Biomedical subjects

David A Brown

Publications and source records attributed to David A Brown.

71 records · Page 4Linked to original sources

PubMed2003

Effects of a melanogenic bicyclic monoterpene diol on cell cycle, p53, TNF-alpha, and PGE2 are distinct from those of UVB.

PURPOSE: Bicyclic monoterpene (BMT) diols are small-molecule compounds that mimic ultraviolet radiation (UVR) by inducing melanogenesis. The objective of this study was to compare the effects of 2,2-dimethyl-3-propanyldiol-norbornane (AGI-1140), a novel BMT diol, and ultraviolet B (UVB) on additional cellular responses. METHODS: S91 mouse melanoma cells were treated with a range of concentrations of AGI-1140, and examined for induction of melanogenesis and nitric oxide (NO). The effect of AGI-1140 on dendrite outgrowth from human melanocytes was examined by quantitative microscopy. The effect of AGI-1140 and UVB on phosphorylation of p53 serine 15 in human keratinocytes was examined by Western blotting, while the release of tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E2 (PGE2) was determined by enzyme-linked immunosorbent assay. The effects of AGI-1140 and UVB on cell cycle arrest of human melanocytes, keratinocytes, fibroblasts, and endothelial cells were compared using fluorescence-activated cell sorting. RESULTS: Similar to UVB, AGI-1140 induced both melanogenesis and NO in melanoma cells. AGI-1140 also induced dendrite outgrowth from melanocytes, indicative of differentiation. However, whereas UVB induced G2 cell cycle arrest with phosphorylation of p53 at serine 15, AGI-1140 induced G1 cell cycle arrest without this phosphorylation. Additionally, unlike UVB, AGI-1140 did not increase the secretion of TNF-alpha or PGE2, mediators of UVB-induced immunosuppressive and inflammatory responses in the skin that may contribute to carcinogenesis. CONCLUSION: This study shows that melanogenesis can be induced by AGI-1140 without many of the deleterious effects associated with UVB.

Animals↗

PubMed2003

Macrophage inhibitory cytokine 1 in fetal membranes and amniotic fluid from pregnancies with and without preterm labour and premature rupture of membranes.

The placenta and fetal membranes are the site of expression of macrophage inhibitory cytokine (MIC-1), a member of the transforming growth factor (TGF)-beta superfamily. We hypothesized that MIC-1 may act as an immune regulator in pregnancy complications associated with intrauterine inflammation. Decidual cells, chorionic trophoblasts and amnion epithelial cells were identified by immunohistochemistry as the predominant MIC-1-containing cell type in term membranes. Amnion and choriodecidual explants all produced MIC-1 in culture, the latter having the greatest production rate (206 +/- 74.5 pg/mg tissue/24 h, n=6; mean +/- SEM). Production was not responsive to stimulation by pro-inflammatory cytokines. MIC-1 was detectable in 217 transabdominal amniotic fluid (AF) samples taken from 15 to 41 weeks gestation, concentrations ranging from 0.9-51.1 ng/ml. AF MIC-1 concentrations in pregnancies with premature rupture of membranes (PROM) or preterm labour, either with or without microbial invasion of the amniotic cavity, were not significantly different from those delivered at term either with or without labour. Treatment with MIC-1 (0.25-25 ng/ml) did not alter production of interleukin-6 or -8 by amnion or choriodecidual cells in vitro. We conclude that AF MIC-1 is derived from the fetal membranes and decidua, but that MIC-1 is unlikely to be involved in the pathophysiology of preterm birth or PROM.

Amniotic Fluid↗

PubMed2003

Mortality among hourly motor vehicle manufacturing workers.

We evaluated mortality among 198,245 motor vehicle industry workers during the period of 1973 to 1995. Workers' mortality rates were lower than expected overall (40,131 observed/43,859 expected deaths, standardized mortality ratio [SMR] = 92, CI = 91-92) and for all major cause of death categories except cancer (SMR = 100, CI = 98-102). Mortality rates were higher than expected for lung cancer overall (SMR = 110, CI = 107-113) and among employees in transmission/gear manufacturing (SMR = 121, CI = 112-130), casting operations (SMR = 122, CI = 110-135), engine manufacturing (SMR = 111, CI = 101-123), and vehicle assembly (SMR = 111, CI = 105-117); for stomach cancer in engine manufacturing (SMR = 147, CI = 110-192); and for prostate cancer in casting operations (SMR = 128, CI = 102-158). Excesses of lung cancer in transmission, vehicle assembly, and casting operations and of stomach cancer in engine manufacturing have been observed in other investigations. Further information on employees' occupational exposures and personal attributes is required to clarify the interpretation of these results.

