with an abnormal mucosal barrier such as inflammatory bowel disease.

Actins↗
PubMed2000

Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi's sarcoma clinical stage.

OBJECTIVE: To determine the relationship between human herpesvirus 8 (HHV-8 or Kaposi's sarcoma-associated herpesvirus) peripheral blood virus load and Kaposi's sarcoma (KS) clinical stage. DESIGN: Blinded, cross-sectional analysis of peripheral blood HHV-8 DNA levels in persons with AIDS-related KS in Harare, Zimbabwe. METHODS: Subjects were stratified by KS clinical stage. The amount of HHV-8 DNA in plasma and peripheral blood mononuclear cells (PBMC) was determined by quantitative real-time PCR amplification of the HHV-8 open reading frame 26. RESULTS: Thirty-one HIV-1/HHV-8-coinfected persons were studied: 26 subjects had histologically confirmed KS (one stage II, 11 stage III and 14 stage IV) and five subjects had antibodies to HHV-8 but did not have KS. The age, CD4 lymphocyte count and plasma HIV-1 RNA levels were similar in all groups. HHV-8 DNA was detected in the plasma of all HHV-8-infected subjects (range < 2.4 to 5.2 log10 copies/ml), but plasma HHV-8 DNA levels were not associated with KS disease stage. In contrast, the amount of HHV-8 DNA in PBMC (range < 0.7 to 4.5 log10 copies/microg) was strongly associated with KS clinical stage (P = 0.005). Among stage IV KS cases, there was a linear relationship between plasma and PBMC HHV-8 DNA levels (r2 = 0.42; P = 0.01). CONCLUSION: The strong association observed between the extent of KS disease and the levels of HHV-8 DNA in PBMC provides further evidence for a relationship between HHV-8 virus load and KS pathogenesis.

Adult↗
PubMed2000

'Infront outback' goes national.

The National Rural Health Alliance, the Toowoomba Hospital Foundation and the Cunningham Centre have agreed to merge the two biennial conferences for rural and remote health that have been running in alternate years since 1991. This means that in March 2001, the National Rural Health Conference will, for the first time, incorporate 'Infront Outback', the Australian Rural and Remote Health Scientific Conference. There will, therefore, be one major biennial rural heath conference, dealing coherently with health scientific research and policy development. The recommendations to governments and national bodies that result should be even stronger and more highly regarded than has been the case to date.

Australia↗
PubMed1999

Human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) infection in men receiving treatment for HIV-1 infection.

OBJECTIVE: To determine the prevalence of human herpesvirus 8 (HHV-8) infection in men treated for HIV-1 infection in Denver, Colorado. DESIGN: Cross-sectional analysis METHODS: Blood samples were obtained from 216 HIV-1-infected men. Antibody to latency-associated nuclear antigen (LANA) was detected by an immunofluorescent assay and the presence of HHV-8 in peripheral blood mononuclear cells (PBMC) was detected by polymerase chain reaction amplification. RESULTS: Among HIV-1-infected men who did not have Kaposi's sarcoma (KS), prevalence of HHV-8 infection was 46% (95% confidence interval [CI], 0.39-0.52). LANA seropositivity was common both among subjects with KS and subjects without KS (69% versus 42%; p = .06), but detection of HHV-8 DNA in peripheral blood was strongly associated with a diagnosis of KS (44% versus 10%; p = .001). In a univariate analysis of study subjects without KS, neither the odds of LANA seropositivity nor detection of HHV-8 DNA in PBMC was significant for CD4+ lymphocyte count, HIV-1 virus load, the use of three drug antiretroviral regimens or the prior occurrence of non-KS AIDS-related conditions. CONCLUSION: Although antibodies to HHV-8 are common among HIV-1-infected men, detection of HHV-8 DNA in PBMC is uncommon and is associated with a diagnosis of Kaposi's sarcoma.

AIDS-Related Opportunistic Infections↗
PubMed1999

Calcified plaque cross-sectional area in human arteries: correlation between intravascular ultrasound and undecalcified histology.

