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Biomedical subjects

D M Brown

Publications and source records attributed to D M Brown.

At least 19 recordsLinked to original sources
PubMed2007

Risk assessment of unsuitable winter conditions for manure and nutrient application across Ontario.

Practical guidelines addressing the timing of manure and nutrient application must consider the concerns of the farm operators while ensuring the protection of the environment. An approach was developed and analyzed through case studies to determine the first recommended day in the spring, and the last in the fall, for manure and nutrient application based on probability analysis. Since most manure and nutrient application guidelines recommend avoiding adverse conditions, the three criteria established to perform a risk assessment were: (i) a frost depth greater than 0.05 m; (ii) a snow accumulation of greater than 0.05 m; and (iii) a soil volumetric water content greater than or equal to that of the plastic limit for the soil. Climatic data and typical soil information for seven locations in Ontario were used to model volumetric soil water contents, frost depths, and snow accumulation from the simultaneous heat and water (SHAW) model for a 48-yr period (1954-2001). Applying the three criteria to the modeled output, the average range between the least limiting probability (0.1, or one in ten year occurrence) and the greatest limiting probability (0.001, or one in one thousand year occurrence) analyzed among the locations was 16 d in the spring as compared to 29 d in the fall. Although geographical location affected the predicted spring start and fall end recommended manure and nutrient application dates, local climate and soil hydraulic properties also played an important part in the determination of these days. Overall the prediction method developed performed reasonably well and provided insight into the environmental factors influencing manure and nutrient application timing.

Animals↗
PubMed2006

The effect of oxidative stress on macrophages and lung epithelial cells: the role of phosphodiesterases 1 and 4.

Reactive oxygen species (ROS) have been implicated in various pulmonary diseases by causing direct injury to lung epithelial cells. Signalling activity of cells through transcription factors such as nuclear factor kappa B (NF-kappaB) and AP-1 have been shown to be regulated by ROS, and the release of pro-inflammatory cytokines demonstrated in the study of inflammatory disease. In this study, we examined the effect of the oxidant tert-butylhydroperoxide (tBHP) on mouse J774 macrophages and its ability to cause the release of the pro-inflammatory cytokine tumour necrosis factor alpha (TNF-alpha). The role of calcium as a signalling molecule was studied using various calcium antagonists. The role of the signalling molecule cAMP was also investigated using phosphodiesterase inhibitors PDE1 and PDE4 families. Oxidative stress was investigated in lung epithelial (A549) cells with and without calcium antagonists and PDE inhibitors with regard to their ability to modulate release of the neutrophil chemoattractant interleukin 8 (IL-8). The oxidant tBHP significantly increased the cytosolic calcium concentration in J774 macrophages, which was prevented by the PDE1 inhibitor. The production of TNF-alpha protein by J774 macrophages was mediated by a pathway involving calcium as addition of calcium antagonists inhibited the tBHP stimulated increase in the cytokine. Inhibitors of both PDE1 and PDE4 completely prevented the tBHP stimulated TNF-alpha release suggesting that the cAMP pathway may be important in the oxidant induced signalling pathway leading to gene expression of pro-inflammatory cytokines. In the presence of oxidant alone, A549 epithelial cells released significant amounts of IL-8, which was inhibited by both calcium antagonist treatment and PDE inhibition treatment. These data suggest that ROS-mediated lung inflammation could be mediated at least in part by calcium and elevated PDE activity associated with decreased cAMP in both macrophages and epithelial cells. Inhibition of these pathways may provide a route for treatment of inflammatory lung diseases.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

Factors affecting attrition in a longitudinal study of patients with AIDS.