Accidents, Occupational↗

PubMed2003

Leadership in healthcare: better understanding of the challenges is required.

The healthcare system is facing unique challenges that are distinct from the issues that face any other type of organization or corporation. Leadership in this milieu requires an equally distinct set of skills and knowledge. Leatt and Porter offer a theoretical analysis of leadership development, yet more needs to be done to probe into the challenge of providing leadership in the healthcare continuum.

Administrative Personnel↗

PubMed2003

MIC-1 serum level and genotype: associations with progress and prognosis of colorectal carcinoma.

PURPOSE: Macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the tumor growth factor beta (TGF-beta) superfamily. Several observations suggest that it plays a role in colorectal carcinoma (CRC). In particular, MIC-1 is markedly up-regulated in colorectal cancers as well as in premalignant adenomas. This study examines the relationship of serum MIC-1 levels and genotypes to clinical and pathologic features of colonic neoplasia. EXPERIMENTAL DESIGN: We confirmed the presence of MIC-1 in CRC tissue and the cell line CaCo-2. The normal range for serum MIC-1 levels was defined in 260 healthy blood donors, and the differences between normal subjects and 193 patients having adenomatous polyps or CRC were then determined. In a separate cohort of 224 patients, we evaluated the relationship of MIC-1 serum level and genotype to standard tumor parameters and outcome measures. RESULTS: MIC-1 was expressed in CRC tissue and the cancer cell line CaCo-2. There was a progressive increase in serum MIC-1 levels between normal individuals [mean (M) = 495 pg/ml, SD = 210), those with adenomatous polyps (M = 681 pg/ml, SD = 410), and those with CRC (M = 783 pg/ml, SD = 491)]. Serum MIC-1 level was correlated with the extent of disease so that the levels were higher in patients with higher Tumor-Node-Metastasis stage. There were significant differences in time to relapse and overall survival between subjects with different MIC-1 levels and genotypes. CONCLUSIONS: This study identifies a strong association between MIC-1 serum levels and neoplastic progression within the large bowel. We suggest that the measurement of serum MIC-1 levels and determination of MIC-1 genotype may have clinical use in the management of patients with CRC.

Adenoma↗

PubMed2003

A bicyclic monoterpene diol and UVB stimulate BRCA1 phosphorylation in human keratinocytes.

BRCA1 (breast cancer-associated gene 1) is a tumor suppressor gene that plays a role in DNA repair when phosphorylated. Many DNA-damaging agents including UVC and hydrogen peroxide have been shown to induce phosphorylation of BRCA1. Results of this study now show that both UVB and a bicyclic monoterpene diol (BMT diol) result in phosphorylation of BRCA1. This phosphorylation was maximal 2 h after treatment with either agent and declined to basal levels by 24 h. Inhibitor studies revealed that both UVB and the BMT diol phosphorylate BRCA1 through the FK506-binding protein-FKBP rapamycin-associated binding protein pathway, but the BMT diol also led to phosphorylation of BRCA1 through casein kinase II. This suggests that the signaling pathways for UVB and the BMT diol may diverge. Results of this study also show that the BMT diol stimulates the repair of UVB-induced cyclobutane pyrimidine dimers (CPD). Inhibitors of BMT diol-induced BRCA1 phosphorylation blocked the BMT diol-stimulated repair of CPD. This indicates that the BMT diol induces the phosphorylation of BRCA1, which, in turn, leads to an increase in repair of UVB-induced CPD. Therefore, this BMT diol may be useful for ameliorating the damaging effects of UVB.

BRCA1 Protein↗

PubMed2003

Integrated vector management guidelines for adult mosquitoes.