BACKGROUND: The purpose of this investigation was to quantify the amount of intralesional calcium detected by intravascular ultrasound (IVUS) compared with undecalcified histology in human arteries. This method preserves intralesional calcium and reduces sectioning artifacts, thereby providing an accurate measure of calcium plaque morphology. METHODS AND RESULTS: Ten arterial segments (5 coronary, 5 iliac) were obtained at autopsy. IVUS imaging was performed with a 4.9F catheter at an automated pullback rate of 1.0 mm/s. The undecalcified arteries were dehydrated in ascending alcohol and polymerized in glycol methylmethacrylate. The arteries were cut into 200-microm sections with an Isomet low-speed saw and stained with Goldner's trichrome. The lumen cross-sectional area, the calcium plaque cross-sectional area, the calcium plaque depth, length, and angle of arc of calcified plaque were measured from the IVUS images and histologic sections. In 24 selected cross sections, there were 38 separate calcium plaques. An independent observer correctly identified 34 of 38 calcified plaques for a sensitivity of 89% and specificity of 97%. The total mean calcified plaque cross-sectional area measured from histology was 4.6 +/- 4.1 mm2 compared with 2.8 +/- 2.3 mm2 by IVUS (P =.002). Plaque depth measured by histology was 1.2 +/- 0.4 mm versus 0.7 +/- 0.2 mm by IVUS (P =.001). The length of calcium plaques measured by histology was 3.6 +/- 1.78 mm versus 3.6 +/- 1.5 mm for IVUS (r = 0.79). CONCLUSIONS: IVUS accurately depicts circumferential calcified lesions with high sensitivity (89%) and specificity (97%). However, IVUS underestimates the total calcified plaque cross-sectional area by 39%. This is mainly because of the inability of the ultrasound to penetrate intralesional calcium, which leads to an underestimation of the depth of calcium by 45%.

Adult↗
PubMed1998

Comparison of the prevalence of antibodies to human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) in Brazil and Colorado.

The prevalence of human herpesvirus 8 (HHV-8; Kaposi's sarcoma [KS] herpesvirus) infection was determined by IFA in 297 persons living in Brazil and Colorado. The prevalence of antibody to HHV-8 in human immunodeficiency virus (HIV) type 1-seropositive gay men with and without KS was similar in Brazil and Colorado. In Brazil, the prevalence of HHV-8 antibody was significantly greater in HIV-1-seronegative gay men than in HIV-1-seronegative male intravenous drug users. HHV-8-seropositive Brazilian gay men who had a clinical diagnosis of KS or who were infected with HIV-1 had significantly higher titers of HHV-8 antibody than did HHV-8-seropositive, HIV-1-seronegative Brazilian gay men. These findings provide further support for the association between HHV-8 infection and KS and suggest that, as in the United States, HHV-8 infection is transmitted sexually in Brazil.

Adolescent↗
PubMed1998

Cell biology and possible therapeutic applications of anti-CD3-activated killer-T cells (review).

Polyclonal T lymphocyte populations can be stimulated with anti-CD3 antibody to proliferate, secrete cytokines, and mediate MHC-unrestricted cytotoxic activity against a wide range of tumor target cells. Because anti-CD3-activated killer-T (AK-T) cells may be useful in the immunotherapy of human cancers, it is important to understand the signaling pathways and cell-surface structures involved in the induction and tumoricidal effector function of AK-T cells. Studies in the mouse model system have characterized the cytokines, signal transduction pathways, and costimulatory molecules involved in AK-T cell development. The recognition/adhesion and subsequent signaling events which lead to tumoricidal activity by mouse AK-T cells have also been defined. These findings, providing they translate accurately to the human system, may allow for the design of effective strategies to use AK-T cells for the treatment of human cancers. However, to date, the encouraging results obtained with anti-CD3 antibody/AK-T cell-based immunotherapies in mouse models of cancer have not been duplicated in clinical trials. The most likely explanation for this dis-appointing result is that tumor-reactive T lymphocytes in long term tumor-bearers fail to function correctly in the tumor microenvironment due to tumor-induced immune suppression and defects in key signal transduction molecules. It is clear that a detailed understanding of the inhibitory effect of established tumors on host T cells and the means to overcome tumor-induced immunosuppression are needed before anti-CD3 antibody/AK-T cell-based immunotherapies can be expected to succeed in the clinical setting.

Animals↗
PubMed1997

Synchronization of estrus and ovulation and associated endocrine changes in Bos indicus cows.