Anecdotal data have suggested that retention of HIV-infected patients with immune recovery in longitudinal studies may be difficult as they resume normal activities. This study evaluated risk factors for attrition among patients with AIDS in a cohort study in the era of highly active antiretroviral therapy. Patients with AIDS enrolled in the Longitudinal Study of Ocular Complications of AIDS were evaluated every three months with demographic, clinical and laboratory data collected. Lost to follow-up was defined as any patient who missed all study visits and could not be contacted for 12 consecutive months, who had not died and who did not re-enter the study at a later date. Of the 1,052 patients studied, 77 (7.3%) were lost to follow-up (rate = 0.03/person year). In the multivariate analysis, factors associated with attrition were CD4+ T-cell count category (hazard ratio (HR) = 2.03; 95%CI: 1.01, 4.24; P = 0.05 for CD4+ count < or = 50 cells/microL and HR = 1.96; 95%CI: 1.12, 3.40; P = 0.02 for CD4+ count 51-200 cells/microL) and detectable HIV viral load (HR = 1.29; 95%CI: 1.07, 1.53; P < 0.001 for HIV viral load >400 copies/mL). These data suggest that patients with compromised immunologic status are at an increased risk for being lost to follow-up.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Effects of PM10 in human peripheral blood monocytes and J774 macrophages.

The effects of PM10, one of the components of particulate air pollution, was investigated using human monocytes and a mouse macrophage cell line (J774). The study aimed to investigate the role of these nanoparticles on the release of the pro-inflammatory cytokine TNF-alpha and IL-1alpha gene expression. We also investigated the role of intracellular calcium signalling events and oxidative stress in control of these cytokines and the effect of the particles on the functioning of the cell cytoskeleton. We showed that there was an increase in intracellular calcium concentration in J774 cells on treatment with PM10 particles which could be significantly reduced with concomitant treatment with the calcium antagonists verapamil, the intracellular calcium chelator BAPTA-AM but not with the antioxidant nacystelyn or the calmodulin inhibitor W-7. In human monocytes, PM10 stimulated an increase in intracellular calcium which was reduced by verapamil, BAPTA-AM and nacystelyn. TNF-alpha release was increased with particle treatment in human monocytes and reduced by only verapamil and BAPTA-AM. IL-1alpha gene expression was increased with particle treatment and reduced by all of the inhibitors. There was increased F-actin staining in J774 cells after treatment with PM10 particles, which was significantly reduced to control levels with all the antagonists tested. The present study has shown that PM10 particles may exert their pro-inflammatory effects by modulating intracellular calcium signalling in macrophages leading to expression of pro-inflammatory cytokines. Impaired motility and phagocytic ability as shown by changes in the F-actin cytoskeleton is likely to play a key role in particle clearance from the lung.

Air Pollutants↗
PubMed2004

Effect of coal mine dust and clay extracts on the biological activity of the quartz surface.

Modification of the quartz surface by aluminium salts and metallic iron have been shown to reduce the biological activity of quartz. This study aimed to investigate the ability of water soluble extracts of coal mine dust (CMD), low aluminium clays (hectorite and montmorillonite) and high aluminium clays (attapulgite and kaolin) to inhibit the reactivity of the quartz surface. DQ12 induced significant haemolysis of sheep erythrocytes in vitro and inflammation in vivo as indicated by increases in the total cell numbers, neutrophil cell numbers, MIP-2 protein and albumin content of bronchoalveolar lavage (BAL) fluid. Treatment of DQ12 with CMD extract prevented both haemolysis and inflammation. Extracts of the high aluminium clays (kaolin and attapulgite) prevented inhibition of DQ12 induced haemolysis, and the kaolin extract inhibited quartz driven inflammation. DQ12 induced haemolysis by coal mine dust and kaolin extract could be prevented by pre-treatment of the extracts with a cation chellator. Extracts of the low aluminium clays (montmorillonite and hectorite) did not prevent DQ12 induced haemolysis, although the hectorite extract did prevent inflammation. These results suggest that CMD, and clays both low and rich in aluminium, all contain soluble components (possibly cations) capable of masking the reactivity of the quartz surface.

Administration, Inhalation↗
PubMed2004

Inhibition of neutrophil recruitment by ES of Nippostrongylus brasiliensis.

It has been reported that excretory-secretory (ES) material from the parasitic nematode Nippostrongylus brasiliensis has potential modulatory effects on the host's immune system. We observed that intratracheal instillation of ES from the L3 stage of the parasite reduced neutrophil numbers in LPS-induced inflammation as assessed by bronchoalveolar lavage.