A written document was developed to clarify the District's adult mosquito-management tactics to other interested individuals and agencies. The program described consists of 7 discrete components: 1) initiation criteria, 2) treatment area delineation, 3) agricultural and land-use practices, 4) meteorological conditions, 5) continuance criteria, 6) termination criteria, and 7) factors influencing implementation. The guidelines were adopted as policy by the District's Board of Trustees in 1998 and have been implemented in each of the last 5 years. The adult mosquito population is monitored with 6 Mosquito Magnets traps strategically located in the rice culture areas. Samples are collected daily and laboratory technicians notify the Adulticide/Airplane Coordinator of collection results before 1:00 p.m.

Agriculture↗

PubMed2003

The western black-legged tick, Ixodes pacificus, in the Sutter Buttes.

The western black-legged tick, Ixodes pacificus, was collected from Huff Canyon in the Sutter Buttes in north central California, Sutter County. The Sutter Buttes are within the Sacramento Valley and outside the normal distribution of I. pacificus in California. Adult I. pacificus were collected via flagging as they quested along deer trails; subadult life stages were collected from three species of lizard, Elgaria multicarinata, Sceloporus occidentalis, and S. graciosus. Adult ticks were tested for the presence of spirochetes using the standard IFA with a monoclonal antibody specific for OSPA. Of the ticks tested, 3.3% were identified as positive for the presence of the spirochete Borrelia burgdorferi. These results present the first published account of Ixodes pacificus as well as the first detection of B. burgdorferi in the Sutter Buttes, Sutter County, California.

Animals↗

PubMed2002

Junctional signaling microdomains: bridging the gap between the neuronal cell surface and Ca2+ stores.

Growing evidence suggests that plasma membranes are locally differentiated into microdomains that are important interaction sites for organization of signaling molecules. These signaling microdomains create local conditions that enhance molecular interactions, excluding others, thereby ensuring speed, spatial localization, and specificity of signal transduction. With the special emphasis on InsP(3) and Ca(2+) signaling pathways, we will discuss here the evolving concept of signaling microdomains that provide a key framework for understanding the differential regulation of many cellular target proteins.

Calcium↗

PubMed2002

Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study.

BACKGROUND: Macrophage inhibitory cytokine-1 (MIC-1) is part of the TGF-beta superfamily. Raised concentrations of MIC-1 in serum arise in several disease states, can be detected in normal individuals, and can partly be genetically determined. We aimed to investigate whether MIC-1 has a role in atherothrombosis. METHODS: We did a prospective, nested, case-control study in 27628 initially healthy women. Of these women, we established baseline concentrations of MIC-1 in 257 who subsequently had myocardial infarction, stroke, or died from a cardiovascular event (cases) and in 257 matched for age and smoking status, who did not report cardiovascular disease during 4-year follow-up (controls). We also assessed polymorphisms in the MIC-1 gene (MIC-1 H and MIC-1 D) in all 514 women. FINDINGS: MIC-1 concentrations were higher at baseline in women who subsequently had cardiovascular events than in those who did not (618 vs 538 pg/mL, p=0.0002). Concentrations above the 90th percentile (>856 pg/mL) were associated with a 2.7-fold increase in risk (95% CI 1.6-4.9, p=0.001). This effect was independent of traditional cardiovascular risk factors and at least additive to that of C-reactive protein. There was no significant association between MIC-1 polymorphism and vascular events. INTERPRETATION: MIC-1 could be a novel target for cardiovascular disease prevention.

Cardiovascular Diseases↗

PubMed2002

Characterization and channel coupling of the P2Y(12) nucleotide receptor of brain capillary endothelial cells.

Rat brain capillary endothelial (B10) cells express an unidentified nucleotide receptor linked to adenylyl cyclase inhibition. We show that this receptor in B10 cells is identical in sequence to the P2Y(12) ADP receptor ("P2Y(T)") of platelets. When expressed heterologously, 2-methylthio-ADP (2-MeSADP; EC(50), 2 nm), ADP, and adenosine 5'-O-(2-thio)diphosphate were agonists of cAMP decrease, and 2-propylthio-D-beta,gamma-difluoromethylene-ATP was a competitive antagonist (K(B), 28 nm), as in platelets. However, 2-methylthio-ATP (2-MeSATP) (EC(50), 0.4 nm), ATP (1.9 microm), and 2-chloro-ATP (190 nm), antagonists in the platelet, were also agonists. 2-MeSADP activated (EC(50), 0.1 nm) GIRK1/GIRK2 inward rectifier K(+) channels when co-expressed with P2Y(12) receptors in sympathetic neurons. Surprisingly, P2Y(1) receptors expressed likewise gave that response; however, a full inactivation followed, absent with P2Y(12) receptors. A new P2Y(12)-mediated transduction was found, the closing of native N-type Ca(2+) channels; again both 2-MeSATP and 2-MeSADP are agonists (EC(50), 0.04 and 0.1 nm, respectively). That action, like their cAMP response, was pertussis toxin-sensitive. The Ca(2+) channel inhibition and K(+) channel activation are mediated by beta gamma subunit release from a heterotrimeric G-protein. G alpha subunit types in B10 cells were also identified. The presence in the brain capillary endothelial cell of the P2Y(12) receptor is a significant extension of its functional range.