The effects of 4 estrus synchronization treatments on intervals to and synchrony of estrus and ovulation, on timing of the preovulatory LH surge and associated changes in plasma progesterone, LH, FSH, and 17beta-estradiol (E(2)) were investigated in 48 Bos indicus cows. Treatment 1 consisted of 2 injections of PGF(2alpha) 14 d apart (n = 12); Treatment 2 of a subcutaneous 3-mg norgestomet implant and an intramuscular injection of 3 mg of norgestomet and 5 mg estradiol valerate, with the implant removed 10 d later (n = 12; norgestomet-estradiol); Treatment 3 of norgestomet-estradiol, with a subcutaneous injection of PMSG given at time of implant removal (Day 10; n = 12); and Treatment 4 of norgestomet implant (as for Treatments 2 and 3) inserted for 10 d, with an intramuscular injection of PGF(2alpha) given at the time of implant removal (n = 12). The experiment was conducted in 2 replicates (24 cows/replicate, 6 cows/group). Estrus, ovulation and timing of the preovulatory surge of LH varied less in cows treated with norgestomet-estradiol and PMSG than in cows in Treatments 1 and 4 (P < 0.008). Treatment with PMSG reduced variation in ovulation times and timing of the LH surge in cows treated with norgestomet-estradiol (P < 0.02). Concentrations of E(2) were higher in cows in Treatments 2 and 3 on the final day of treatment and at about 6 h post ovulation compared with cows in Treatments 1 and 4 (P < 0.05). Different methods for synchronizing estrus did not alter sequential endocrine and behavioral changes in relation to the timing of the LH peak, and the results were consistent with current recommendations for insemination times in Bos taurus cattle.

Journal Article↗
PubMed1997

Anti-CD3-activated killer T cells: Interleukin-6 modulates the induction of major histocompatibility complex-unrestricted cytotoxicity and the expression of genes coding for cytotoxic effector molecules.

We have investigated the role of interleukin-6 (IL-6) in the induction of major histocompatibility complex (MHC)-unrestricted cytotoxicity, as well as granzyme B, perforin, and Fas ligand gene expression, following mouse T lymphocyte activation with anti-CD3 monoclonal antibody (mAb). The generation of anti-CD3-activated killer-T (AK-T) cells was inhibited when anti-IL-6 neutralizing mAb was added at initiation of culture but not 24 h later, indicating that IL-6 is involved at an early stage of AK-T cell development. However, AK-T cell induction in the presence of exogenous IL-6 did not result in enhanced cytotoxicity, suggesting that saturating levels of IL-6 are normally synthesized in AK-T cell cultures. The inhibitory effect of IL-6 neutralization on AK-T cell generation could not be attributed to a defect in AK-T cell proliferation or to an inability of AK-T cells to recognize and adhere to P815 tumor target cells. However, IL-2 synthesis and CD25 expression were downregulated in AK-T cell cultures performed in the presence of anti-IL-6 mAb. In addition, IL-6 neutralization resulted in decreased expression of granzyme B and perforin, but not Fas ligand, mRNA. Exogenous IL-2 (50 U/ml) added at initiation of culture completely reversed the inhibitory effect of anti-IL-6 mAb on AK-T cell development, restoring CD25 expression and tumoricidal activity, as well as granzyme B and perforin mRNA expression, to control levels. We conclude that IL-6 modulates AK-T cell induction through an IL-2-dependent mechanism.

Animals↗
PubMed1996

Linkage mapping of microdissected clones from distal mouse chromosome 16.

A total of 38 unique segments generated by microdissection of mouse chromosome 16 (MMU16), sequence independent amplification (SIA) and cloning were sequentially mapped on the distal portion of the chromosome with two mouse backcross panels. Some reference markers from other sources were retyped in the panels and results integrated with those for our microdissected DNA segments. The clone map is most highly refined in its distal portion, which stretches from reference marker D16Mit71 to D16Mit5, and the highest density of clones is in the region defined by markers D16Mit5 and D16Mit141. This map on distal mouse chromosome 16 should be a useful tool for the mouse genome project and for studies of genes in the region.

Animals↗
PubMed1996

Anti-CD3-activated killer T cells: interferon-gamma and interleukin-10 cross-regulate granzyme B expression and the induction of major histocompatibility complex-unrestricted cytotoxicity.

We have investigated the effect of interferon-gamma (IFN-gamma) and interleukin (IL)-10 on granzyme B expression and the induction of major histocompatibility complex (MHC)-unrestricted cytotoxic activity in mouse T cell cultures following activation with anti-CD3 monoclonal antibody (mAb). First, metabolic inhibitors of granule-dependent and granule-independent cytolytic pathways were used to show that anti-CD3-activated killer T (AK-T) cells kill allogeneic P815 mastocytoma target cells primarily by the granule-dependent granzyme/perforin pathway. In comparison to control AK-T cells, lower levels of cytolytic activity were evident when AK-T cells were generated in the presence of anti-IFN-gamma neutralizing mAb or exogenous IL-10, whereas enhanced cytotoxicity was observed when AK-T cell cultures contained anti-IL-10 neutralizing mAb or exogenous IFN-gamma. In addition, granzyme B mRNA expression by AK-T cells was diminished when IFN-gamma bioactivity was neutralized or exogenous IL-10 was present in AK-T cell-cultures, whereas neutralization of IL-10 bioactivity or the addition of exogenous IFN-gamma resulted in increased expression of granzyme B mRNA. Similar results were obtained when granzyme B enzymatic activity in AK-T cell lysates was quantified using a colorimetric granzyme B assay. Altered cytotoxic potential, granzyme B mRNA expression, and granzyme B enzymatic activity following T cell activation in the presence of anti-IFN-gamma or anti-IL-10 neutralizing mAb or exogenous IFN-gamma or IL-10 could not be attributed to gross changes in T cell activation status or to altered percentages of CD4+ and CD8+ T cells in AK-T cell cultures. We conclude that IFN-gamma and IL-10 cross-regulate the induction of the granule-dependent cytolytic machinery of AK-T cells.