Animals↗
PubMed2003

Calcium and ROS-mediated activation of transcription factors and TNF-alpha cytokine gene expression in macrophages exposed to ultrafine particles.

Ultrafine (Uf) particles are a component of particulate air pollution suggested to be responsible for the health effects associated with elevations of this pollutant. We have previously suggested that Uf particles, through the induction of oxidative stress, may induce inflammation in the lung, thus exacerbating preexisting illness in susceptible individuals. Alveolar macrophages are considered to play a key role in particlemediated inflammation and lung disease. The effect of Uf particles on rat alveolar macrophages and human blood monocytes was investigated with reference to the roles of calcium and reactive oxygen species (ROS). TNF-alpha protein release, intracellular calcium concentration, TNF-alpha mRNA expression, and transcription factor activation were studied as end points after treatment of rat alveolar macrophages or peripheral blood monocytes. The calcium channel blocker verapamil, the intracellular calcium chelator BAPTA-AM, the calmodulin inhibitor W-7, and the antioxidants Trolox and Nacystelin (NAL) were included in combination with Uf particles. Verapamil reduced intracellular calcium concentration in rat alveolar macrophages on stimulation with Uf particles. This effect was also apparent with transcription factor AP-1 activation. All antagonists and antioxidants reduced Uf-stimulated nuclear localization of the p50 and p65 subunits of NF-kappaB in human monocytes. Verapamil, BAPTA-AM, and NAL reduced Uf-stimulated TNF-alpha protein release, whereas only verapamil reduced Uf-stimulated mRNA expression in rat alveolar macrophages. In human monocytes, verapamil, Trolox, BAPTA-AM, and W-7 reduced Uf-stimulated TNF-alpha protein release. These findings suggest that Uf particles may exert proinflammatory effects by modulating intracellular calcium concentrations, activation of transcription factors, and cytokine production through a ROS-mediated mechanism.

Acetylcysteine↗
PubMed2001

Aluminium lactate treatment of DQ12 quartz inhibits its ability to cause inflammation, chemokine expression, and nuclear factor-kappaB activation.

In 1997, an IARC Working Group classified quartz (crystalline silica) as a Group 1 lung carcinogen, but only in some industries, i.e., the quartz hazard is a variable entity. The reactivity of the quartz surface may underlie its ability to cause inflammation, and treatments that ameliorate this reactivity will reduce the quartz hazard. In this study we treated quartz (Q) with aluminium lactate (AL), a procedure that is reported to decrease the quartz hazard, and explored the effect this had on the highly reactive quartz surface and on proinflammatory events in rat lungs. Aluminium lactate-treated quartz showed a reduced surface reactivity as measured by electron spin resonance and the hemolysis assay. Eighteen hours after instillation of Q into the rat lung, there was massive inflammation as indicated by the number of neutrophils in the bronchoalveolar lavage (BAL). In addition, Q induced an increase in BAL macrophage inflammatory protein-2 (MIP-2) while ALQ had no significant effect compared to control. Epithelial damage, as indicated by BAL protein and gamma glutamyl transpeptidase, also increased with Q but not with ALQ. Furthermore, Q induced an increase in MIP-2 mRNA by BAL cells while ALQ had no effect compared to controls. There was an increase in nuclear binding of the transcription nuclear factor kappaB (NF-kappaB) in the Q-exposed BAL cells and again no effect on nuclear NF-kappaB binding in BAL cells from ALQ-exposed rats. In conclusion, treatment of the quartz surface with aluminium lactate reduced the reactivity of the particles both in terms of hydroxyl radical generation and in terms of the induction of molecular signaling events leading to inflammation.

Aluminum Compounds↗
PubMed2001

Size-dependent proinflammatory effects of ultrafine polystyrene particles: a role for surface area and oxidative stress in the enhanced activity of ultrafines.