Adenylate Cyclase Toxin↗

PubMed2002

A novel dizinc bridged hydroxamate model for hydroxamate inhibited zinc hydrolases.

Reaction of Zn(OAc)(2).2H2O with tmen leads to the formation of [Zn(tmen)(OAc)2] (I) which reacts with benzohydroxamic acid to form Zn(BA)2.H2O (II) and the novel dizinc hydroxamate bridged complex [Zn2(mu-OAc)2(OAc)(mu-BA)(tmen)] (III), which may also be prepared by self-assembly and whose structure closely mimics that of the native hydroxamate inhibited Aeromonas proteolytica aminopeptidase.

Aeromonas↗

PubMed2002

Signaling microdomains define the specificity of receptor-mediated InsP(3) pathways in neurons.

M(1) muscarinic (M(1)AChRs) and B(2) bradykinin (B(2)Rs) receptors are two PLCbeta-coupled receptors that mobilize Ca(2+) in nonexcitable cells. In many neurons, however, B(2)Rs but not M(1)AChRs mobilize intracellular Ca(2+). We have studied the membrane organization and dynamics underlying this coupling specificity by using Trp channels as biosensors for real-time detection of PLCbeta products. We found that, in sympathetic neurons, although both receptors rapidly produced DAG and InsP(3) as messengers, only InsP(3) formed by B(2)Rs has the ability to activate IP(3)Rs. This exclusive coupling results from spatially restricted complexes linking B(2)Rs to IP(3)Rs, a missing partnership for M(1)AChRs. These complexes allow fast and localized rises of InsP(3), necessary to activate the low-affinity neuronal IP(3)R. Thus, these signaling microdomains are of critical importance for the induction of selective responses, discriminating proinflammatory information associated with B(2)Rs from cholinergic neurotransmission.

Actins↗

PubMed2002

Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2.

Polycystin-1 (PC1), a 4,303-amino acid integral membrane protein of unknown function, interacts with polycystin-2 (PC2), a 968-amino acid alpha-type channel subunit. Mutations in their respective genes cause autosomal dominant polycystic kidney disease. Using a novel heterologous expression system and Ca(2+) and K(+) channels as functional biosensors, we found that full-length PC1 functioned as a constitutive activator of G(i/o)-type but not G(q)-type G-proteins and modulated the activity of Ca(2+) and K(+) channels via the release of Gbetagamma subunits. PC1 lacking the N-terminal 1811 residues replicated the effects of full-length PC1. These effects were independent of regulators of G-protein signaling proteins and were lost in PC1 mutants lacking a putative G-protein binding site. Co-expression with full-length PC2, but not a C-terminal truncation mutant, abrogated the effects of PC1. Our data provide the first experimental evidence that full-length PC1 acts as an untraditional G-protein-coupled receptor, activity of which is physically regulated by PC2. Thus, our study strongly suggests that mutations in PC1 or PC2 that distort the polycystin complex would initiate abnormal G-protein signaling in autosomal dominant polycystic kidney disease.

GTP-Binding Proteins↗

PubMed2002

Liposome-encapsulated ursolic acid increases ceramides and collagen in human skin cells.