Animals↗
PubMed1995

The use of demineralized bone powder in an onlay graft model.

Demineralized bone powder has been shown previously to successfully induce bone formation. The purpose of this study was to use demineralized bone powder in an onlay graft situation using implantable molds. Demineralized bone powder was placed within a mold and rigidly attached to the frontal bones of 30 New Zealand White rabbits by screw fixation. Periosteum was not closed over the mold. A control group had the mold placed without demineralized bone powder used. After 12 weeks of growth, the animals were sacrificed and the frontal bone was analyzed for bone growth using standardized histology and fluorescent microscopy. One hundred percent of the animals (30 of 30) that received demineralized bone powder underwent bone growth in the precise shape of the mold (p < 0.001). There was no new bone development in the control group (n = 8). Placement of larger molds duplicated these results (n = 20) with a 650 percent increase in frontal bone thickness within 12 weeks after placement of demineralized bone powder. This model mimics onlay bone grafting, and perhaps this technique may replace onlay grafting or alloplastic implantation in certain circumstances, avoiding the extra morbidity and donor-site defects associated with bone grafting.

Animals↗
PubMed1995

Degeneration of Sertoli and spermatogenic cells in homozygous and heterozygous weaver mice.

In the neurological mutant mouse weaver (wv/wv), the majority of males are infertile due to hypospermatogenesis. Heterozygous weaver mice (wv/+) cease mating successfully when males reach an average age of 3.5 months. The contents of epididymal fluid were scored for the number of sperm and sperm motility in wv/wv, wv/+ and controls. Testes were examined in mice of the three genotypes at various ages using light and electron microscopy. In wv/+ males, sperm counts were significantly lower than in controls and were significantly higher than in wv/wv. The seminiferous epithelium in weaver mice appears depleted soon after puberty and a wide range of degenerative changes was identified in both germ cells and Sertoli cells. Analogous cellular aberrations were detected in heterozygous males, but they appeared at an older age and were not as severe as in wv/wv. We hypothesize that in weaver homo- and heterozygosity the damage of Sertoli cells may induce degeneration of germinal cells and particularly affect the most advanced spermatogenic cells.

Animals↗
PubMed1994

Human giant cell tumors of the bone (osteoclastomas) are estrogen target cells.

The decrease in estrogen levels that follows the onset of menopause results in rapid bone loss and osteoporosis. The major effect of estrogen deficiency on bone metabolism is an increase in the rate of bone resorption, but the precise mechanism by which this occurs remains unresolved. A recently developed technique for the isolation of avian osteoclasts has been modified to obtain highly purified multinucleated cells from human giant cell tumors. These osteoclast-like cells have been examined for evidence of estrogen receptors (ERs) and responses to 17 beta-estradiol (17 beta-E2). Analysis of giant-cell RNA demonstrated expression of ER mRNA. Furthermore, immunoblot analysis revealed that the giant cells contained a 66-kDa protein that was recognized by a monoclonal antibody specific for the human ER. When isolated multinucleated cells were cultured on slices of bone, there was a dose-dependent decrease in resorption in response to treatment detectable at 10 pM 17 beta-E2. Treatment with 10 nM 17 alpha-estradiol or vehicle (control) did not inhibit resorption. Moreover, the multinucleated cells isolated from these tumors had decreased mRNA levels for cathepsin B, cathepsin D, and tartrate-resistant acid phosphatase (TRAP) as well as secreted cathepsin B and TRAP enzyme activity in response to treatment with 10 nM 17 beta-E2. In contrast to these data, no change in gene expression was detected in mononuclear cells from these tumors in response to 17 beta-E2 treatment. These data support the proposition that human osteoclasts are target cells for estrogen and that estrogen can inhibit bone resorption by human osteoclasts.

Acid Phosphatase↗