Studies into the effects of ultrafine particles in the lung have shown adverse effects considered to be due in part to the particle size. Air pollution particles (PM(10)) are associated with exacerbations of respiratory disease and deaths from cardiovascular causes in epidemiological studies and the ultrafine fraction of PM(10) has been hypothesized to play an important role. The aim of the present study was to investigate proinflammatory responses to various sizes of polystyrene particles as a simple model of particles of varying size including ultrafine. In the animal model, we demonstrated that there was a significantly greater neutrophil influx into the rat lung after instillation of 64-nm polystyrene particles compared with 202- and 535-nm particles and this was mirrored in other parameters of lung inflammation, such as increased protein and lactate dehydrogenase in bronchoalveolar lavage. When surface area instilled was plotted against inflammation, these two variables were directly proportional and the line passed through zero. This suggests that surface area drives inflammation in the short term and that ultrafine particles cause a greater inflammatory response because of the greater surface area they possess. In vitro, we measured the changes in intracellular calcium concentration in mono mac 6 cells in view of the potential role of calcium as a signaling molecule. Calcium changes after particle exposure may be important in leading to proinflammatory gene expression such as chemokines. We demonstrated that only ultrafine polystyrene particles induced a significant increase in cytosolic calcium ion concentration. Experiments using dichlorofluorescin diacetate demonstrated greater oxidant activity of the ultrafine particles, which may explain their activity in these assays. There were significant increases in IL-8 gene expression in A549 epithelial cells after treatment with the ultrafine particles but not particles of other sizes. These findings suggest that ultrafine particles composed of low-toxicity material such as polystyrene have proinflammatory activity as a consequence of their large surface area. This supports a role for such particles in the adverse health effects of PM(10).

Animals↗
PubMed2001

Dietary fat reduction behaviors in college students: relationship to dieting status, gender and key psychosocial variables.

The primary objectives were to assess dietary fat reduction/avoidance behaviors within a sample of college students, and to assess the strength of the relationship between self reported fat avoidance and a number of variables including body mass index (BMI), self-esteem, and responses to the Eating Disorder Inventory (EDI) and Eating Attitudes Test (EAT). A total of 210 female and 114 male undergraduate students were administered a food habits questionnaire (which assessed four dietary fat reduction behaviors), the EDI, the dieting subscale of the EAT, and the Coopersmith Self-Esteem Inventory. Measured heights and weights were used to compute BMI. Thirty-eight percent of the females and 13% of the males reported that they had dieted with the express purpose of losing weight in the past 12 months. The finding that females in general and female dieters in particular, scored higher on the EAT dieting subscale, and relied on three of the four dietary fat reduction behaviors to a greater extent than did males, supports the assertion that women rely heavily on dietary fat avoidance as a method to reduce caloric intakes. In females, the finding that a greater degree of fat avoidance was associated with significantly lower levels of self-esteem and higher scores on the EAT and on six of the eight EDI subscales suggested that fat avoidance may be a predictor of eating pathology and/or psychosocial problems in college-aged women.

Adolescent↗
PubMed2001

Tumours can act as adjuvants for humoral immunity.

Tumour cells transfected with cDNAs encoding non-self proteins were used to investigate the ability of the immune system to respond to immunogenic antigens expressed by tumours. Secreted, intracellular and surface proteins were used as model antigens, as these reflect the potential forms of tumour antigens. Syngeneic BALB/c mice injected with viable line 1 lung carcinoma or EMT6 mammary tumour cells secreting ovalbumin (OVA) or prostate-specific antigen (PSA) produced very high immunoglobulin G (IgG) antibody titres, equivalent to those of mice injected with protein in Freund's complete adjuvant (FCA). Secretion of the antigens was not necessary as tumour cells expressing a cell-surface antigen (HER-2/Neu) or an intracellular antigen - green fluorescence protein (GFP) - also generated high-titre antigen-specific IgG antibodies. In interleukin-4 (IL-4)-deficient mice, both IgG1 and IgG2a were produced in response to OVA administered in FCA, whereas in response to tumour-produced antigen, the antibodies switched from predominantly IgG1 to IgG2a, indicating that the mechanisms responsible for antibody induction differed between these forms of immunization. In contrast to the line 1 and EMT6 tumours, which are of BALB/c origin, OVA- or PSA-producing B16 melanoma cells, which are of C57BL/6 origin, failed to elicit antibody production. This was not the result of strain differences, as a similar finding was observed when the tumours were grown in (BALB/c x C57BL/6)F1 mice, but appeared to be caused by intrinsic differences in the tumours. Furthermore, co-injection of both B16/OVA and line 1 tumours resulted in production of anti-OVA antibody, indicating that B16 tumours were not immunosuppressive, but instead line 1 tumours appear to exert an adjuvant effect.