Skin wrinkling and xerosis associated with aging result from decreases in dermal collagen and stratum corneum ceramide content. This study demonstrated that ursolic acid incorporated into liposomes (URA liposomes) increases both the ceramide content of cultured normal human epidermal keratinocytes (NHEK), and the collagen content of cultured normal human dermal fibroblasts. In addition, URA liposomes increased the ceramide content of the skin of human subjects, with increases in hydroxy ceramides occurring after only 3 days of treatment. Both URA liposomes and retinoic acid decreased markers of keratinocyte differentiation (keratin 1, keratin 10 and involucrin) in cultured NHEK. Thus, URA liposomes have effects on keratinocyte differentiation and dermal fibroblast collagen synthesis similar to those of retinoids. However, this study showed that URA liposomes increase ceramides in NHEK, in contrast to the decreases previously shown to be caused by retinoids. URA liposomes have the potential to be used alone or in combination with other agents to restore or maintain skin ceramide and collagen content.

Biomarkers↗

PubMed2002

Short- and long-term results of open heart surgery in patients with abdominal solid organ transplant.

OBJECTIVES: Cardiac disease is a common cause of mortality and morbidity in patients with abdominal solid organ transplant. Improvement of the results of abdominal organ transplantation has contributed to an increasing pool of patients who require open heart surgery. We investigated short- and long-term results of open heart surgery in patients with functioning abdominal solid organ transplants. METHODS: We retrospectively examined 60 patients (52.5 years in average) undergoing coronary artery bypass grafting and/or valve surgery since July 1988 after abdominal organ transplantation. There were 22 females (37%). They consisted of 46 kidney, nine kidney-pancreas and five liver recipients. Cardiac surgery was performed 68.9 months after transplantation. Preoperative serum creatinine level was 2.1 mg/dl, and 11 patients (18%) had creatinine level more than 3.0 mg/dl. Eleven patients (18%) were operated upon on non-elective basis. Twelve patients (20%) were not given stress-dose steroids postoperatively. RESULTS: Three patients died early after surgery (5.0%). Twenty-six major complications were seen in 17 patients (28%), including deterioration of renal function in seven (three patients required temporary hemodialysis), three major infections, two bleeding complications, and two strokes. No graft loss was encountered. No differences were seen in mortality and morbidity between patients with or without stress-dose steroids. Multivariate analysis identified cardiopulmonary bypass time (P<0.05) as a risk factor for operative death, preoperative creatinine level (P<0.05), cardiopulmonary bypass time (P<0.05) and the amount of fresh frozen plasma used (P<0.05) for major complication, non-elective surgery (P<0.01) for deterioration of renal function. Thirteen patients died and five kidney allografts failed late after surgery. Three- and 5-year patient and graft survivals were 70.8 and 66.8, 84.5 and 84.5%, respectively. Multivariate regression analysis identified female gender (P<0.05), body mass index (P<0.001) and non-elective surgery (P<0.001) as risk factors for late death, and preoperative creatinine level (P<0.05) for late graft loss. CONCLUSIONS: Open heart surgery can be performed with acceptable short- and long-term results in patients with functioning abdominal transplants. Stress-dose steroid may be unnecessary in selected patients. Aggressive use of open heart surgery in this patient population to avoid non-elective surgery may further improve early and late surgical outcomes.

Adult↗

PubMed2002

Measurement of UVB-Induced DNA damage and its consequences in models of immunosuppression.

Exposure to UVB results in formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts in DNA. These can be quantified by a variety of techniques including alkaline gel electrophoresis, ELISAs, Southwestern blotting, and immunohistochemistry. Damage to DNA results in activation of damage response pathways, as indicated by Western blotting using antibodies specific for p53 and breast cancer-associated gene 1 (BRCA1) phosphorylation. The signal from DNA damage to activation of these response pathways appears to be mediated by FKBP12-rapamycin-associated protein (FRAP), since these phosphorylation events are blocked by rapamycin. UVB-induced DNA damage also leads to induction of immunosuppressive cytokines including tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-10 in skin. Induction of TNF-alpha by UVB is readily detectable in cultured normal human epidermal keratinocytes (NHEKs) using ELISA, while induction of IL-10 is readily detectable in cultured mouse keratinocytes but not in NHEKs. Induction of DNA damage by liposome-encapsulated HindIII results in induction of immunosuppressive responses similar to UVB. Clinical testing shows that liposome-encapsulated T4 endonuclease V or photolyase stimulates repair of CPDs in the skin of human subjects, and prevents UVB-induced immunosuppression. Stimulation of repair and prevention of immunosuppression have been linked to prevention of skin cancer by liposome-encapsulated T4 endonuclease V in repair-deficient xeroderma pigmentosum patients.

Animals↗