Adjuvants, Immunologic↗
PubMed2001

Management of neurocytomas: case report and review of the literature.

The purpose of this report is to review the available literature on the presentation, pathology, and treatment of central nervous system (CNS) neurocytomas. A case report of an extraventricular neurocytoma is presented along with a comprehensive literature search of patients with a diagnosis of CNS neurocytoma. CNS neurocytomas are rare neoplasms, with fewer than 240 cases reported in the literature. The majority of neurocytomas are found in the ventricular system of the brain. Immunohistochemistry is frequently used to help distinguish this tumor from other CNS neoplasms. MIB-1 proliferation index is commonly used in an attempt to predict biologic behavior. Little is known about the management of patients with this tumor, because most reports are from the pathologic literature and contain sparse information regarding clinical management. Neurocytomas are rare CNS tumors with varied biologic behavior. MIB-1 index may help direct adjuvant therapy. An excellent prognosis can be expected if a gross total resection is achieved. Postoperative radiation therapy (RT) may be considered after subtotal resection. Otherwise, RT is an option for medically inoperable or recurrent disease.

Aged↗
PubMed2001

Human papillomavirus virus-like particles are efficient oral immunogens when coadministered with Escherichia coli heat-labile enterotoxin mutant R192G or CpG DNA.

Certain human papillomaviruses (HPVs) cause most cervical cancer, which remains a significant source of morbidity and mortality among women worldwide. HPV recombinant virus-like particles (VLPs) are promising vaccine candidates for controlling anogenital HPV disease and are now being evaluated as a parenteral vaccine modality in human subjects. Vaccines formulated for injection generally are more costly, more difficult to administer, and less acceptable to recipients than are mucosally administered vaccines. Since oral delivery represents an attractive alternative to parenteral injection for large-scale human vaccination, the oral immunogenicity of HPV type 11 (HPV-11) VLPs in mice was previously investigated; it was found that a modest systemic neutralizing antibody response was induced (R. C. Rose, C. Lane, S. Wilson, J. A. Suzich, E. Rybicki, and A. L. Williamson, Vaccine 17:2129-2135, 1999). Here we examine whether VLPs of other genotypes may also be immunogenic when administered orally and whether mucosal adjuvants can be used to enhance VLP oral immunogenicity. We show that HPV-16 and HPV-18 VLPs are immunogenic when administered orally and that oral coadministration of these antigens with Escherichia coli heat-labile enterotoxin (LT) mutant R192G (LT R192G) or CpG DNA can significantly improve anti-VLP humoral responses in peripheral blood and in genital mucosal secretions. Our results also suggest that LT R192G may be superior to CpG DNA in this ability. These findings support the concept of oral immunization against anogenital HPV disease and suggest that clinical studies involving this approach may be warranted.

Adjuvants, Immunologic↗
PubMed2001

Requirements for assembly of poliovirus replication complexes and negative-strand RNA synthesis.

HeLa cells were transfected with several plasmids that encoded all poliovirus (PV) nonstructural proteins. Viral RNAs were transcribed by T7 RNA polymerase expressed from recombinant vaccinia virus. All plasmids produced similar amounts of viral proteins that were processed identically; however, RNAs were designed either to serve as templates for replication or to contain mutations predicted to prevent RNA replication. The mutations included substitution of the entire PV 5' noncoding region (NCR) with the encephalomyocarditis virus (EMCV) internal ribosomal entry site, thereby deleting the 5'-terminal cloverleaf-like structure, or insertion of three nucleotides in the 3Dpol coding sequence. Production of viral proteins was sufficient to induce the characteristic reorganization of intracellular membranes into heterogeneous-sized vesicles, independent of RNA replication. The vesicles were stably associated with viral RNA only when RNA replication could occur. Nonreplicating RNAs localized to distinct, nonoverlapping regions in the cell, excluded from the viral protein-membrane complexes. The absence of accumulation of positive-strand RNA from both mutated RNAs in transfected cells was documented. In addition, no minus-strand RNA was produced from the EMCV chimeric template RNA in vitro. These data show that the 5'-terminal sequences of PV RNA are essential for initiation of minus-strand RNA synthesis at its 3' end.

Cytoplasmic Vesicles↗
PubMed2000

Salvage radiotherapy for prostate cancer recurrence after cryosurgical ablation.

OBJECTIVES: To retrospectively determine the outcome of patients treated with salvage three-dimensional conformal radiotherapy (RT) for prostate cancer recurrence after cryosurgical ablation of the prostate (CSAP). Biochemical control rates and morbidity were analyzed. METHODS: Between January 1990 and November 1999, a total of 49 patients initially treated with CSAP were later irradiated because of a rising prostate-specific antigen (PSA) level and/or a positive biopsy at Allegheny General Hospital. The clinical stage before cryosurgery was T1c in 7 patients; T2a in 7 patients; T2b in 10 patients; T3 in 17 patients; and T4 and/or N1 in 8 patients. The Gleason score was 6 or lower in 29 patients, 7 in 11 patients, and 8 or higher in 9 patients. The mean pre-CSAP PSA level was 15.7 ng/mL (range 2.4 to 45). One patient had a PSA level less than 4 ng/mL, 16 had a PSA level of 4 to 10 ng/mL, 21 had a PSA level of 10 to 20 ng/mL, and 11 had a PSA level greater than 20 ng/mL. Before the start of RT, a complete restaging workup was performed and was negative for distant metastatic disease in all 49 patients. The mean interval to recurrence after CSAP was 19 months (range 3 to 78). The mean RT dose to the planning target volume was 62.9 Gy (range 50.4 to 68.4). RESULTS: The mean pre-RT PSA level was 2.4 ng/mL (range 0.1 to 7.4). After RT, the mean nadir PSA level was 0.4 ng/mL (range 0 to 4.2). The mean time to PSA nadir was 5.8 months (range 1 to 15). In 42 patients, the PSA nadir was less than 1.0 ng/mL, in 5 patients the PSA nadir was greater than 1 ng/mL, and in 2 patients the PSA level remained stable. With a median follow-up time of 32 months (range 12 to 85), the overall biochemical control rate was 61%. The mean time to biochemical failure was 14.5 months (range 1 to 47). Of 30 patients with a pre-RT PSA level of 2.5 ng/mL or less, the disease of 22 (73%) was controlled compared with only 8 (42%) of 19 with a pre-RT PSA level greater than 2.5 ng/mL (P = 0.040). Biochemical control occurred in 18 (69%) of 26 patients with a dose of 64 Gy or greater compared with only 12 (52%) of 23 patients with a dose of less than 64 Gy (P = 0.024). The disease of 20 (70%) of 29 patients with a Gleason score of 6 or lower was controlled versus 10 (50%) of 20 patients with a Gleason score of 7 or greater (P = 0.064). Only 2 patients developed subacute morbidity (proctitis and a urethral stricture). All complications resolved with conservative measures. CONCLUSIONS: Salvage RT for prostate cancer recurrence after CSAP appears feasible. Our preliminary experience revealed that post-CSAP RT in patients with prostate cancer appears to effectively diminish the post-RT PSA level to a nadir of 1.0 ng/mL or less in most patients. The pre-RT PSA level and radiation dose may be important predictors of biochemical control in the salvage setting. RT as described was associated with minimal toxicity to the gastrointestinal/genitourinary systems. Additional prospective randomized studies are necessary to better assess the role of RT in the treatment of these patients.

Aged↗